Patent application title: DIAGNOSIS OF HEREDITARY SPASTIC PARAPLEGIAS (HSP) BY INDENTIFICATION OF A MUTATION IN THE KIAA1840 GENE OR PROTEIN
Inventors:
Hamid Azzedine (Bagneux, FR)
Alexis Brice (Paris, FR)
Alexis Brice (Paris, FR)
Giovanni Stevanin (Sevran, FR)
Filippo Santorelli (Naple, IT)
Paola Denora (Rome, IT)
IPC8 Class: AC12Q168FI
USPC Class:
435 61
Class name: Chemistry: molecular biology and microbiology measuring or testing process involving enzymes or micro-organisms; composition or test strip therefore; processes of forming such composition or test strip involving nucleic acid
Publication date: 2011-06-02
Patent application number: 20110129819
Abstract:
The invention relates to an ex vivo method of diagnosing or predicting an
hereditary spastic paraplegias (HSP), in a subject, which method
comprises detecting a mutation in the KIAA1840 gene or protein
(spatacsin), wherein said mutation is indicative of. an hereditary
spastic paraplegias (HSP).Claims:
1. An ex vivo method of diagnosing or predicting an hereditary spastic
paraplegias (HSP), in a subject, which method comprises detecting a
mutation in the KIAA1840 gene or protein (spatacsin), as compared to a
control population, wherein said mutation is indicative of a hereditary
spastic paraplegia (HSP).
2. The method according to claim 1, which comprises the step consisting of detecting a KIAA1840 mutation in a nucleic acid sample obtained from the subject, as compared to a control population, wherein the presence of a mutation is indicative of a hereditary spastic paraplegia (HSP).
3. The method according to claim 1, wherein said KIAA1840 mutation is selected from the group consisting of: the substitutions: c.6100C>T, c.2198T>G, c.118OT1 c.1235C>G, c.2833A>G, C.1951OT, c.869+1G>A, c. 1679 OG, c.2316+1G>A, c.2444G>T, C.2444+1OC, c.2697G>A, C.5470OT, C.5870OG, C.6091OT, c.6477+4 A>G, C.6856OT, c.1282A>T, C.5974OT, the deletions: c.529-533delATATT, c.6451delG, c.6832.sub.--6833delAG, c.1203delA, c.1549.sub.--1550delCT, c.6737.sub.--6740delTTGA, c.1471.sub.--1472delCT, c.1692delA, c.2716delC, c.1668delT, c.704.sub.--705delAT, c.5989.sub.--5992delCTGT, c.5532.sub.--5533delCA, c.5769delT, c.6739.sub.--6742delGAGT, c.4307.sub.--4308delAA c.733.sub.--734delAT, and the insertions: c.7029.sub.--7030insT, c.2850.sub.--2851insT, c.3741.sub.--3742insA, c.5982.sub.--5983insCTCT, c.5986.sub.--5987insT, c.3075.sub.--3076insA c.2842.sub.--2843insG.
4. The method according to claim 1, which comprises the step consisting of detecting a mutation in the KIAA1840 protein or detecting a truncated form of the KIAA1840 protein contained in a sample obtained from the subject, as compared to a control population, wherein the presence of a mutation in the KIAA1840 protein or a truncated form of the KIAA1840 protein is indicative of a hereditary spastic paraplegia (HSP).
5. The method according to claim 4, wherein a monoclonal or polyclonal antibody recognizing the wild-type KIAA1840 protein is used to detect the presence of the wild-type protein or one of its truncated forms.
6. The method according to claim 4, wherein the truncated KIAA1840 protein is selected from the group consisting of SEQ ID NO:149 to SEQ ID NO:164 and SEQ ID NO:166 to SEQ ID NO:188.
7. An isolated nucleic acid specifically hybridizable to a region of KIAA1840 gene sequence that contains a mutation selected from the group consisting of the substitutions: c.6100C>T, c.2198T>G, c.118C>T, c.1235C>G, c.2833A>G, c.1951C>T, c.869+1G>A, c. 1679 OG, c.2316+1G>A, c.2444G>T, c.2444+1G>C, c.2697G>A, C.5470OT, C.5870OG, C.6091OT, c.6477+4 A>G, C.6856OT, c.1282A>T C.5974OT, the deletions: c.529-533delATATT, c.6451delG, c.6832.sub.--6833delAG, c.1203delA, c.1549.sub.--1550delCT, c.6737.sub.--6740delTTGA, c.1471.sub.--1472delCT, c.1692delA, c.2716delC, c.1668delT, c.704.sub.--705delAT, c.5989.sub.--5992delCTGT, c.5532.sub.--5533delCA, c.5769delT, c.6739.sub.--6742delGAGT, c.4307.sub.--4308delAA c.733.sub.1.sub.--734delAT, and the insertions: c.7029.sub.--7030insT, c.2850.sub.--2851insT, c.3741.sub.--3742insA, c.5982.sub.--5983insCTCT, c.5986.sub.--5987insT, c.3075.sub.--3076insA c.2842.sub.--2843insG.
8. An isolated nucleic acid specifically hybridizable to a region consisting of 10 nucleotides upstream and 10 nucleotides downstream of a mutation selected from the group consisting of the substitutions: c.6100C>T, c.2198T>G, C.118OT, C.1235OG, c.2833A>G, c.1951C>T, c.869+1G>A, c. 1679 OG, c.2316+1G>A, c.2444G>T, c.2444+1G>C, c.2697G>A, C.5470OT, C.5870OG, c.6091C>T, c.6477+4 A>G, C.6856OT, c.1282A>T C.5974OT, the deletions: c.529-533delATATT, c.6451delG, c.6832.sub.--6833delAG, c.1203delA, c.1549.sub.--1550delCT, c.6737.sub.--6740delTTGA, c.1471.sub.--1472delCT, c.1692delA, c.2716delC, c.1668delT, c.704.sub.--705delAT, c.5989.sub.--5992delCTGT, c.5532.sub.--5533delCA, c.5769delT, c.6739.sub.--6742delGAGT, c.4307.sub.--4308delAA c.733.sub.--734delAT, and the insertions: c.7029.sub.--7030insT, c.2850.sub.--2851insT, c.3741.sub.--3742insA, c.5982.sub.--5983insCTCT, c.5986.sub.--5987insT, c.3075.sub.--3076insA c.2842.sub.--2843insG, of the KIAA1840 gene sequence.
9. An isolated nucleic acid complementary to a region of KIAA1840 gene sequence that contains a mutation selected from the group consisting of: the substitutions: c.6100C>T, c.2198T>G, c.118C>T, c.1235C>G, c.2833A>G, C.1951OT, c.869+1G>A, c. 1679 OG, c.2316+1G>A, c.2444G>T, c.2444+1G>C, c.2697G>A, C.5470OT, c.5870C>G, C.6091OT, c.6477+4 A>G, C.6856OT, c.1282A>T C.5974OT, the deletions: c.529-533delATATT, c.6451delG, c.6832.sub.--6833delAG, c.1203delA, c.1549.sub.--1550delCT, c.6737.sub.--6740delTTGA, c.1471.sub.--1472delCT, c.1692delA, c.2716delC, c.1668delT, c.704.sub.--705delAT, c.5989.sub.--5992delCTGT, c.5532.sub.--5533delCA, c.5769delT, c.6739.sub.--6742delGAGT, c.4307.sub.--4308delAA c.733.sub.--734delAT, and the insertions: c.7029.sub.--7030insT, c.2850.sub.--2851insT, c.3741.sub.--3742insA, c.5982.sub.--5983insCTCT, c.5986.sub.--5987insT, c.3075.sub.--3076insA c.2842.sub.--2843insG.
10. Isolated nucleic acid according to claim 9, consisting of at least 20 nucleotides.
11. The use of an isolated nucleic acid according to any of claims 7 to 10 as a primer or probe.
12. An isolated nucleic acid, which comprises or consists in a KIAA1840 gene sequence that contains one or several mutation(s) selected from the group consisting of the substitutions: c.6100C>T, c.2198T>G, c.118OT1 c.1235C>G, c.2833A>G, c.1951C>T, c.869+1G>A, c. 1679 OG, c.2316+1 G>A, c.2444G>T, c.2444+1G>C, c.2697G>A, C.5470OT, c.5870C>G, C.6091 OT, c.6477+4 A>G, C.6856OT, c.1282A>T C.5974OT, the deletions: c.529-533delATATT, c.6451delG, c.6832.sub.--6833delAG, c.1203delA, c.1549.sub.--1550delCT, c.6737.sub.--6740delTTGA, c.1471.sub.--1472delCT, c.1692delA, c.2716delC, c.1668delT, c.704.sub.--705delAT, c.5989.sub.--5992delCTGT, c.5532.sub.--5533delCA, c.5769delT, c.6739.sub.--6742delGAGT, c.4307.sub.--4308delAA c.733.sub.--734delAT, and the insertions: c.7029.sub.--7030insT, c.2850.sub.--2851insT, c.3741.sub.--3742insA, c.5982.sub.--5983insCTCT, c.5986.sub.--5987insT, c.3075.sub.--3076insA c.2842.sub.--2843insG or a sequence complementary thereto.
13. An isolated polypeptide which comprises the amino acid sequence of KIAA1840 containing one or several mutation(s) selected from the group consisting of p.Q40X, p.H77_F178delfsX178, p.H235RfsX246, p.M245VfsX246, p.K401 KfsX415, p.S412X, p.K428X, p.L491 DfsX556, p.L517LfsX556, p.F556LfsX577, p.S560X, p.V564VfsX577, p.R651X, p.L733X, p.R815M, P.W899X, p.Q906SfsX920, p.R945G, p.R945GfsX950, p.L950FfsX953, p.V948GfsX953, p.E1026RfsX1029, p.P1248TfsX1264, p.Q1436RfsX1442, P.R1824X, p.S1844SfsX1857, p.S1923RfsX1950, p.S1957X, p.R1992X, p.L1995LfsX2000, p.C1996LfsX1999, p.L1997.sub.--1998delfsX2056, p.R2031X, p.R2034X, p.A2151 PfsX2172, p.12246_E2247delfsX2260, p.E2247_S2248delfsX2260, p.S2278LfsX2338, p.R2286X and p.V2344CfsX2349.
14. An isolated monoclonal or polyclonal antibody that specifically recognizes a KIAA1840 protein containing a mutation selected from the group consisting of p.Q40X, p.H77_F178delfsX178, p.H235RfsX246, p.M245VfsX246, p.K401 KfsX415, p.S412X, p.K428X, p.L491 DfsX556, p.L517LfsX556, p.F556LfsX577, p.S560X, p.V564VfsX577, p.R651X, p.L733X, p.R815M, P.W899X, p.Q906SfsX920, p.R945G, p.R945GfsX950, p.L950FfsX953, p.V948GfsX953, p.E1026RfsX1029, p.P1248TfsX1264, p.Q1436RfsX1442, P.R1824X, p.S1844SfsX1857, p.S1923RfsX1950, p.S1957X, p.R1992X, p.L1995LfsX2000, p.C1996LfsX1999, p.L1997.sub.--1998delfsX2056, p.R2031X, p.R2034X, p.A2151PfsX2172, p.12246_E2247delfsX2260, p.E2247_S2248delfsX2260, p.S2278LfsX2338, p.R2286X and p.V2344CfsX2349.
Description:
[0001] The invention relates to the identification of mutations in the
KIAA1840 gene or protein, associated with a hereditary spastic
paraplegias (HSP), and to diagnostic applications that benefit from this
identification.
[0002] Hereditary spastic paraplegias (HSP) are genetically heterogeneous Mendelian disorders characterized by weakness, spasticity and loss of vibratory sense in the lower limbs (Harding et al. 1983 and Tallaksen et al. 2001). They reveal themselves clinically through difficulties in walking possibly evolving into total paralysis of both legs. The physiopathology of this set of diseases is, to date, relatively undocumented; however, anatomopathological data make it possible to conclude that the attack is limited to the pyramidal tracts responsible for voluntary motricity in the spinal cord (Reid, 1997). The incidence of HSPs, which remains difficult to estimate because of rare epidemiological studies and the considerable clinical variability, varies from 0.9:100000 in Denmark, 3 to 9.6:100000 in certain regions of Spain (Polo et al., 1991) or 14:100000 in Norway (Skre, 1974) (approximately 3:100000 in France). Various clinical and genetic forms of HSP exist. The so-called "pure" HSPs, which correspond to isolated spasticity of the lower limbs, are clinically distinguished from the "complex" HSPs, for which the spasticity of the legs is associated with other clinical signs of neurological or non-neurological type (Bruyn et al., 1991).
[0003] Although forms of HSP have been recognized for over a century, new phenotypes are regularly described, demonstrating wide clinical heterogeneity. Genetically, autosomal dominant (AD), autosomal recessive (AR) and X-linked inheritance are observed and almost 32 genetic loci have been identified, but only 12 genes have been cloned (Flink et al. 2006). According to the putative roles of these genes, mitochondrial function, protein folding and axonal transport have been implicated in the dying back of pyramidal tract axons in these disorders.
[0004] The most common forms of AD-HSP, accounting for about 40-50% of cases, are caused by mutations in the SPG4 and SPG3A genes that encode for spastin and atlastin, respectively (Hazan et al. 1990, Zhao et al. 2001 and international patent application WO 01/18198). In contrast to AD forms, no major gene accounts for AR-HSP, which is less common and more varied in clinical presentation, implying greater genetic heterogeneity. The four AR-HSP genes cloned so far, encoding for paraplegin (SPG7, MIM#607259 (OMIM database, www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM)), (Casari et al. 1998) spartin (SPG20; MIM#275900), (Patel et al. 2002) and maspardin (SPG21, MIM 248900) (Simpson et al. 2003) as well as the gene responsible for the related spastic ataxia of Charlevoix Saguenay (ARSACS, MIM#270550) (Engert et al. 2000) probably represent less than 5% of all cases (Fink et al. 2003).
[0005] A very common form of AR-HSP associates spastic paraplegia, mental or cognitive deficit and thin corpus callosum (Winner et al. 2005). The majority of the families appear to be linked to SPG11 on chromosome 15, which was the third AR-HSP locus to be identified (Martinez et al. 1999). This entity is particularly prevalent in Japan (Shibasaki et al. 2000), but is also found in North-America, the Middle-East and Europe (Martinez et al 1999 and Lossos et al. 2006 and Casali et al. 2004 and Winner et al. 2004 and Stevanin et al. 2006). The typical clinical features of SPG11 consist of early-onset spastic paraplegia (usually <20 years), urinary bladder dysfunction, deep sensory deficits in the legs and cognitive impairment that progress insidiously to severe functional disability over a period of 10-20 years. Some patients also develop arm involvement, dysarthria, contractures and muscle atrophy. Auxiliary studies frequently identify a thin corpus callosum (TCC) with white matter lesions and variable cerebral cortical atrophy on magnetic resonance imaging (MRI), variable cortical and thalamic glucose hypometabolism on positron emission tomography and predominantly axonal motor or sensorimotor peripheral neuropathy on nerve conduction studies (Winner et al. 2004).
[0006] Linkage to chromosome 15q has been reported so far in 31 families in which the patients presented with the typical SPG11 phenotype. In the initial study, a maximum multipoint combined LOD score of 3.14 was detected in seven AR-HSP families in a region between D15S1007 and D15S1012, although patients from only 2 kindreds of North-American and Italian ancestries presented with a TCC (Martinez et al. 1999). A second study reported a group of 10 out of 13 Japanese families with a homogeneous phenotype of AR-HSP-TCC with a cumulative LOD score of 9.68 in the D15S971 to D15S117 interval (Shibasaki et al. 2000). Casali et al. also reported 5 Italian kindreds that showed significant linkage (Z=3.35) to the interval flanked by markers D15S1007 and D15S978 (Casali et al. 2004). More recently, the analysis of 8 additional kindreds (Z=11.5) including 3 large consanguineous families, allowed the locus to be restricted by the inventors to the 6 cM interval between markers D15S1044 and D15S143 (Lossos et al. 2006 and Stevanin et al. 2006) a region that did not overlap with the interval defined in the originally mapped families (Martinez et al. 1999), therefore showing genetic heterogeneity among families linked to 15q and more closely resembling the locus for amyotrophic lateral sclerosis ALS5 (Hentati et al, 1998). It is of note that in the work published by Martinez et al (1999), only 2 of 8 pedigrees presented with the typical SPG11 phenotype with TCC and patients from these 2 families were linked to a larger region on chromosome 15 overlapping the region described in recent reports (Lossos et al. 2006 and Stevanin et al. 2006). More recently, the SPG11 locus was further refined to the 4.6 cM region (according to the Marschfield genetic map, http://research.marshfieldclinic.org/genetics/GeneticResearch/compMaps.as- p) between markers D15S968-D15S132 (Olmez et al, 2006) confirming the results of the inventors (FIG. 2).
[0007] The inventors have now identified the gene responsible for the most frequent form of Autosomal Recessive Hereditary Spastic Paraplegia (AR-HSP). They have indeed demonstrated that the disease is caused by mutations in the KIAA1840 gene (also known as FLJ21439), affecting the spatacsin protein expression (Stevanin et al., 2007). This is supported by four pieces of evidence. First, the inventors have excluded 17 out of about 40 genes assigned to the SPG11 candidate interval after significant reduction of its size to the 3.2 cM interval (according to the Marschfield genetic map) between markers D15S778 and D15S659 (FIGS. 1 to 4). The analysis of 2 of these genes has been reported previously (Stevanin et al, 2006). Secondly, the inventors have identified 43 different mutations segregating in 47 families (FIGS. 5 to 9), 16 of which linked previously to the SPG11 locus with a highly significant 28.1 maximal combined lod score (FIGS. 1 and 2), 8 of them already published as linked (Casali et al, 2004; Lossos et al, 2006 and Stevanin et al, 2006). Thirdly, the inventors have identified mutations, absent in at least 140 control chromosomes, that were all, leading to abnormal splicing of the messenger RNA and/or leading to a truncated protein. Finally, the inventors have demonstrated that all mutated families, except 2 in which magnetic resonance imaging could not be performed (TUN2 and TUN14), presented with the typical AR-HSP-TCC phenotype. In addition, several of these families shared the same mutation with similar surrounding haplotypes when they came from the same geographical origins, suggesting regional founder effects (FIGS. 6 and 7). Mutations in KIAA1840 affected 47 of 91 AR-HSP-TCC families in the study carried out by the inventors making this genetic entity very frequent among AR-HSP-TCC (75% was estimated in a previous study, Stevanin et al, 2006). The invention therefore provides the identification of the major gene responsible of AR-HSP-TCC and probably of AR-HSPs in general and opens thereby new opportunities to improve diagnosis and genetic counseling of said disease. Moreover, the invention also provides a mean to improve the medical care management of patient affected with said disease. In addition, since most patients with spastic paraplegia have isolated forms, it is conceivable that this new gene could account for a small proportion of these patients as well. Indeed, in Europe, due to the small size of the families, recessively inherited diseases are often found in apparently isolated cases.
[0008] A first aspect of the invention thus relates to the identification of mutations in the KIAA1840 gene or protein, associated with a hereditary spastic paraplegias (HSP), and to diagnostic application that benefits from this identification.
[0009] A second aspect of the invention relates to an isolated nucleic acid, specifically hybridizable to a region of KIAA1840 gene sequence that contains a mutation selected from the group consisting of
[0010] the substitutions: c.6100C>T, c.2198T>G, c.118C>T, c.1235C>G, c.2833A>G, c.1951C>T, c.869+1G>A, c. 1679 C>G, c.2316+1G>A, c.2444G>T, c.2444+1G>C, c.2697G>A, c.5470C>T, c.5870C>G, c.6091C>T, c.6477+4 A>G, c.6856C>T, c.1282A>T and c.5974C>T,
[0011] the deletions: c.529-533delATATT, c.6451delG, c.6832--6833delAG, c.1203delA, c.1549--1550delCT, c.6737--6740delTTGA, c.1471--1472delCT, c.1692delA, c.2716delC, c.1668delT, c.704--705delAT, c.5989--5992delCTGT, c.5532--5533delCA, c.5769delT, c.6739--6742delGAGT, c.4307--4308delAA and c.733--734delAT, and
[0012] the insertions: c.7029--7030insT, c.2850--2851insT, c.3741--3742insA, c.5982--5983insCTCT, c.5986--5987insT, c.3075--3076insA and c.2842--2843insG.
[0013] Such an isolated nucleic acid can be used as a primer or probe.
[0014] More preferentially the invention relates to an isolated nucleic acid, which comprises a KIAA1840 gene sequence that contains one or several mutation(s) selected from the group consisting of [0015] the substitutions: c.6100C>T, c.2198T>G, c.118C>T, c.1235C>G, c.2833A>G, c.1951C>T, c.869+1G>A, c. 1679 C>G, c.2316+1G>A, c.2444G>T, c.2444+1G>C, c.2697G>A, c.5470C>T, c.5870C>G, c.6091C>T, c.6477+4 A>G, c.6856C>T, c.1282A>T c.5974C>T, [0016] the deletions: c.529-533delATATT, c.6451delG, c.6832--6833delAG, c.1203delA, c.1549--1550delCT, c.6737--6740delTTGA, c.1471--1472delCT, c.1692delA, c.2716delC, c.1668delT, c.704--705delAT, c.5989--5992delCTGT, c.5532--5533delCA, c.5769delT, c.6739--6742delGAGT, c.4307--4308delAA c.733--734delAT, and [0017] the insertions: c.7029--7030insT, c.2850--2851insT, c.3741--3742insA, c.5982--5983insCTCT, c.5986--5987insT, c. 3075--3076insA c.2842--2843insG or a sequence complementary thereto.
[0018] Another aspect of the invention relates to an isolated polypeptide which comprises the amino acid sequence of KIAA1840 containing one or several mutation(s) selected from the group consisting of p.Q40X, p.I177_F178delfsX178, p.H235RfsX246, p.M245VfsX246, p.K401KfsX415, p.S412X, p.K428X, p.L491DfsX556, p.L517LfsX556, p.F556LfsX577, p.S560X, p.V564VfsX577, p.R651X, p.L733X, p.R815M, p.W899X, p.Q906SfsX920, p.R945G, p.R945GfsX950, p.L950FfsX953, p.V948GfsX953, p.E1026RfsX1029, p.P1248TfsX1264, p.Q1436RfsX1442, p.R1824X, p.S1844SfsX1857, p.S1923RfsX1950, p.S1957X, p.R1992X, p.L1995LfsX2000, p.C1996LfsX1999, p.L1997--1998delfsX2056, p.R2031X, p.R2034X, p.A2151 PfsX2172, p.I2246_E2247delfsX2260, p.E2247_S2248delfsX2260, p.S2278LfsX2338, p.R2286X and p.V2344CfsX2349.
[0019] Another aspect of the invention relates to an isolated monoclonal or polyclonal antibody that specifically recognizes a KIAA1840 protein containing a mutation selected from the group consisting of p.Q40X, p.I177_F178delfsX178, p.H235RfsX246, p.M245VfsX246, p.K401KfsX415, p.S412X, p.K428X, p.L491DfsX556, p.L517LfsX556, p.F556LfsX577, p.S560X, p.V564VfsX577, p.R651X, p.L733X, p.R815M, p.W899X, p.Q906SfsX920, p.R945G, p.R945GfsX950, p.L950FfsX953, p.V948GfsX953, p.E1026RfsX1029, p.P1248TfsX1264, p.Q1436RfsX1442, p.R1824X, p.S1844SfsX1857, p.S1923RfsX1950, p.S1957X, p.R1992X, p.L1995LfsX2000, p.C1996LfsX1999, p.L1997--1998delfsX2056, p.R2031X, p.R2034X, p.A2151 PfsX2172, p.I2246_E2247delfsX2260, p.E2247_S2248delfsX2260, p.S2278LfsX2338, p.R2286X and p.V2344CfsX2349.
[0020] Another aspect of the present invention relates to the use of a monoclonal or polyclonal antibody recognizing the wild type protein to identify truncated forms of the protein.
Definitions
[0021] A "coding sequence" or a sequence "encoding" an expression product, such as a RNA, polypeptide, protein, or enzyme, is a nucleotide sequence that, when expressed, results in the production of that RNA, polypeptide, protein, or enzyme, i.e., the nucleotide sequence encodes an amino acid sequence for that polypeptide, protein or enzyme. A coding sequence for a protein may include a start codon (usually ATG) and a stop codon.
[0022] The term "gene" means a DNA sequence that codes for or corresponds to a particular sequence of amino acids which comprise all or part of one or more proteins or enzymes, and may or may not include regulatory DNA sequences, such as promoter sequences, which determine for example the conditions under which the gene is expressed. Some genes, which are not structural genes, may be transcribed from DNA to RNA, but are not translated into an amino acid sequence. Other genes may function as regulators of structural genes or as regulators of DNA transcription. In particular, the term gene may be intended for the genomic sequence encoding a protein, i.e. a sequence comprising regulator, promoter, intron and exon sequences.
[0023] As used herein, the term "oligonucleotide" refers to a nucleic acid, generally of at least 10, preferably at least 15, and more preferably at least 20 nucleotides, preferably no more than 100 nucleotides, still preferably no more than 70 nucleotides, and which is hybridizable to a KIAA1840 genomic DNA, cDNA, or mRNA. Oligonucleotides can be labelled according to any technique known in the art, such as with radiolabels, fluorescent labels, enzymatic labels, sequence tags, etc. A labelled oligonucleotide may be used as a probe to detect the presence of a mutated KIAA1840 nucleic acid. Alternatively, oligonucleotides (one or both of which may be labelled) can be used for amplifying a KIAA1840 nucleic acid, for instance by PCR (Saiki et al., 1988), to detect the presence of a mutation. Generally, oligonucleotides are prepared synthetically, preferably on a nucleic acid synthesizer. Accordingly, oligonucleotides can be prepared with non-naturally occurring phosphoester analog bonds, such as thioester bonds, etc.
[0024] A nucleic acid molecule is "hybridizable" or "hybridizes" to another nucleic acid molecule, such as a cDNA, genomic DNA, or RNA, when a single stranded form of the nucleic acid molecule can anneal to the other nucleic acid molecule under the appropriate conditions of temperature and solution ionic strength (Sambrook et al., 1989).
[0025] The conditions of temperature and ionic strength determine the "stringency" of the hybridization. For preliminary screening for homologous nucleic acids, low stringency hybridization conditions, corresponding to a Tm (melting temperature) of 55° C., can be used, e.g., 5×SSC, 0.1% SDS, 0.25% milk, and no formamide; or 30% formamide, 5×SSC, 0.5% SDS). Moderate stringency hybridization conditions correspond to a higher Tm, e.g., 40% formamide, with 5× or 6×SCC. High stringency hybridization conditions correspond to the highest Tm, e.g., 50% formamide, 5× or 6×SCC. SCC is a 0.15 M NaCl, 0.015 M Na-citrate. Hybridization requires that the two nucleic acids contain complementary sequences, although depending on the stringency of the hybridization, mismatches between bases are possible. The appropriate stringency for hybridizing nucleic acids depends on the length of the nucleic acids and the degree of complementation, variables well known in the art. The greater the degree of similarity or homology between two nucleotide sequences, the greater the value of Tm for hybrids of nucleic acids having those sequences. The relative stability (corresponding to higher Tm) of nucleic acid hybridizations decreases in the following order: RNA:RNA, DNA:RNA, DNA:DNA. For hybrids of greater than 100 nucleotides in length, equations for calculating Tm have been derived (see Sambrook et al., 1989, 9.50-9.51). For hybridization with shorter nucleic acids, i.e., oligonucleotides, the position of mismatches becomes more important, and the length of the oligonucleotide determines its specificity (see Sambrook et al., 1989 II.7-11.8). A minimum length for a hybridizable nucleic acid is at least about 10 nucleotides, preferably at least about 15 nucleotides, and more preferably the length is at least about 20 nucleotides.
[0026] In a specific embodiment, the term "standard hybridization conditions" refers to a Tm of 55° C., and utilizes conditions as set forth above. In a preferred embodiment, the Tm is 60° C. In a more preferred embodiment, the Tm is 65° C. In a specific embodiment, "high stringency" refers to hybridization and/or washing conditions at 68° C. in 0.2×SSC, at 42° C. in 50% formamide, 4×SSC, or under conditions that afford levels of hybridization equivalent to those observed under either of these two conditions.
[0027] As used herein, an "amplification primer" is an oligonucleotide for amplification of a target sequence by extension of the oligonucleotide after hybridization to the target sequence or by ligation of multiple oligonucleotides which are adjacent when hybridized to the target sequence. At least a portion of the amplification primer hybridizes to the target. This portion is referred to as the target binding sequence and it determines the target-specificity of the primer. In addition to the target binding sequence, certain amplification methods require specialized non-target binding sequences in the amplification primer. These specialized sequences are necessary for the amplification reaction to proceed and typically serve to append the specialized sequence to the target. For example, the amplification primers used in Strand Displacement Amplification (SDA) include a restriction endonuclease recognition site 5' to the target binding sequence (U.S. Pat. No. 5,455,166 and U.S. Pat. No. 5,270,184). Nucleic Acid Based Amplification (NASBA), self-sustaining sequence replication (3SR) and transcription based amplification primers require an RNA polymerase promoter linked to the target binding sequence of the primer. Linking such specialized sequences to a target binding sequence for use in a selected amplification reaction is routine in the art. In contrast, amplification methods such as PCR which do not require specialized sequences at the ends of the target, generally employ amplification primers consisting of only target binding sequence.
[0028] As used herein, the terms "primer" and "probe" refer to the function of the oligonucleotide. A primer is typically extended by polymerase or ligation following hybridization to the target but a probe typically is not. A hybridized oligonucleotide may function as a probe if it is used to capture or detect a target sequence, and the same oligonucleotide may function as a primer when it is employed as a target binding sequence in an amplification primer. It will therefore be appreciated that any of the target binding sequences disclosed herein for amplification, detection or quantisation of KIAA1840 may be used either as hybridization probes or as target binding sequences in primers for detection or amplification, optionally linked to a specialized sequence required by the selected amplification reaction or to facilitate detection.
[0029] As used herein, the terms "KIAA1840 gene" (or its synonyms: FLJ21439, ENSG00000104133 or SPG11) denotes a KIAA1840 gene of any species, especially human, but also other mammals or vertebrates to which the methods of the invention can apply. The human KIAA1840 gene encodes a large protein of 2443 amino-acids (aa) of unknown function that the inventors have named Spatacsin (SEQ ID NO: 2). Homo sapiens KIAA1840 gene is localized on chromosome 15 and its Coding Sequence (CDS) is deposited in Genebank under accession number NM--025137, or AB058743 (5'-3' forward strand shown SEQ ID NO: 1). Human KIAA1840 gene shares 85% identity with the homologous protein in dog, and 76% and 73% identity with the mouse and rat homologues and 59% with the chicken homologue. Homology is less than 25% with orthologous proteins, of smaller sizes, in tetraodon and drosophila. KIAA1840 homologous proteins at NCBI database are: dog XP--544657, gallus XP--413940.1, mouse BAE27954, rat XP--242139.3, and at Ensembl database; drosophila CG13531, tetraodon GSTENG00003909001. The human KIAA1840 gene contains 40 exons spanning 101 Kbases of genomic DNA on chromosome 15q21.1. The intron-exon structure of the complementary strand of the KIAA1840 gene is further indicated in Table 1 below and in FIG. 5.
TABLE-US-00001 TABLE 1 Exon-intron boundaries of the human KIAA1840 gene (according to the Ensembl database) Posi- tion in SEQ ID Length No Exon/Intron NO: 1 (bp) Sequence 5' upstream ..........cgacgcagtcaggttccggcgaaagtgaccggaagtaaccgccgggccaa sequence 1 ENSE 0 258 GATGGCTGCAGAGGAAGGGGTCGCGAGTGCTGCTTCCGCCGGCGGTAGCTGGGGCACCGCGGCCATGGGG 00001183257 CGGGTTCTACCGATGCTGTTGGTGCCAGTCCCCGCCGAGGCGATGGGGCAGCTCGGCTCCCGGGCGCAGCT GCGCACACAGCCGGAGGCTCTGGGGAGCCTGACGGCTGCGGGCAGCCTCCAAGTGCTTTCTTTGACGCCT- G GCAGCCGGGGCGGGGGTCGCTGCTGCCTGGAGGGCCCCTTCTGGCA Intron 1-2 2,774 gtaagtgctgagggagagttgggcc..........aataaatctaaactttttttcttag 2 ENSE 258 185 CTTTCTATGGGAGGATTCTCGTAACAGCAGCACACCAACTGAAAAGCCCAAACTGCTCGCTCTTGGTGAAAAT 00001183253 TATGAACTGCTTATCTATGAATTTAATTTGAAAGATGGAAGATGTGATGCAACCATTTTGTATAGCTGTAGTA- GG GAGGCATTGCAAAAGCTCATTGACGATCAAGATATCA Intron 2-3 1,128 gtaagtatctacaggtggtctttca..........gaaataatatccttttgttttgtag 3 ENSE 443 225 GTATTTCCTTATTGTCTTTGAGAATCCTGTCATTTCACAATAACACATCATTACTGTTCATCAACAAATGTGT- CAT 00001183250 CCTACATATTATATTTCCTGAAAGAGATGCTGCAATTAGAGTACTCAACTGTTTCACACTTCCCTTGCCTGCA- CA GGCAGTGGACATGATTATTGACACGCAGCTCTGCAGAGGAATTCTTTTTGTTTTGAGTAGTTTAGGCTGG- ATCT Intron 3-4 1,782 gtatccttggtggtagaagtgttga..........attttcttttaactctaactaaaag 4 ENSE 668 202 ACATTTTTGATGTTGTGGATGGTACATATGTAGCTCATGTGGATTTAGCACTTCACAAAGAAGACATGTGTAA- T 00001183246 GAGCAGCAACAGGAGCCAGCCAAGATTTCTTCATTTACTTCACTGAAAGTTTCTCAAGACCTCGATGTTGCAG- T GATTGTCAGCTCCTCCAACTCCGCAGTTGCTCTTAACTTAAATTTGTATTTCAG Intron 4-5 4,828 gtatgtagatgactgcagtttctaa..........tgtctatcattatttttaaatgtag 5 ENSE 870 138 GCAACACCCAGGACACCTACTGTGTGAAAGAATACTAGAAGATCTTCCTATTCAAGGACCTAAGGGCGTAGAT 00001183241 GAAGATGATCCTGTTAACTCTGCCTACAACATGAAACTGGCCAAGTTTTCCTTCCAAATTGATAG Intron 5-6 189 gtacagaaacttccttttcatgtag..........aagttatattttaccttgtttccag 6 ENSE 1008 449 GTCTTGGAAAGCCCAGCTATCATCATTGAATGAAACAATAAAGAACTCCAAACTGGAGGTTTCCTGTTGTGCT- C 00001183238 CATGGTTCCAGGATATTTTGCATTTGGAGTCACCTGAATCTGGTAACCACAGTACAAGTGTGCAGAGCTGGGC CTTCATTCCACAGGACATAATGCATGGGCAATATAATGTTCTACAGAAAGATCATGCCAAGACCAGTGAT- CCAG GAAGATCATGGAAAATAATGCACATCAGTGAACAAGAGGAACCCATAGAGCTTAAATGTGTGTCTGTGAC- AGG ATTCAC TGCACTGTTTACTTGGGAAGTGGAAAGGATGGGCTATACCATTACCCTCTGGGATTTGGAGACCCAGGGC- ATG CAGTGTTTTTCCCTTGGCACAAAGTGTATTCCTGTAGACAGTAGTGGAGACCAGCAGCTGTGCTTTGTTT- TGAC AG Intron 6-7 2,479 gtgagactgtcttgtattagattga..........aagctaacttttatttttcctatag 7 ENSE 1457 146 AGAATGGACTCTCTCTGATTTTGTTTGGTTTGACTCAAGAAGAGTTTTTAAACAGACTCATGATCCATGGAAG- T 00001183236 GCCAGCACTGTGGACACTCTTTGTCATCTCAATGGCTGGGGAAGGTGCTCAATTCCCATACATGCACTAGAG Intron 7-8 15,228 gtaacagaattaaatgcccaagaac..........atttttattttcctcctcatttcag 8 ENSE 1603 133 GCCGGGATAGAAAATCGTCAGCTGGACACAGTAAATTTCTTTTTGAAGAGCAAGGAAAATCTTTTTAATCCAT- C 00001105929 CTCAAAATCTTCTGTATCTGATCAGTTTGATCACTTGTCATCCCATTTATATTTAAGAA Intron 8-9 4,116 gtaagtggaataaagatttctacat..........gttaatttctttggttctttctcag 9 ENSE 1736 156 ATGTGGAAGAGCTGATACCAGCATTGGATTTACTTTGCTCGGCAATTAGAGAAAGTTATTCTGAACCCCAAAG- C 00001105933 AAACACTTTTCAGAACAATTGCTTAATCTTACACTGTCTTTCCTTAACAACCAAATAAAGGAGCTTTTCATTC- ACA CTGAAG Intron 9-10 388 gtaagaatagcagctaggaaggggg..........attggcacattggtattttccatag 10 ENSE 1892 176 AACTAGATGAACATCTGCAAAAAGGAGTGAACATTTTGACTAGCTACATTAATGAACTTCGAACCTTCATGAT- AA 00001105923 AGTTTCCTTGGAAGCTAACAGATGCTATAGATGAATATGATGTACATGAAAATGTCCCCAAAGTAAAGGAGAG- C AATATATGGAAGAAACTCAGCTTTGAG Intron 10-11 2,161 gtaagtacgaataatcatcacttct..........aaggcaaacgtttttcttttcctag 11 ENSE 2068 177 GAAGTTATTGCCAGCGCCATTTTAAACAACAAAATACCAGAGGCACAGACTTTCTTCAGGATTGATAGTCATT- C 00001105941 TGCTCAAAAACTTGAGGAGCTTATTGGCATAGGCCTAAATTTGGTCTTTGACAATTTAAAAAAGAACAATATA- AA GGAAGCCTCTGAACTTTTGAAGAATATG Intron 11-12 3,531 gtgagtggtgtaatccataaagtct..........ttttggttttctatgtttattttag 12 ENSE 2245 72 GGGTTTGATGTAAAAGGCCAATTGCTCAAGATCTGCTTCTATACAACTAATAAAAATATACGTGACTTTTTG 00001183220 Intron 12-13 380 gtaggtaaaggtgagactacatagt..........ctgctttaattactttttattcaag 13 ENSE 2317 128 GTTGAAATTTTAAAAGAAAAAAATTATTTTTCTGAAAAAGAGAAAAGAACTATAGACTTCGTGCATCAAGTTG- AG 00001183213 AAGCTTTATTTGGGACATTTCCAAGAAAATATGCAAATCCAGTCATTTCCCAG Intron 13-14 285 gtagtctcattagtcctcttttgat..........aaaaaatttatatcactgtttttag 14 ENSE 2445 176 GTACTGGATAAAGGAACAAGATTTTTTCAAGCACAAGTCTGTTTTGGACTCATTCCTGAAATATGATTGTAAA- GA 00001183208 TGAATTTAACAAACAGGACCATAGAATTGTGTTAAATTGGGCTCTGTGGTGGGATCAACTAACACAAGAATCC- A TCCTTCTCCCCAGGATAAGTCCAGAAG Intron 14-15 1,355 gcaagtgtgagagagcctgaaatat..........ttaaaatgtgttttttttcatgtag 15 ENSE 2621 214 AATACAAATCATATTCCCCTGAAGCCCTCTGGAGATACCTCACAGCTCGCCATGATTGGTTAAACATTATCTT- A 00001183204 TGGATTGGAGAATTTCAAACCCAGCATAGTTATGCTTCACTTCAGCAGAACAAATGGCCCCTTCTGACTGTTG- A TGTTATTAACCAGAATACTTCCTGTAACAACTACATGAGGAATGAAATTTTAGATAAGCTGGCCAG Intron 15-16 4,623 gtattataactgttgaactaatacc..........tgacatcctataaatctgtccatag 16 ENSE 2835 204 GAATGGGGTTTTTTTGGCATCTGAACTGGAAGACTTTGAATGCTTCCTCCTAAGACTGAGCCGTATTGGAGGT 00001047610 GTAATACAGGATACCCTCCCTGTTCAAAACTACAAGACCAAAGAAGGTTGGGATTTCCATTCTCAATTCATTC- T CTATTGTTTGGAGCACAGTCTGCAGCATCTTCTTTATGTCTACCTTGACTGTTACAA Intron 16-17 1,826 gtgagtactgagaatgcatttgtcc..........aggtttttgtttgattatatacag 17 ENSE 3039 107 ACTTAGTCCTGAAAATTGTCCCTTTTTGGAAAAAAAAGAGTTACATGAAGCACACCCTTGGTTTGAATTTTTA- GT 00001287244 TCAGTGTCGACAAGTTGCCAGTAACTTAACAG Intron 17-18 2,444 gtatgggtatactgtattaaacaca..........aaaaacactgtcttttattttccag 18 ENSE 3146 146 ATCCCAAACTGATCTTCCAGGCTAGCCTTGCAAATGCTCAGATTTTGATTCCCACCAATCAGGCCAGTGTAAG- C 00001047605 AGTATGCTATTGGAAGGACATACCCTCCTGGCCCTTGCTACTACAATGTATTCTCCTGGGGGTGTCAGTCAG Intron 18-19 2,234 gtatggatagcactttatgacaaaa..........acctgttatctgtttttttacttag 19 ENSE 3292 162 GTTGTTCAGAATGAAGAAAATGAAAACTGTTTGAAGAAAGTGGATCCCCAGCTATTGAAGATGGCATTAACTC- C 00001047617 TTACCCCAAGCTAAAAACTGCTCTCTTCCCACAGTGCACTCCTCCTAGTGTCCTGCCATCTGATATTACAATC- T ACCACCTTATTCAG Intron 19-20 2,352 gtacagtatttaggtggccaatatt..........ctgtttaacttttcccctttttcag 20 ENSE 3454 67 TCATTATCACCCTTTGATCCTAGCAGATTGTTTGGCTGGCAGTCTGCTAACACACTAGCTATAGGAG 00001047612 Intron 20-21 5,392 gtaagtcatcatgggtacttcttga..........taatattgttttactttccccctag 21 ENSE 3521 166 ATGCATGGAGTCATCTCCCACATTTCTCTAGCCCTGACCTGGTTAATAAATATGCTATAGTGGAACGTCTGAA- T 00001047594 TTTGCTTATTATTTACATAATGGGCGGCCATCATTTGCATTTGGTACTTTTCTGGTCCAGGAATTAATCAAGA- GC AAGACTCCCAAGCAGCT Intron 21-22 1,630 gtgagtatttaaaatataattttagt..........tgattttgattcctttctttttcag 22 ENSE 3687 206 GATCCAGCAAGTAGGCAATGAAGCCTATGTTATAGGGCTCTCCTCCTTCCACATACCTTCAATAGGAGCTGCA 00001047598 TGTGTTTGTTTCTTAGAATTGCTTGGCCTTGACAGCCTCAAGCTCAGAGTTGATATGAAAGTGGCCAATATAA- T TTTGAGCTACAAGTGCAGAAATGAAGATGCTCAGTACAGCTTTATCAGAGAGTCTGTAG Intron 22-23 257 gtacagcaccttttatctggcctgc..........attttgttgtttatatttcttacag 23 ENSE 3893 109 CCGAAAAACTATCTAAACTAGCTGATGGTGAAAAGACAACCACAGAAGAATTGCTTGTTCTCTTAGAAGAAGG- T 00001047622 ACATGGAACAGCATTCAGCAACAGGAAATAAAGAG
Intron 23-24 1,321 gtttgtgagttgcagtctcagcctc..........cccccacctctaattctgattatag 24 ENSE 4002 160 GTTATCCAGTGAATCTAGCAGCCAATGGGCATTAGTGGTGCAGTTCTGCAGGCTACACAATATGAAACTAAGC 00001047619 ATATCTTACCTTAGAGAATGTGCCAAAGCAAATGATTGGCTGCAGTTCATTATTCACAGCCAACTCCACAACT- A CCACCCAGCAGAG Intron 24-25 428 gtaagccactaattgttagcagtca..........tttaatcatctgatatgccttctag 25 ENSE 4162 273 GTGAAATCCCTTATCCAGTACTTCAGCCCAGTCATTCAAGACCACTTAAGGCTGGCTTTTGAGAACTTGCCCT- C 00001047603 AGTGCCCACCTCCAAAATGGACAGCGATCAAGTCTGCAATAAGTGCCCCCAGGAACTTCAAGGAAGCAAACAA GAGATGACCGATTTATTTGAAATTCTGCTCCAATGCTCAGAGGAGCCAGACTCCTGGCACTGGCTTCTGG- TTG AAGCAGTGAAACAACAGGCCCCTATCCTCAGTGTTCTGGCCTCATGTCTCCAG Intron 25-26 623 gtgaggatcatgagaagcctgaagt..........tgttattttatttatcccgtggcag 26 ENSE 4435 201 GGTGCCAGTGCCATTTCTTGTCTCTGTGTTTGGATCATCACTTCTGTGGAGGACAATGTTGCAACTGAAGCAA- T 00001047590 GGGACACATTCAGGACTCAACAGAGGACCATACCTGGAACCTTGAGGATCTTTCAGTCATCTGGAGAACATTA TTAACAAGACAAAAGAGCAAAACTCTCATCAGAGGTTTCCAGCTTTTCTTTAAG Intron 26-27 2,820 gtagtgatagttgcttcacttcttt..........atttttttcaaactctttgtcaaag 27 ENSE 4636 108 GATTCCCCGTTACTACTGGTGATGGAGATGTATGAACTGTGTATGTTCTTCAGGAATTATAAAGAAGCTGAAG- C 00001047613 TAAACTTCTGGAGTTTCAGAAGAGCCTTGAAACG Intron 27-28 2,916 gtaagttggaattatggtgctcttt..........ctaagcttctctttttctttcatag 28 ENSE 4744 163 CTTAACACAGCAGCCACAAAGGTCCACCCTGTCATCCCTGCCATGTGGCTGGAGGATCAGGTGTGTTTCCTTT 00001047595 TGAAGCTTATGCTACAGCAGTGTAAGACCCAGTATGAGCTGGGGAAGCTTTTACAGCTCTTTGTTGAAAGAGA GCATCTCTTCTCTGATG Intron 28-29 3,401 gtaagacaatccttacagttaagtt..........ttatatccttttctctttggcacag 29 ENSE 4907 215 GTCCAGATGTGAAAAAGCTTTGCATCCTTTGCCAGATTTTGAAGGATACATCCATAGCCATTAATCATACAAT- TA 00001047608 TTACCAGCTACAGCATTGAGAATCTTCAGCATGAATGTAGATCTATTTTGGAAAGACTGCAGACAGATGGACA- A TTCGCTTTGGCCAGGAGGGTAGCAGAATTAGCTGAGTTACCTGTGGACAACTTGGTTATTAAAGAG Intron 29-30 1,077 gtatcatcggtctttttttttttttt..........aaatctgctttgttaaatttcacag 30 ENSE 5122 745 ATAACACAGGAAATGCAGACCCTAAAACACATTGAACAGTGGTCACTAAAACAAGCAAGAATTGACTTCTGGA- A 00001047607 AAAATGCCATGAGAATTTTAAGAAAAATTCAATTTCAAGCAAAGCAGCTTCTTCCTTTTTCTCAACCCAGGCC- CA TGTGGCATGTGAGCACCCAACTGGATGGAGCAGCATGGAGGAGCGCCATCTGCTGCTCACCTTGGCAGGG- C ACTGGCTTGCCCAGGAGGACGTGGTGCCCTTGGATAAGCTGGAGGAGCTGGAGAAGCAGATCTGGCTGTG- C CGCATCACCCAGCACACTCTTTGAAGAAATCAGGAGGAAACAGAGCCCAGATTTTCTCGACAGATCTCAA- CTA GTGGTGAACTTTCCTTTGATAGTTTAGCCAGTGAGTTTTCCTTCTCCAAGTTGGCTGCTCTGAACACATC- AAAA TACTTAGAACTTAACAGCCTTCCATCCAAAGAGACATGCGAGAATAGATTGGATTGGAAAGAGCAGGAGT- CAC TAAACTTTTTGATTGGGCGCCTACTGGATGATGGCTGTGTGCATGAAGCAAGTAGAGTATGCCGGTATTT- TCAT TTTTATAATCCAGATGTCGCCTTGGTATTGCACTGCAGAGCACTGGCCTCAGGGGAAGCTAGTATGGAGG- ATC TGCACCCAGAGATCCATGCTCTCCTACAAAGTGCTGAGCTGCTTGAGGAAGAAGCACCCGACATTCCCCT- AAG GAGAGTCCACAGCA Intron 30-31 8,772 gtaagtgaaggagatagatggccc..........ccctcagacttgtatttgcttccag 31 ENSE 5867 140 CTTCAAGTCTGGATAGTCAGAAGTTTGTGACAGTGCCCTCCAGTAATGAAGTGGTAACTAACCTGGAAGTGCT 00001047614 GACAAGCAAATGCCTCCATGGGAAGAACTACTGTCGACAGGTCCTCTGTCTGTATGATCTTGCCAAG Intron 31-32 1,156 gtatgtgccaaggggtggggctcct..........ttgactggctttgtcttcctctcag 32 ENSE 6007 199 GAGTTGGGCTGTTCCTACACAGATGTTGCTGCTCAGGATGGTGAAGCCATGCTCCGGAAAATCTTGGCCTCTC 00001123435 AGCAGCCTGACCGATGCAAACGAGCCCAGGCCTTCATCAGCACACAGGGCCTTAAGCCAGATACTGTGGCTG AACTCGTGGCAGAAGAGGTGACACGGGAGCTGCTTACTTCATCACAGGGAACAG Intron 32-33 726 gtgccctaccccccggggattccca..........cctgtcttcacacctctctgtacag 33 ENSE 6206 138 GACATAAGCAGATGTTCAACCCAACAGAGGAAAGCCAGACATTTCTTCAGCTGACCACTCTGTGTCAAGACCG 00001123426 CACATTGGTAGGCATGAAGTTGTTGGATAAGATTTCCTCCGTTCCCCATGGGGAACTGTCTTGCA Intron 33-34 2,024 gtaagttattgacctttttcttaca..........atcttaccagtgcccaccctcccag 34 ENSE 6344 134 CCACAGAGCTCCTGATCCTGGCCCATCATTGCTTCACCCTGACGTGCCACATGGAGGGCATCATCCGAGTCC 00001123415 TACAGGCCGCCCACATGCTCACAGATAACCACCTGGCCCCCAGTGAGGAGTATGGGCTGGTG Intron 34-35 1,019 gtaagtagccccctcaaccccagtc..........tgcgagctgtcctcccacttcacag 35 ENSE 6478 108 GTACGGCTCCTCACTGGCATTGGAAGGTACAACGAGATGACATACATATTTGATTTGCTGCATAAAAAGCACT- A 00001123405 CTTTGAAGTGCTAATGAGGAAGAAGTTGGATCCG Intron 35-36 1,805 gtaggtgcaaagtaatgagctccag..........gctttttcccttttattctgggcag 36 ENSE 6586 169 AGTGGTACCCTGAAAACAGCCCTGCTGGACTACATCAAACGCTGCCGTCCTGGAGACAGTGAAAAGCACAAT 00001123397 ATGATTGCCCTGTGCTTCAGCATGTGCCGGGAGATTGGCGAGAACCACGAGGCAGCTGCCCGCATCCAACTG AAATTGATTGAGTCTCAGCCCTGGG Intron 36-37 1,118 gtgagtgaggtcacagccacactac..........caaatcttctttatttcccctacag 37 ENSE 6755 89 AGGACAGCCTCAAGGATGGGCACCAGCTGAAACAACTGCTGCTGAAGGCCCTGACTCTGATGTTGGATGCAG 00000684756 CAGAGAGTTATGCCAAG Intron 37-38 207 gtaacccaaaggcttttttcagact..........gtgcctctccacccttgttcctcag 38 ENSE 6844 156 GACTCCTGTGTGCGACAGGCCCAGCACTGTCAGCGGCTCACCAAGTTGATAACTCTGCAGATTCACTTTCTGA 00000684735 ACACTGGCCAGAACACAATGCTCATCAACTTGGGCCGCCACAAGCTGATGGACTGTATTCTGGCCCTACCTCG GTTCTACCAG Intron 38-39 1,155 gtgagcaagaaagcaaactgtagcc..........gtccttcttcacctctccttttaag 39 ENSE 7000 152 GCTTCTATTGTGGCTGAGGCCTACGATTTTGTTCCAGATTGGGCTGAAATTTTATACCAGCAAGTGATTCTTA- A 00000684706 AGGAGACTTTAATTACTTGGAAGAATTTAAGCAGCAAAGGTTATTAAAGTCCAGTATATTTGAAGAGATTTCC- AA AAA Intron 39-40 1,245 gtaagtattaaaagttgactgtaaa..........ctgtacattatgtttctttatctag 40 ENSE 7152 600 ATATAAACAACATCAGCCTACTGACATGGTCATGGAAAACCTGAAGAAATTACTCACATATTGTGAAGATGTT- TA 00000884381 CCTGTATTACAAGTTGGCATACGAACACAAGTTTTATGAAATTGTAAATGTGCTTCTGAAGGACCCTCAGACA- G GTTGCTGTCTAAAGGACATGCTAGCAGGTTAGATGATTTCATAGGTGTCTGTTTTCTTGTACTGTTAGCA- GATT CTGACAGATGTGATGAGAAGAAGAATGCATTGGAGATCTTTGCTAAAGTTGAACAATCCCGGTACTGTAC- CATA TCAGTCCTTTGTGGGTAGTAGGTAGCAAGTAAGAAACTTTTCAGGAGGAAATTCCTATTTAAAATAGATT- GATTT TAGATGATTGTTCATCCACACCATTTTATATAGATACTAGTATTAAGATCAAAAGCTTCCTCTTCCTCAG- GACAG CTTCTACTTTAGATGATCCAATAATGATTAAAGAATACCTGTACCTGCAGATTCCAGTTTCAAAGAAATT- TAATTA TTATTTACACAGTTAAGGAACAGGTGATACATTTTCATTTGTTAGAAACTGATCTTTCTGTAATAAAATA- GATTTT C 3' aattcagtgtatgtcattattactgctaaggaaatcttagcccttgtctg.......... downstream sequence
[0030] As used herein, the term "Spatacsin" denotes the SPAsticity with Thin or Corpus callosum Syndrom protein, which is encoded by the KIAA1840 gene. The sequence of the human form is shown in SEQ ID NO:2.
[0031] The terms "mutant' and "mutation" mean any detectable change in genetic material, e.g. DNA, RNA, cDNA, or any process, mechanism, or result of such a change. This includes gene mutations, in which the structure (e.g. DNA sequence) of a gene is altered, any gene or DNA arising from any mutation process, and any expression product (e.g. protein or enzyme) expressed by a modified gene or DNA sequence. Generally a mutation is identified in a subject by comparing the sequence of a nucleic acid or polypeptide expressed by said subject with the corresponding nucleic acid or polypeptide expressed in a control population. A mutation in the genetic material may also be "silent", i.e. the mutation does not result in an alteration of the amino acid sequence of the expression product.
[0032] In the context of the instant application, mutations identified in KIAA1840 gene are designated pursuant to the nomenclature of Den Dunnen et al. 2001 (http://www.genomic.unimelb.edu.au/mdi/mutnomen/). As defined by Dunnen and Antonarakis at the nucleic acid level, substitutions are designated by "c.position(nt)>(nt)", e.g. "c.118C>G denotes that at nucleotide 118 of the reference sequence C is changed to a G. The mutation at the protein level is denoted p.Q40X: which means that a glutamine (Q) at position 40 encoded by CAG is replaced by a STOP (TAG) codon (Q40X). Deletions are designated by "del" after the deleted interval (followed by the deleted nucleotides). For instance 529--533delATATT denotes a ATATT deletion from nucleotides 529 to 533. The consequence of this deletion, p.I177_F178delfsX, is a deletion of aminoacids at positions 177 and 178 and a frameshift (fs) in the coding sequence leading to the appearance of a premature STOP codon (X). An alternative nomenclature is to indicate the position of the stop codon in the resulting protein after the X; p.I177--178delfsX178 indicates that the stop codon resulting from the mutation is at codon 178. Insertions are designated by "ins," followed by the inserted nucleotides. For example, c.7029--7030insT denotes that a T was inserted after nucleotide 7029. This leads to the replacement of valine (V) by cysteine (C) at position 2344 and to a frameshift of the coding sequence and a premature STOP codon at amino-acid 2349 (fsX): p.V2344CfsX or p.V2344CfsX2349. When a mutation is predicted to alter the splicing of the mRNA because the variant modifies a nucleotide of the consensus sequence for splicing (acceptor or donor site), the "r.?" denotes that the consequences of the mutation could not be checked at the RNA level, but is likely (as verified at http://rulai.cshl.edu/new_alt_exon_db2/HTML/score.html).
[0033] The term "hereditary spastic paraplegias (HSP)" denotes genetically heterogeneous Mendelian disorders characterized by weakness, spasticity and loss of vibratory sense in the lower limbs. The term "Autosomal Recessive Hereditary Spastic Paraplegia" or "AR-HSP" denotes spastic paraplegia that is transmitted as an autosomal recessive trait. Patients with HSP or AR-HSP can have a pure phenotype, or, more often, a complex phenotype that associates various neurological signs (cerebellar ataxia, mental retardation, peripheral neuropathy, etc). The term "AR-HSP-TCC" denotes an AR-HSP with Thin Corpus Callosum usually associated with, mental or cognitive deficit and peripheral neuropathy. Families without proved TCC can also be mutated in this gene either because of slow progression of the disease in the patient or because magnetic resonance imaging (MRI) couldn't be performed due to patient refusal or impossibility (patients leaving far from cities in North-Africa--this is the case for families FSP400, FSP393 and FSP343).
[0034] As used herein, the term "subject" denotes a mammal, such as a rodent, a feline, a canine, and a primate. Preferably a subject according to the invention is a human.
Mutations in the KIAA1840 Gene and Spatacsin Protein
[0035] The inventors identified various mutations in the KIAA1840 gene.
[0036] Fortythree different mutations on human KIAA1840 gene were indeed identified in 47 families, including the 16 linked ones, all at the homozygous state, except in 16 kindreds. They were either nonsense mutations (n=13), deletions (n=17), insertions (n=7), or splice site mutations (n=6) in the coding sequence, and resulted theoretically in an abnormally spliced mRNA or a truncated protein in all cases.
[0037] In one family, linked with a maximal 3.1 multipoint lod score to SPG11, a missense R945G mutation segregated at the homozygous state in both patients and was not detected in 150 control chromosomes. The mutation is probably not only affecting the nature of the amino-acid. Position of this variant was in the 5'-splice site consensus sequence (2 bases before the end of exon 15). The score of the 5'-splicing sequence changed from 4.9 for the wild type to 2.7 for the variant (Alternative Splicing Database: :http://rulai.cshl.edu/new_alt_exon_db2/HTML/score.html) suggesting that this variant could act at both the RNA level (splicing effect) and at the protein level (missense change). Indeed, this was confirmed by direct sequencing (using primers GCTCTGTGGTGGGATCAACT and TGCTTACACTGGCCTGATTG) on mRNA isolated from lymphoblasts of an affected family member (FSP670-5) in which an alternative splice site is generated downstream in intron 15 leading to a 65 bp insertion and a premature stop codon (c.2833A>G, r.2834+1--2834+65ins, p.R945GfsX950). It cannot be excluded, however, that splicing occurs at its normal place in a small amount of messenger RNA and that a full length protein is generated with the G variant at position 945. Similarly, the mutation c.2444G>T, p.R815M likely affects not only the amino-acid but also splicing of exon 13 since the splice score down from 3.7 to 0.2 for the mutation. In addition, the c.869+1G>A, c.2316+1G>A, c.2444+1G>C and c.6477+4A>G, are all clearly affecting the acceptor splicing concensus sequence (see splice scores in table 2) and likely alter the splicing of exons 4, 12, 13 and 34, respectively. The mutations identified by the inventors are presented on the following Table 2.
TABLE-US-00002 TABLE 2 Mutations identified in the KIAA1840 CDS (SEQ ID NO: 1) and protein (SEQ ID NO: 2) Family code Family code xo Mutations (Origins) at the (Origins) at the Nucleotide variants mRNA or Protein variants SEQ ID NO: homozygous state heterozygous state c.118C > T, P.Q40X 149 FSP672 (Israel) c.529_533delATATT p.I177_F178 > 150 FSP386 (Portugal) ITA17 (Brazil) S177fsX178 FSP754 (Portugal) FSP831 (Portugal) 4 c.704_705delAT p.H235RfsX246 166 SPD199 (Turkey) 4 c.733_734delAT, p.M245VfsX246 151 TUN2 (Tunisia) FSP117 TUN3 (Tunisia) (France) TUN4 (Tunisia) TUN22 (Tunisia) Intron 4 c.869 + 1G > A r.? FSP847 (Argentina) Splice score down from 9.8. to -0.9 6 c.1203delA, p.K401KfsX415 152 PE (Italy) 6 c.1235C > G, p.S412X 153 FSP393 (Portugal) 6 c.1282A > T p.K428X 167 FSP830 (Portugal) 7 c.1471_1472delCT p.L491DfsX556 168 FSP522 (France) 7 c.1549_1550delCT, p.L517LfsX556 154 FSP343 (Algeria) (non typical) 8 c.1668delT p.F556LfsX577 169 SAL646 (France) 8 c.1679C > G p.S560X 170 ITA16SB (Italy) 8 c.1692delA p.V564VfsX577 171 DKD (Italy) 10 c.1951C > T, p.R651X 155 MP (Italy) FSP683 (Romania) ITA28VAC (Italy) 11 c.2198T > G, p.L733X 156 OS (Italy) Intron 12 c.2316 + 1G > A r.? FSP892 (Norway) Splice score down from 6.2 to -4.5 13 c.2444G > T p.R815M and/or r.? 172 ITA28VAC Splice score down from (Italy) 3.7 to 0.2 Intron 13 c.2444 + 1G > C r.? ITA16 (Brazil) Splice score down from 3.7 to -7 15 c.2697G > A p.W899X 173 ITA10 (Italy) 15 c.2716delC p.Q906SfsX920 174 ITA9 (Italy) 15 c.2833A > G, r.2834 + 1_2834 + 65ins, 165 FSP670 (Israel) ITA14 (Italy) p.R945G or p.R945GfsX950 Splice score down from 188 4.9 to 2.7 16 c.2842_2843insG, p.V948GfsX953 157 PE (Italy) 16 c.2850_2851insT, p.L950FfsX953 158 MP (Italy) 17 c.3075_3076insA p.E1026RfsX1029 175 ITA8 (Germany) 22 c.3741_3742insA p.P1248TfsX1264 176 ITA17 (Brazil) 25 c.4307_4308delAA p.Q1436RfsX1442 177 FSP398 (Israel) ITA16 (Brazil) 30 c.5470C > T p.R1824X 178 ITA8 (Germany) 30 c.5532_5533delCA p.S1844SfsX1857 179 FSP522 (France) 30 c.5769delT p.S1923RfsX1950 180 FSP838(Saudi-Arabia) 31 c.5870C > G p.S1957X 181 ITA16SB (Italy) 31 c.5974C > T, p.R1992X 159 FSP117 (France) 31 c.5982_5983insCTCT p.L1995LfsX2000 182 DKD (Italy) 31 c.5986_5987insT p.C1996LfsX1999 183 FSP398 (Israel) 31 c.5989_5992delCTGT p.11997_Y1998 > 184 FSP683 M1997fsX2056 (Romania) 32 c.6091C > T p.R2031X 185 ITA1 (Turkey) 32 c.6100C > T, p.R2034X 160 FSP446 (Morocco), FSP221 (Algeria), FSP732 (Algeria), FSP400 (Algeria) FSP792 (Algeria) FSP845 (Morocco) TUN9 (Tunisia) TUN12 (Tunisia) TUN14 (Tunisia) 34 c.6451delG, p. A2151 P fsX2172 161 SAL1608 (France) Intron 34 c.6477 + 4 A > G r.? FSP830 Splice score down from (Portugal) 9.6 to 6.6 36 c.6737_6740delTTGA, p.I2246_E2247 > 162 FSP920 (Japan) FSP343 S2246fsX2260 (Algeria) 36 c.6739_6742delGAGT p.E2247_S2248 > 186 SAL646 L2247fsX2260 (France) 37 c.6832_6833delAG, p.S2278LfsX2338 163 FSP75 (Portugal) 38 c.6856C > T p.R2286X 187 ITA14 (Italy) 39 c.7029_7030insT, p.V2344CfsX2349 164 FSP515 (Tunisia) indicates data missing or illegible when filed
[0038] Each mutation are herein numbered according to human KIAA1840 CDS and amino acid sequence as shown in SEQ ID NO: 1 and SEQ ID NO:2.
[0039] Accordingly, the invention relates to an isolated nucleic acid specifically hybridizable to a region of KIAA1840 gene coding sequence (SEQ ID NO:1) that contains a mutation selected from the group consisting of [0040] the substitutions c.6100C>T, c.2198T>G, c.118C>T, c.1235C>G, c.2833A>G, c.1951C>T, c.869+1G>A, c. 1679 C>G, c.2316+1G>A, c.2444G>T, c.2444+1G>C, c.2697G>A, c.5470C>T, c.5870C>G, c.6091C>T, c.6477+4 A>G, c.6856C>T, c.1282A>T and c.5974C>T, [0041] the deletions: c.529-533delATATT, c.6451delG, c.6832--6833delAG, c.1203delA, c.1549--1550delCT, c.6737--6740delTTGA, c.1471--1472delCT, c.1692delA, c.2716delC, c.1668delT, c.704--705delAT, c.5989--5992delCTGT, c.5532--5533delCA, c.5769delT, c.6739--6742delGAGT, c.4307--4308delAA and c.733--734delAT, and [0042] the insertions: c.7029--7030insT, c.2850--2851insT, c.3741--3742insA, c.5982--5983insCTCT, c.5986--5987insT, c.3075--3076insA and c.2842--2843insG.
[0043] In one embodiment of this aspect of the invention, the isolated nucleic acid according to the invention consists of at least 10 nucleotides, preferably 20 nucleotides, more preferably 40 nucleotides.
[0044] In a preferred embodiment, such an isolated nucleic acid is specifically hybridizable to a region consisting of 10 nucleotides upstream and 10 nucleotides downstream of a mutation selected from the group consisting of [0045] the substitutions: c.6100C>T, c.2198T>G, c.118C>T, c.1235C>G, c.2833A>G, c.1951C>T, c.869+1G>A, c. 1679 C>G, c.2316+1G>A, c.2444G>T, c.2444+1G>C, c.2697G>A, c.5470C>T, c.5870C>G, c.6091C>T, c.6477+4 A>G, c.6856C>T, c.1282A>T c.5974C>T, [0046] the deletions: c.529-533delATATT, c.6451delG, c.6832--6833delAG, c.1203delA, c.1549--1550delCT, c.6737--6740delTTGA, c.1471--1472delCT, c.1692delA, c.2716delC, c.1668delT, c.704--705delAT, c.5989--5992delCTGT, c.5532--5533delCA, c.5769delT, c.6739--6742delGAGT, c.4307--4308delAA c.733--734delAT, and [0047] the insertions: c.7029--7030insT, c.2850--2851insT, c.3741--3742insA, c.5982--5983insCTCT, c.5986--5987insT, c.3075--3076insA c.2842--2843insG, of the KIAA1840 gene sequence.
[0048] Preferably, "specifically hybridizable" means "hybridizable under conditions at 68° C. in 0.2×SSC, at 42° C. in 50% formamide, 4×SSC, or under conditions that afford levels of hybridization equivalent to those observed under either of these two conditions".
[0049] In an alternative manner, a sequence "specifically hybridizable" to a target sequence means a sequence showing a percentage of sequence identity with the sequence complementary of said target sequence of at least about 70%, preferably at least about 80%, more preferably at least about 90%, most preferably at least about 95%.
[0050] Said nucleic acid according to the invention may be an oligonucleotide.
[0051] Preferably, said nucleic acid or oligonucleotide is complementary to a region of the KIAA1840 gene that contains at least one of the identified mutations.
[0052] In one embodiment of this aspect of the invention, the isolated nucleic acid according to the invention consists of at least 10 nucleotides, preferably 20 nucleotides, more preferably 40 nucleotides.
[0053] Such a nucleic acid according to the invention may advantageously be used as a primer or probe.
[0054] A further object of the present invention relates to an isolated nucleic acid, which comprises or consists in a KIAA1840 gene coding sequence (SEQ ID NO:1) that contains one or several mutation(s) selected from the group consisting of [0055] the substitutions: c.6100C>T, c.2198T>G, c.118C>T, c.1235C>G, c.2833A>G, c.1951C>T, c.869+1G>A, c. 1679 C>G, c.2316+1G>A, c.2444G>T, c.2444+1G>C, c.2697G>A, c.5470C>T, c.5870C>G, c.6091C>T, c.6477+4 A>G, c.6856C>T, c.1282A>T c.5974C>T, [0056] the deletions: c.529-533delATATT, c.6451delG, c.6832--6833delAG, c.1203delA, c.1549--1550delCT, c.6737--6740delTTGA, c.1471--1472delCT, c.1692delA, c.2716delC, c.1668delT, c.704--705delAT, c.5989--5992delCTGT, c.5532--5533delCA, c.5769delT, c.6739--6742delGAGT, c.4307--4308delAA c.733--734delAT, and [0057] the insertions: c.7029--7030insT, c.2850--2851insT, c.3741--3742insA, c.5982--5983insCTCT, c.5986--5987insT, c.3075--3076insA c.2842--2843insG or a sequence complementary thereto.
[0058] In one embodiment of this aspect of the invention, the isolated nucleic acid according to the invention consists of at least 10 nucleotides, preferably 20 nucleotides, more preferably 40 nucleotides.
[0059] In another embodiment, the invention relates to an isolated polypeptide which comprises the polypeptide sequence of KIAA1840 containing one or several mutation(s) selected from the group consisting of p.Q40X, p.I177_F178delfsX178, p.H235RfsX246, p.M245VfsX246, p.K401KfsX415, p.S412X, p.K428X, p.L491 DfsX556, p.L517LfsX556, p.F556LfsX577, p.S560X, p.V564VfsX577, p.R651X, p.L733X, p.R815M, p.W899X, p.Q906SfsX920, p.R945G, p.R945GfsX950, p.L950FfsX953, p.V948GfsX953, p.E1026RfsX1029, p.P1248TfsX1264, p.Q1436RfsX1442, p.R1824X, p.S1844SfsX1857, p.S1923RfsX1950, p.S1957X, p.R1992X, p.L1995LfsX2000, p.C1996LfsX1999, p.L1997--1998delfsX2056, p.R2031X, p.R2034X, p.A2151PfsX2172, p.I2246_E2247delfsX2260, p.E2247_S2248delfsX2260, p.S2278LfsX2338, p.R2286X and p.V2344CfsX2349.
Diagnostic Method
[0060] The inventors have further shown that KIAA1840mutants are associated with a hereditary spastic paraplegias (HSP) which is characterized by weakness, spasticity and often loss of vibration sense in the lower limbs. More particular, the inventors have shown that KIAA1840 mutations as above described correlate in all patients with mild mental impairment, a thin corpus callosum (TCC) (AR-HSP-TCC) and frequent polyneuropathy (72% of the patients) in a series of 45 families with the full clinical criteria of SPG11. In the 2 other kindreds, cerebral imaging was not available to verify the presence of a thin corpus callosum (TUN2 and TUN14).
[0061] Therefore the invention provides an ex vivo method of diagnosing or predicting a hereditary spastic paraplegia (HSP) in a subject, which method comprises detecting a mutation in the KIAA1840 gene or protein (spatacsin), as compared to a control population, wherein the presence of a mutation is indicative of an hereditary spastic paraplegia (HSP).
Nucleic Acids Assays:
[0062] According to a first embodiment the mutations may be detected by analysing a KIAA1840 nucleic acid molecule. In the context of the invention, KIAA1840 nucleic acid molecules include mRNA, genomic DNA and cDNA derived from mRNA. DNA or RNA can be single stranded or double stranded. These may be utilized for detection by amplification and/or hybridization with a probe, for instance.
[0063] Thus the invention provides an ex vivo method of diagnosing or predicting a hereditary spastic paraplegia (HSP), in a subject, which method may comprise the step consisting of detecting a KIAA1840 mutation in a nucleic acid sample obtained from the subject, wherein the presence of a mutation is indicative of a hereditary spastic paraplegia (HSP).
[0064] The nucleic acid sample may be obtained from any cell source or tissue biopsy. Non-limiting examples of cell sources available include without limitation blood cells, buccal cells, epithelial cells, fibroblasts, or any cells present in a tissue obtained by biopsy or post-mortem. Cells may also be obtained from body fluids, such as blood, plasma, serum, lymph, etc. DNA may be extracted using any methods known in the art, such as described in Sambrook et al., 1989. RNA may also be isolated, for instance from tissue biopsy, using standard methods well known to the one skilled in the art such as guanidium thiocyanate-phenol-chloroform extraction (Chomocyznski et al., 1987).
[0065] A KIAA1840 mutation according to the invention may be found and located in many exons, including exon 1 and exon 39 (Table 2).
[0066] KIAA1840 mutations may be detected in a RNA or DNA sample, preferably after amplification. For instance, the isolated RNA may be subjected to coupled reverse transcription and amplification, such as reverse transcription and amplification by polymerase chain reaction (RT-PCR), using specific oligonucleotide primers that are specific for a mutated site or that enable amplification of a region containing the mutated site. According to a first alternative, conditions for primer annealing may be chosen to ensure specific reverse transcription (where appropriate) and amplification; so that the appearance of an amplification product be a diagnostic of the presence of a particular KIAA1840 mutation. Otherwise, RNA may be reverse-transcribed and amplified, or DNA may be amplified, after which a mutated site may be detected in the amplified sequence by hybridization with a suitable probe or by direct sequencing, or any other appropriate method known in the art. For instance, a cDNA obtained from RNA may be cloned and sequenced to identify a mutation in KIAA1840 sequence.
[0067] Actually numerous strategies for genotype analysis are available (Antonarakis et al., 1989; Cooper et al., 1991; Grompe, 1993). Briefly, the nucleic acid molecule may be tested for the presence or absence of a restriction site. When a base substitution mutation creates or abolishes the recognition site of a restriction enzyme, this allows a simple direct enzymatic test for the mutation. Further strategies include, but are not limited to, direct sequencing, restriction fragment length polymorphism (RFLP) analysis; hybridization with allele-specific oligonucleotides (ASO) that are short synthetic probes which hybridize only to a perfectly matched sequence under suitably stringent hybridization conditions; allele-specific PCR; PCR using mutagenic primers; ligase-PCR, HOT cleavage; denaturing gradient gel electrophoresis (DGGE), temperature denaturing gradient gel electrophoresis (TGGE), single-stranded conformational polymorphism (SSCP) and denaturing high performance liquid chromatography (DHPLC) (Kuklin et al., 1997). Direct sequencing may be accomplished by any method, including without limitation chemical sequencing, using the Maxam-Gilbert method; by enzymatic sequencing, using the Sanger method; mass spectrometry sequencing; sequencing using a chip-based technology (see e.g. Little et al., 1996); and real-time quantitative PCR. Preferably, DNA from a subject is first subjected to amplification by polymerase chain reaction (PCR) using specific amplification primers. However several other methods are available, allowing DNA to be studied independently of PCR, such as the rolling circle amplification (RCA), the Invader® assay, or oligonucleotide ligation assay (OLA). OLA may be used for revealing base substitution mutations. According to this method, two oligonucleotides are constructed that hybridize to adjacent sequences in the target nucleic acid, with the join sited at the position of the mutation. DNA ligase will covalently join the two oligonucleotides only if they are perfectly hybridized (Nickerson et al., 1990).
[0068] The inventors designed a series of primers, manually or using Oligo6 (MBI, Cascade, Colo.), in order to amplify all coding exons of 18 genes from the candidate interval (primers and conditions available on request), including the mutated KIAA1840 gene (see Table 4). PCR-amplified fragments of genomic DNA were then purified using exonuclease 1 (New England Biolabs, 2 U/5 μl PCR product) and shrimp alkaline phosphatase (Roche, 1 U/5 μl of PCR product) and sequenced using the fluorescent dideoxy-terminator method (BigDye v3, Applied Biosystem) on an automated ABI-3730 sequencer according to the manufacturer's recommendations. With the use of the software package SeqScape (Applied Biosystems), sequences were aligned and compared to consensus sequences.
[0069] Protein Assays
[0070] According to a second embodiment said mutation may be detected in KIAA1840 protein or a truncated form of the KIAA1840 protein may be detected, as compared to a control population.
[0071] All of the identified mutations of the KIAA840 gene create some deletions of the C-terminal part of the spatacsin protein, in some cases because of aberrant splicing (FIG. 5). These deletions result in truncated proteins of sequences SEQ ID NO: 149 to SEQ ID NO:164 and SEQ ID NO:166 to SEQ ID NO:188, respectively. Those due to aberrant splicing, either very likely, could not be precised because the modification of the splicing could not be evidenced in mRNA directly, except in family FSP670 (r.2834+1--2834+65ins, p.R945GfsX950). It can not be excluded, however, that a shorten protein fragment may be synthesized due to the activation of new ATGs after the stop codon.
[0072] Said mutation may be detected according to any appropriate method known in the art. In particular a sample, such as a tissue biopsy, obtained from a subject may be contacted with antibodies specific of the mutated form of KIAA1840 protein, i.e. antibodies that are capable of distinguishing between a mutated form of KIAA1840 and the wild-type protein (or any other protein), to determine the presence or absence of a KIAA1840 specified by the antibody. An antibody recognizing the wild type protein could also be used to check the presence of the protein or its abnormal location or size and could then be used as a diagnostic tool as well.
[0073] Antibodies that specifically recognize a mutated KIAA1840 protein also make part of the invention. The antibodies are specific of mutated KIAA1840 protein, that is to say they do not cross-react with the wild-type KIAA1840 protein.
[0074] A monoclonal or polyclonal antibody recognizing the wild-type KIAA1840 protein may be used to detect the presence of the wild-type protein or one of its truncated forms. For instance, an antibody recognizing the N-terminal part of the wild-type KIAA1840 protein may also recognize one or several truncated forms and can be used to reveal by immunoblotting, the different forms, wild-type and truncated, according to their molecular weights. An antibody recognizing the wild-type KIAA1840 protein, but not recognizing the truncated forms, can be used for immunoblotting or in immunoassay as ELISA; in that case, an absence of signal reveals the presence of a truncated form in the sample or the absence of synthesis of a stable protein as compared with a positive control comprising the wild-type KIAA1840 protein.
[0075] The antibodies of the present invention may be monoclonal or polyclonal antibodies, single chain or double chain, chimeric antibodies, humanized antibodies, or portions of an immunoglobulin molecule, including those portions known in the art as antigen binding fragments Fab, Fab', F(ab')2 and F(v). They can also be immunoconjugated, e.g. with a toxin, or labelled antibodies.
[0076] Whereas polyclonal antibodies may be used, monoclonal antibodies are preferred for since they are more reproducible in the long run.
[0077] Procedures for raising "polyclonal antibodies" are also well known. Polyclonal antibodies can be obtained from serum of an animal immunized against the spatacsin complex, which may be produced by genetic engineering for example according to standard methods well-known by one skilled in the art. Typically, such antibodies can be raised by administering mutated KIAA1840 protein or peptides of this protein subcutaneously to New Zealand white rabbits which have first been bled to obtain pre-immune serum. The antigens can be injected at a total volume of 100 μl per site at six different sites. Each injected material may contain adjuvants with or without pulverized acrylamide gel containing the protein or polypeptide after SDS-polyacrylamide gel electrophoresis. The rabbits are then bled two weeks after the first injection and periodically boosted with the same antigen three times every six weeks. A sample of serum is then collected 10 days after each boost. Polyclonal antibodies are then recovered from the serum by affinity chromatography using the corresponding antigen to capture the antibody. This and other procedures for raising polyclonal antibodies are disclosed by Harlow et al. (1988) which is hereby incorporated in the references.
[0078] A "monoclonal antibody" in its various grammatical forms refers to a population of antibody molecules that contains only one species of antibody combining site capable of immunoreacting with a particular epitope. A monoclonal antibody thus typically displays a single binding affinity for any epitope with which it immunoreacts. A monoclonal antibody may therefore contain an antibody molecule having a plurality of antibody combining sites, each immunospecific for a different epitope, e.g. a bispecific monoclonal antibody. Although historically a monoclonal antibody was produced by immortalization of a clonally pure immunoglobulin secreting cell line, a monoclonally pure population of antibody molecules can also be prepared by the methods of the present invention.
[0079] Laboratory methods for preparing monoclonal antibodies are well known in the art (see, for example, Harlow et al., 1988). Monoclonal antibodies (mAbs) may be prepared by immunizing purified mutated KIAA1840 protein into a mammal, e.g. a mouse, rat, human and the like mammals. The antibody-producing cells in the immunized mammal are isolated and fused with myeloma or heteromyeloma cells to produce hybrid cells (hybridoma). The hybridoma cells producing the monoclonal antibodies are utilized as a source of the desired monoclonal antibody. This standard method of hybridoma culture is described in Kohler and Milstein (1975).
[0080] While mAbs can be produced by hybridoma culture the invention is not to be so limited. Also contemplated is the use of mAbs produced by an expressing nucleic acid cloned from a hybridoma of this invention. That is, the nucleic acid expressing the molecules secreted by a hybridoma of this invention can be transferred into another cell line to produce a transformant. The transformant is genotypically distinct from the original hybridoma but is also capable of producing antibody molecules of this invention, including immunologically active fragments of whole antibody molecules, corresponding to those secreted by the hybridoma. See, for example, U.S. Pat. No. 4,642,334 to Reading; PCT Publication No.; European Patent Publications No. 0239400 to Winter et al. and No. 0125023 to Cabilly et al.
[0081] Antibody generation techniques not involving immunisation are also contemplated such as for example using phage display technology to examine naive libraries (from non-immunised animals); see Barbas et al. (1992), and Waterhouse et al. (1993).
[0082] Antibodies raised against mutated KIAA1840 protein may be cross reactive with wild-type KIAA1840 protein. Accordingly a selection of antibodies specific for mutated KIAA1840 protein is required. This may be achieved by depleting the pool of antibodies from those that are reactive with the wild-type KIAA1840 protein, for instance by submitting the raised antibodies to an affinity chromatography against wild-type KIAA1840 protein.
[0083] Alternatively, binding agents other than antibodies may be used for the purpose of the invention. These may be for instance aptamers, which are a class of molecule that represents an alternative to antibodies in term of molecular recognition. Aptamers are oligonucleotide or oligopeptide sequences with the capacity to recognize virtually any class of target molecules with high affinity and specificity. Such ligands may be isolated through Systematic Evolution of Ligands by EXponential enrichment (SELEX) of a random sequence library, as described in Tuerk C. and Gold L., 1990. The random sequence library is obtainable by combinatorial chemical synthesis of DNA. In this library, each member is a linear oligomer, eventually chemically modified, of a unique sequence. Possible modifications, uses and advantages of this class of molecules have been reviewed in Jayasena S. D., 1999. Peptide aptamers consists of a conformationally constrained antibody variable region displayed by a platform protein, such as E. coli Thioredoxin A that are selected from combinatorial libraries by two hybrid methods (Colas et al., 1996).
Kits
[0084] According to another aspect of the invention, the KIAA1840 mutation is detected by contacting the DNA of the subject with a nucleic acid probe, which is optionally labeled.
[0085] Primers may also be useful to amplify, analyse (dHPLC, Southern . . . ) or sequence the portion of the KIAA1840 gene containing the mutated positions of interest.
[0086] Such probes or primers are nucleic acids that are capable of specifically hybridizing with a portion of the KIAA1840 gene sequence containing the mutated positions of interest. That means that they are sequences that hybridize with the portion mutated KIAA1840 nucleic acid sequence to which they refer under conditions of high stringency.
[0087] The present invention further provides kits suitable for determining at least one of the mutations of the KIAA1840 gene.
[0088] The kits may include the following components:
[0089] (i) a probe, usually made of DNA, and that may be pre-labelled. Alternatively, the probe may be unlabelled and the ingredients for labelling may be included in the kit in separate containers; and
[0090] (ii) hybridization reagents: the kit may also contain other suitably packaged reagents and materials needed for the particular hybridization protocol, including solid-phase matrices, if applicable, and standards.
[0091] In another embodiment, the kits may include:
[0092] (i) sequence determination or amplification primers: sequencing primers may be pre-labelled or may contain an affinity purification or attachment moiety; and
[0093] (2) sequence determination or amplification reagents: the kit may also contain other suitably packaged reagents and materials needed for the particular sequencing amplification protocol. In one preferred embodiment, the kit comprises a panel of sequencing or amplification primers, whose sequences correspond to sequences adjacent to at least one of the polymorphic positions, as well as a means for detecting the presence of each polymorphic sequence.
[0094] In a particular embodiment, it is provided a kit which comprises a pair of oligonucleotide primers specific for amplifying all or part of the KIAA1840 gene comprising at least one of the mutated positions that are identified above (see Table 2).
[0095] More preferably, the kits of the invention comprise a pair of primers selected from the pairs shown in Table 3 either for detection by direct sequencing or by screening by dHPLC when they could be set-up (second set of primer pairs).
TABLE-US-00003 TABLE 3 Primers used for PCR or for dHPLC (in parentheses) SEQ ID Exons Mutations For/Rev primers NO: 1 c.118C > T, p.Q40X ccacaggaaacgaatggaat/ggttctgtgaggaaaccacg 3/4 3 c.529_533delATATT, cagggacattgtaggccatc/tcccagctcccaaaactaaa 5/7 p.I177_F178delfsX (ccagttgtaaaattgtgacc)/(tcaatcaacacttctaccac) (6)/(8) 4 c.733_734delAT, caggttctttcttgtggcatca/cgaggatatttttaacctcttatca 9/10 p.M245VfsX (gttaggcatacttacaaaactggc)/(cgaggatatttttaacctcttatca) (11)/(12) c.704_705delAT, p.H235RfsX246 c.869 + 1G > A, r.? 6 c.1203delA, p.K401KfsX; gaacatctttgccctggttt/caggcactgaggcagaagta 13/15 c.1235C > G, p.S412X (ctgtgacaggtgttaagtta)/(atctaatacaagacagtctc) (16) c.1282A > T, p.K428X 7 c.1549_1550delCT, aaaaatcaattcctaaatcataatcc/tcttttaaagccaaaaagggtaaa 17/19 p.L517LfsX (tagtactgaagtattgagta)/(ttaagtaatgttcttgggca) (20) 8 c.1668delT, cttgccccagattgcataat/tccaaaaagtacgtaaaatccca 57/58 p.F556LfsX577 c.1679C > G, p.S560X c.1692delA, p.V564VfsX577 10 c.1951C > T, p.R651X cccaggactaatcatgaagga/atccccaaaccgataaaacc 21/22 11 c.2198T > G, p.L733X cggtgtgtcttccactagctc/acccagccattctcagtgtt 23/25 (gttacataaatgtataatccctg )/(cattttaagactttatggattac) (24)/(26) 12 c.2316 + 1G > A, r.? tttgaaagagcagaaagctatgg/tgaaggggttgtcacactttt 61/62 13 c.2444G > T, p.R815M ttgtggcaaaagaaaatttgtg/gagaatgcaggctcagttcc 63/64 and/or r.? c.2444 + 1G > C, r.? 15 c.2833A > G, cacagcgagatcctgtctca/cctcactgtaagatgatgccc 27/28 r.2834 + 1_2834 + 65ins, p.R945GfsX950 or p.R945G c.2697G > A, p.W899X c.2716delC, pQ906SfsX920 16 c.2842_2843insG, cctttaaatactacagtggtgcaga/ccaactgttgagatggagaaaa 29/31 p.V948GfsX; (tgtgggcatgatttggtcta)/(acctgctcaaggacaaatgc) (30)/(32) c.2850_2851insT, p.L950FfsX 17 c.3075_3076insA, ttgtttccagatcatgaagaatatg/tcagatagctgaccacagcc 67/68 p.E1026RfsX1029 22 c.3741_3742insA, agtcagcttaagggaagcgg/gaagataaccattttctcccca 77/78 p.P1248TfsX1264 25 c.4307_4308delAA, aaaaggcaccatacagctttg/ggaaacacatgctggaacct 83/84 p.Q1436RfsX1442 30 c.5470C > T, p.R1824X tgaggtgggaggatctcttg/gatgtgttcagagcagccaa 93/94 c.5532_5533delCA, and p.S1844SfsX1857 taagctggaggagctggaga/ttgttgtccccttaacttgg 95/96 c.5769delT, p.S1923RfsX1950 31 c.5974C > T, p.R1992X tttgaagtatcccagggtgg/ccaccattccccaaagataa 33/34 c.5870C > G, p.S1957X c.5982_5983insCTCT, p.L1995LfsX2000 c.5986_5987insT, p.C1996LfsX1999 c.5989_5992delCTGT, p.L1997_Y1998 > M1997fs X2056 32 c.6100C > T, R2034X ttacctggatttggctttgg/tgcaatccagaaacttgagaga 35/37 c.6091C > T, p.R2031X (cctggcttctaaaagtggcc)/(aagcacaacatccaaatcctt) (36)(38) 34 c.6451delG, p.A2151PfsX atgttggcaggaactccatc/ctcctttggagcaacctctg 39/40 c.6477 + 4 A > G, r.? 36 c.6737_6740delTTGA, ttccaacaggaaagcacaca/cagctacttgggaggctgag 41/43 p.I2246_E2247delfsX (caacaggaaagcacacatgc)/(gtgtggctgtgacctcactc) (42)/(44) c.6739_6742delGAGT, p.E2247_S2248 > L2247fs X2260 37 c.6832_6833delAG, gcattagaaggggcactgaa/ctcacaacggtattcacccc 45/47 p.S2278LfxX (aacatggctgggatgtttct)/(ttcctggttggcctatgatg) (46)/(48) 38 c.6856C > T, p.R2286X ttttgtccttgggctctttc/cctggttctgtcactagccc 101/102 39 c.7029_7030insT, aagggtttaagataatttgggga/ggattcttgatactgctttgcc 49/51 p.V2344CfsX (aatgccaaacacacacctga)/(ctcaaagcagaggcaaggag) (50)/(52)
Therapeutic Methods
[0096] The inventors have demonstrated that the all, except one, mutations identified in the KIAA1840 gene cause truncation of the protein, suggesting that pathogenicity results from loss of function.
[0097] These results identify mutated KIAA1840 gene as target for the preventive or curative treatment of a hereditary spastic paraplegia.
[0098] Thus the invention further relates to a method of treatment of an HSP which comprises the step of administering a subject in need thereof with a KIAA1840 nucleic acid, i.e. a nucleic acid sequence that encodes a wild-type KIAA1840 protein, so that spatacsin is expressed in vivo by the cells of the subject that have been transfected with said nucleic acid. Accordingly, said method leads to an overexpression of wild-type spatacsin which compensates expression of defective mutated KIAA1840 protein.
[0099] The invention also relates to the use of a KIAA1840 nucleic acid for the manufacture of a medicament intended for the treatment of an HSP.
[0100] In the context of the invention, the term "treating" or "treatment", as used herein, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
[0101] Preferably said KIAA1840 nucleic acid is administered in a therapeutically effective amount. A "therapeutically effective amount" is intended for a minimal amount of active agent (e.g., KIAA1840 nucleic acid) which is necessary to impart therapeutic benefit to a subject. For example, a "therapeutically effective amount" to a mammal is such an amount which induces, ameliorates or otherwise causes an improvement in the pathological symptoms, disease progression or physiological conditions associated with or resistance to succumbing to a disorder.
[0102] The administered polynucleotide comprises the nucleotide sequence SEQ ID NO:1, or any homologous or similar sequence as defined below:
[0103] a) a sequence showing at least 70%, preferably at least 75% or 80% or 85% or 90% or 95% or 99%, sequence similarity with SEQ ID NO:1;
[0104] b) a sequence hybridizing with SEQ ID NO:1, or its complementary sequence, under stringent conditions;
[0105] c) a sequence encoding a protein of sequence SEQ ID NO:2, or any sequence substantially similar with SEQ ID NO:2.
[0106] The term "sequence similarity" in all its grammatical forms refers to the degree of identity or correspondence between nucleic acid or amino acid sequences of proteins that may or may not share a common evolutionary origin. Preferably the degree of sequence identity is calculated compared with the totality of a reference sequence.
[0107] In a specific embodiment, two DNA sequences are "substantially homologous" or "substantially similar" when at least 70%, preferably at least 75% or 80% or 85% or 90% or 95% or 99%, of the nucleotides match over the defined length of the DNA sequences, as determined by sequence comparison algorithms, such as BLAST, FASTA, DNA Strider, etc. Sequences that are substantially homologous can be identified by comparing the sequences using standard software available in sequence data banks, or in a Southern hybridization experiment under, for example, stringent conditions as defined for that particular system.
[0108] Similarly, in a particular embodiment, two amino acid sequences are "substantially similar" when greater than 80%, preferably than 85% or 90% or 95% or 99%, of the amino acids are similar (functionally identical). "Functionally identical" polypeptides are those in which a given amino acid residue has been changed without altering the overall conformation and function of the polypeptide, including, but not limited to, replacement of an amino acid with one having similar properties (such as, for example, polarity, hydrogen bonding potential, acidic, basic, hydrophobic, aromatic, and the like). Amino acids with similar properties are well known in the art. For example, arginine, histidine and lysine are hydrophilic-basic amino acids and may be interchangeable. Similarly, isoleucine, a hydrophobic amino acid, may be replaced with leucine, methionine or valine. Such changes are expected to have little or no effect on the apparent molecular weight or isoelectric point of the protein or polypeptide. Preferably, the similar sequences are identified by alignment using, for example, the GCG (Genetics Computer Group, Program Manual for the GCG Package, Version 7, Madison, Wis.) pileup program, or any of the programs described above (BLAST, FASTA, etc.).
[0109] Preferably the KIAA1840 nucleic acid sequence according to the invention is associated with elements that enable for regulation of its expression, such as a promoter sequence.
[0110] Such a nucleic acid may be in the form of a DNA vector. The terms "vector" means the vehicle by which a DNA or RNA sequence (e.g. a foreign gene) can be introduced into a host cell, so as to transform the host and promote expression (e.g. transcription and translation) of the introduced sequence. A common type of vector is a "plasmid", which generally is a self-contained molecule of double-stranded DNA, usually of bacterial origin, that can readily accept additional (foreign) DNA and which can readily introduced into a suitable host cell. A plasmid vector often contains coding DNA and promoter DNA and has one or more restriction sites suitable for inserting foreign DNA.
[0111] The KIAA1840 nucleic acid may be introduced into a target cell by means of any procedure known for the delivery of nucleic acids to the nucleus of cells, ex vivo, on cells in culture or removed from an animal or a patient, or in vivo.
[0112] Ex vivo introduction may be performed by any standard method well known by one skilled in the art, e.g. transfection, electroporation, lipofection, microinjection, transduction, cell fusion, DEAE dextran, calcium phosphate precipitation, or use of a gene gun.
[0113] The above methods do not limit the scope of the invention and it is to be understood that the one skilled in the art may readily make use of any other known appropriate methods for delivering a nucleic acid to a cell in vivo or in vitro.
[0114] The invention also relates to the use of wild-type KIAA1840 protein (spatacsin) for the manufacture of a medicament intended for the treatment of an HSP.
[0115] Thus the invention further relates to a method of treatment of an HSP which comprises the step of administering a subject in need thereof with a therapeutically effective amount of wild-type KIAA1840 protein.
[0116] The KIAA1840 protein may be introduced to a target cell by means of any procedure known for the delivery of proteins to cells, ex vivo, on cells in culture or removed from an animal or a patient, or in vivo.
[0117] Protein delivery is the process by which a protein crosses the cell plasma membrane. Traditionally, methods to introduce antibodies, peptides or other membrane-impermeable molecules into cells include micro-injection and electroporation.
[0118] A number of protein-transduction domains (PTDs) have also been developed that mediate protein delivery into cells. These PTDs or signal peptide sequences are naturally occurring polypeptides of 15 to 30 amino acids, which normally mediate protein secretion in the cells. They are composed of a positively charged amino terminus, a central hydrophobic core and a carboxyl-terminal cleavage site recognized by a signal peptidase. Examples of such membrane-transducing peptides include Trojan peptides, human immunodeficiency virus (HIV)-1 transcriptional activator (TAT) protein or its functional domain peptides, and other peptides containing protein-transduction domains (PTDs) derived from translocation proteins such as Drosophilia homeotic transcription factor Antennapedia (Antp) and herpes simplex virus DNA-binding protein, VP22, and the like. Some commercially available peptides, for example, penetratin 1, Pep-1 (Chariot reagent, Active Motif Inc., CA) and HIV GP41 fragment (519-541), can be used for protein delivery.
[0119] Recently, the use of lipid liposomes or the like that can complex with a protein of interest and promote the delivery of the protein into the cell has also been demonstrated. Products available commercially can be used, such as BioPORTER (Gene Therapy Systems), or ProVectin (Imgenex, San Diego, Calif.).
[0120] The above methods do not limit the scope of the invention and it is to be understood that the one skilled in the art may readily make use of any other known appropriate methods for delivering a protein to a cell in vivo or in vitro.
[0121] The invention will be further illustrated by the following figures and examples.
FIGURES
[0122] FIGS. 1 and 2: Multipoint linkage analysis performed in 16 families for 34 microsatellite markers from chromosome 15q. cM=centimorgan.
[0123] (FIG. 1) Multipoint LOD score values for each family, * Relative position on the genetic map of chromosome 15 (according to http://research.marshfieldclinic.org/genetics).
[0124] (FIG. 2) Cumulative multipoint LOD scores in the 16 linked-families plotted according to the genetic map of chromosome 15.
[0125] FIGS. 3 and 4: Pedigrees of 2 SPG11 families that reduced the candidate interval. Black circles (women) and squares (men) indicate affected members compared to previous publications. The numbers are an internal reference for each sampled individual. Asterisks indicate sampled subjects. Haplotype reconstruction for selected microsatellite markers positioned according to the human genome draft sequence (www.ncbi.nlm.nih.gov, www.ensembl.org) is shown. The homozygous haplotype, in which the mutated gene has been located, is flanked by black boxes. Arrowheads indicate the position of probable recombination events. cM=centimorgan (according to http://research.marshfieldclinic.org/genetics).
[0126] FIG. 5: Critical region of SPG11. (a) Physical map of human chromosome 15q15-21 with selected genetic markers and candidate genes that were sequenced. Distances in megabases are indicated relative to chromosome 15 according to the Ensembl database. Markers defining the reduced candidate interval are in bold. # indicates that these genes (SEMA6D and MAP1A) were analyzed in a previous study(Stevanin et al, 2006). > and < indicate the orientation of the open reading frame (ORF) of each gene. (b) Exon-intron structure of the 101 Kb of the KIAA1840 gene, also known as FLJ21439, with positions of mutations identified in 17 SPG11 families. (c) Putative functional domains (boxes) and their positions on the protein sequence. TM=transmembrane domains. Regions I and II correspond to structurally similar domains based on their hydrophobicity status analysed with DomHCA software.
[0127] FIGS. 6 to 17: Pedigrees and segregation of the 17 mutations detected in KIAA1840. Square symbols are men, the circles are women. The filled symbols are affected individuals, grey or ? symbols indicate patients with an unknown status. The numbers are an internal reference for each sampled individual. Stars indicate sampled subjects. M or m=mutation; +=wild type. Electrophoregrams are shown for the homozygous mutations only. (6, 7) Families with common origins sharing the same mutations. Haplotypes for three close microsatellites segregating with the mutations are highlighted. The correspondence between the numbering of alleles and their size in base pairs is indicated. (8, 10 to 14) Other homozygous mutations. (15) New homozygous mutations. (9, 16, 17) Compound heterozygous mutations.
[0128] FIG. 18: Internal structural duplication in spatacsin
[0129] (a) Hydrophobic cluster analysis (HCA) plots of the internal duplication of two regions in the human sequence. The HCA method is based on the use of a bidimensional plot (HCA plot) from the drawing of the 1D sequence on an alpha helix (3.6 residue/turn, connectivity distance of 4 residues separating two different clusters) which has been shown to offer the best correspondence between clusters and regular secondary structures. Examination of the HCA plot of a protein sequence enables globular regions to be easily distinguished from non globular ones and, in globular regions, secondary structures to be identified. This 2D signature, which is much more highly conserved than the 1D sequence and can be enriched from the comparison of families of highly divergent sequences, enables relevant similarities to be successfully detected at low levels of sequence identity. The form of the clusters is generally indicative of the type of secondary structures (vertical clusters are often associated with beta strands whereas horizontal ones often correspond to alpha helices). DomHCA software: http://www.lmcp.jussieu.fr/%7Emornon/hca.html. Special symbols are used for some amino acids: star for proline, square and dotted square for threonine and serine, diamond for glycine.
[0130] (b) Multiple alignment of the structural repeat domains (I and II, FIG. 3) corresponding to the HCA plots (DomHCA software). Under the multiple alignment, highly conserved residues are indicated by a capital letter when strictly conserved or in lower case if there is some homology. The character "&" means that this position is always occupied by a hydrophobic residue (amino acids FILMVW and Y).
[0131] FIG. 19: Expression profile of KIAA1840 examined by northern blot in human adult brain. The transcripts were present in all brain tissues. Note the 8-Kb transcript more intensely expressed in the cerebellum while the 5.5-Kb transcript is mainly found in the cerebral cortex.
[0132] Table 1: Exon-intron boundaries in the KIAA1840 gene
[0133] Table 2: Mutations found in the KIAA1840 gene in families with AR-HSP-TCC.
[0134] Table 3: Primers used for detecting the mutations either by direct sequencing or by dHPLC
[0135] Table 4: Primers used for the amplification of all exons of the KIAA1840 gene and PCR amplification conditions
[0136] Table 5: PCR conditions and dHPLC conditions to analyze exons of KIAA1840.
[0137] Table 6: dHPLC primers to analyze exons of KIAA1840
EXAMPLE
[0138] Method:
[0139] Subjects: 211 individuals, including 83 affected members and 44 non mutated members, from 91 families.
[0140] All patients were examined by a neurologist. They were selected among 216 families with hereditary spastic paraparesis compatible with recessive transmission collected in our neurogenetic reference center in collaboration with the SPATAX network. They presented a typical "SPG11" phenotype defined as the presence of progressive spastic paraparesis associated with thin corpus callosum on cerebral MRI and mental retardation and neuropathy.
[0141] Blood samples was obtained after written consent from all affected patients and their relatives with approval of the local Ethic committee of Paris-Necker (approval no Mar. 12, 2007 of the comite Consultatif pour Ia Protection des Personnes et la Recherche Biomedicale, to A.D). Genomic DNA was extracted from leukocytes using standard procedures.
[0142] Linkage analysis: The genome scan in family FSP221 was performed using 400 microsatellites, regularly spaced on all chromosomes (ABI-Prism mapping set v2, Applied Biosystems, Foster City, Calif.) and 50 additional polymorphic markers were used to analyze the results. Genotypes were determined by PCR with a fluorescently-labeled primer, electrophoretic migration in an ABI-3730 sequencer (Applied Biosystems) and analysis with Genescan 3.5 (Applied Biosystems). Allegro 1.2 c was used to calculate two-point and multipoint lod scores between the disease phenotype and each of the markers or the map of the markers assuming a complete penetrance, equal allele frequencies for the markers and a mutated allele frequency of 0.0005 (Gudbjartsson et al. 2000). Marker order and genetic distances were obtained from the Ensembl (http://www.ensembl.org) and Marshfield databases (http://research.marshfieldclinic.org/genetics), respectively.
[0143] Mutation detection: A series of primers was designed manually or using Oligo6 (MBI, Cascade, Colo.) in order to amplify all coding exons of 18 genes from the candidate interval (primers and conditions available on request). PCR-amplified fragments of genomic DNA were then purified using exonuclease 1 (New England Biolabs, 2 U/5 μl PCR product) and shrimp alkaline phosphatase (Roche, 1 U/5 μl of PCR product) and sequenced using the fluorescent dideoxy-terminator method (BigDye v3, Applied Biosystem) on an automated ABI-3730 sequencer according to the manufacturer's recommendations. With the use of the software package SeqScape (Applied Biosystems), sequences were aligned and compared to consensus sequences.
[0144] Primers used for the amplification of the KIAA1840 gene are listed in the following Table 4.
[0145] The conditions of the PCR programme are as follows:
[0146] 95° C., 12 min
[0147] then 40 cycles of: [0148] 95° C., 30 s [0149] Annealing Temperature (see Table 4), 30 s, [0150] 72° C., 30 s
[0151] then
[0152] 72° C., 10 min, and
[0153] 15° C., 15 min.
[0154] PCR were performed in 25 μl final volume using 10 pmol of each primer, at final concerntrations of 1.5 mM MgCl2 and 0.24 mM dNTP.
[0155] Taq pol, which is commercially available from Quiagen was used except for exons 6, 12 and 40B where Taq GOLD (Applied Biosystems) was used.
TABLE-US-00004 TABLE 4 Annealing SEQ ID Exon temperature NO : Forward primer Reverse primer ex1 60° C. 3/4 ccacaggaaacgaatggaat ggttctgtgaggaaaccacg ex2 60° C. 53/54 ctgagccccacatttttgtt caagtgctcaatagccccat ex3 60° C. 5/7 cagggacattgtaggccatc tcccagctcccaaaactaaa ex4 60° C. 9/10 caggttctttattgtggcatca cgaggatatttttaacctcttatca ex5 62° C. 55/56 gctaactgcccttaatagagtaaaa aaagggtacagcgtcagcat ex6 TD62-58 13/15 gaacatctttgccctggttt caggcactgaggcagaagta ex7 60° C. 17/19 aaaaatcaattcctaaatcataatcc tcttttaaagccaaaaagggtaaa ex8 60° C. 57/58 cttgccccagattgcataat tccaaaaagtacgtaaaatccca ex9 60° C. 59/60 cagcaaaagggtaatagcagtg cccaaatgtagtaaatggcg ex10 60° C. 21/22 cccaggactaatcatgaagga atccccaaaccgataaaacc ex11 60° C. 23/25 cggtgtgtcttccactagctc acccagccattctcagtgtt ex12 TD62-58 61/62 tttgaaagagcagaaagctatgg tgaaggggttgtcacactttt ex13 60° C. 63/64 ttgtggcaaaagaaaatttgtg gagaatgcaggctcagttcc ex14 60° C. 65/66 atgtggaactgagcctgcat cgacttgcattttaaagaacctg ex15 60° C. 27/28 cacagcgagatcctgtctca cctcactgtaagatgatgccc ex16 62° C. 29/31 cctttaaatactacagtggtgcaga ccaactgttgagatggagaaaa ex17 56° C. 67/68 ttgtttccagatcatgaagaatatg tcagatagctgaccacagcc ex18 60° C. 69/70 tccctcttaaggagaaaaacactg accgggccgagatataaaat ex19 60° C. 71/72 gctagtttgtcttagaaccagaaca ttttgggttgtctcactatcaca ex20 60° C. 73/74 aaggaacatagccagttctgtttt tgcgaactatttttcctttgg ex21 60° C. 75/76 tgcaacttctcaggtacacatct aggctagagtgcagtggcat ex22 60° C. 77/78 agtcagcttaagggaagcgg gaagataaccattttctcccca ex23 60° C. 79/80 ttgtgagtgtttggggagaa ggggatttagtgaaaacacca ex24 64° C. 81/82 tttgttggagaatacactgtgctt catgtctacacaacagaaagaatgc ex25 60° C. 83/84 aaaaggcaccatacagctttg ggaaacacatgctggaacct ex26C 55° C. 85/86 cttctgtctgcttcttggtctt tatcatcattatctgttgttgg ex27 60° C. 87/88 ttaggtgatcccactggctc cccaggagttcaaggctgta ex28 60° C. 89/90 ctgaggagggcttgtttttg tctgtaacttgtttactcccagttg ex29 60° C. 91/92 gatcacaccactgcattcca ggcacctgtagtcccagcta ex30A 60° C. 93/94 tgaggtgggaggatctcttg gatgtgttcagagcagccaa ex30B 60° C. 95/96 taagctggaggagctggaga ttgttgtccccttaacttgg ex31 60° C. 33/34 tttgaagtatcccagggtgg ccaccattccccaaagataa ex32 60° C. 35/37 ttacctggatttggctttgg tgcaatccagaaacttgagaga ex33 60° C. 97/98 caataggccaagggtttcaa tataactcctgctggagggc ex34 62° C. 39/40 atgttggcaggaactccatc ctcctttggagcaacctctg ex35 60° C. 99/100 ggtagcctggaaattagccc tgaaccagaatctgaagcca ex36 62° C. 41/43 ttccaacaggaaagcacaca cagctacttgggaggctgag ex37 60° C. 45/47 gcattagaaggggcactgaa ctcacaacggtattcacccc ex38 60° C. 101/102 ttttgtccttgggctctttc cctggttctgtcactagccc ex39 60° C. 49/51 aagggtttaagataatttgggga ggattcttgatactgctttgcc ex40A 60° C. 103/104 aattagccagggtggtgaca cccacaaaggactgatatgg ex40B TD62-58 105/106 aaggaccctcagacaggttg tcctttaaggcagacaaggg TD = TouchDown 10 cycles decrease of annealing temperature, then 25 stablecycles. Temperatures in Celsius degrees.
[0156] For some exons, it was possible to set up dHPLC conditions to detect variants. Primers different from those used for direct sequencing were specifically designed but they can also be used for direct sequencing. The PCR conditions and dHPLC conditions are indicated on table 5.
TABLE-US-00005 TABLE 5 dHPLC conditions to analyze exons of KIAA1840. Temperature in Celsius degrees. Exon Size T ° PCR T ° DHPLC 2 323 62°-1'-35x 55.3° 3 305 58°-1'-35x 55.1° 4 320 62°-1'-35x 54.8°-52.8° 5 330 60°-1'-35x 54.9° 6 450 58°-1'-35x 54°-53° 7 275 58°-1'-35x 50.6°-52.6° 9 342 62°-1'-35x 54.1.sup. 11 293 57°-1'-35x 54.6° 12 210 62°-1'-35x 52.5° 13 289 62°-1'-35x 51.5° 14 246 62°-1'-35x 55.8° 16 309 62°-1'-35x 55.2° 17 239 62°-1'-35x 53.9° 18 324 58°-1'-35x 53°-50° 20 311 62°-1'-35x 52.3° 22 383 62°-1'-35x 55.8° 23 356 62°-1'-35x 53.1° 24 267 60°-1'-35x 57.1° 25 361 60°-1'-35x 56.6° 27 330 62°-1'-35x 53.6° 28 329 62°-1'-35x 53.5° 29 330 56°-1'-35x 54.2°-56.2° 32 323 60°-1'-35x 58.8° 33 349 62°-1'-35x 57.6° 35 312 62°-1'-35x 54° 36 376 62°-1'-35x 52° 37 313 62°-1'-35x 57.6° 38 315 62°-1'-35x 56.9° 39 380 62°-1'-35x 53.2° 40 390 62°-1'-35x 54.4° 40 321 58°-1'-35x 54.2°
TABLE-US-00006 TABLE 6 dHPLC primers to analyze exons of KIAA1840 Exon PRIMERS F (5'-3')/R (5'-3') SEQ ID NO: 2 accaggtcaactaaactgttctct/tatgctgaaagaccacctgtaga 107/108 3 ccagttgtaaaattgtgacc/tcaatcaacacttctaccac 6/8 4 gttaggcatacttacaaaactggc/cgaggatatttttaacctcttatca 11/12 5 caggagcagtagtaacacaa/aaagggtacagcgtcagcat 109/110 6 ctgtgacaggtgttaagtta/atctaatacaagacagtctc 14/16 7 tagtactgaagtattgagta/ttaagtaatgttcttgggca 18/20 9 gcaggtaataagcctgcagaa/cccccttcctagctgctatt 111/112 11 gttacataaatgtataatccctg/cattttaagactttatggattac 24/26 12 tgttcaaaatagttccattacaaaa/tttcttccaaggttttcttcca 113/114 13 tttgcaaaagtgcttgatttt/tgcaggctcagttccacata 115/116 14 ggaatgatgcctttttctcc/tctcacacttg ccttctgga 117/118 16 tgtgggcatgatttggtcta/acctgctcaaggacaaatgc 30/32 17 aatcatcgcctgagcaaaat/ccagtgactgatccaaagca 119/120 18 ccctcttaaggagaaaaacac/cagccttatcctctgctctt 121/122 20 tggaaaaggggagcagacta/tgcgaactatttttcctttgg 123/124 22 gaggaggccacaaatcacat/gccttagacctcgtcacacc 125/126 23 tgctcaggttttgactttttctc/tttcactgatggcaagatgc 127/128 24 accacccccacctctaattc/ctacacaacagaaagaatgc 129/130 25 ccagctgaaactgaaagttgg/ctgggtacttacttcaggct 131/132 27 cactgtgccctgccttatta/tgtgcctgagtaaccgagtg 133/134 28 tcccagatttggaggttttg/tgcattttaatttcctaactaccc 135/136 29 gctgtagtggcattttattg/cctgggtgacagagcaagac 137/138 32 cctggcttctaaaagtggcc/aagcacaacatccaaatcctt 36/38 33 agctgcagagctccataagc/taggcatccagagcaggaac 139/140 35 ggcatctgaaagcaaccact/ccctccattttcccaagagt 141/142 36 caacaggaaagcacacatgc/gtgtggctgtgacctcactc 42/44 37 aacatggctgggatgtttct/ttcctggttggcctatgatg 46/48 38 ggggtgaataccgttgtgag/acctctgggttccatgagtg 143/144 39 aatgccaaacacacacctga/ctcaaagcagaggcaaggag 50/52 40 agactgctcctctgcactcc/ccgggattgttcaactttagc 145/146 40 cagtatcttaacctgtacat/ccgggattgttcaactttagc 147/148
[0157] Overexpression studies: The KIAA1840 cDNA from clone pf01011 (Kazusa DNA research Institute, Japan) was excised from the pBluescript II SK(+) vector using XhoI/NotI restriction enzymes and cloned in fusion with EGFP in a Sall/Bsp1201 digested pEGFP-C1 vector (Clontech). The construction was verified by direct sequencing after ligation, transformation and plasmid extraction using standard procedures.
[0158] COS-7 cells were maintained in DMEM (Invitrogen) supplemented with 10% fetal bovine serum, penicillin (100 UI/ml) and streptomycin (100 μg/ml). Cells were plated 24 h before transfection on cover slips coated with polyethylenimine and transfected with Lipofectamine-PLUS reagents according to the manufacturer's instructions (Invitrogen). For 6-well plates, 1-2 μg of plasmid DNA was used per well. Cells were analyzed by immunofluorescence 120 h post-transfection. The spatacsin-EGFP fusion protein was observed directly after fixation for 15 min with 4% formaldehyde. Immunocytochemistry was performed, using classical procedures with the following antibodies: rabbit anti-Cox2 (1/200, kind gift of A. Lombes, Paris) and rabbit anti-alpha-COP (1/1000e; Affinity Bioreagent). Cells were counterstained with DAPI (1 μg/ml, Sigma) and mounted with Fluoromount-G (Southern Biotech). Samples were observed with a Leica SP1 confocal microscope. Leica confocal software was used to acquire the images.
[0159] Northern-Blot analysis (Human): Total RNA was extracted from the human post-mortem brain cortex of an healthy individual (Brain Bank of INSERM U679) using the RNAeasy Mini kit (Qiagen). The corresponding cDNAs were synthesized using random hexamers in the presence of Thermoscript reverse transcriptase as recommended by the supplier (Invitrogen). A series of 7 probes of 1.2 Kb covering the entire KIAA1840 cDNA was amplified by PCR at an annealing temperature of 60° C. (primer sequences available on request). Human multiple tissue northern blots (Clontech) were hybridized at 68° C. for 1 hour with a mix of these probes aP32-labeled by random priming (Prime-it II Random Primer Labeling kit, Stratagene) and purified using ProbeQuant G-50 micro columns (Amersham Biosciences) in accordance to the manufacturer's recommendations to reach a specific activity of at least 1×109 cpm/μg. Membranes were then washed as recommended by Clontech then exposed to X-Ray film for autoradiography.
[0160] In situ hybridization (rat): Young (P1, P6, P15 and P21, n=1 each) and adult (P68, 200 g, n=2) Sprague Dawley rats (Charles River) were killed by decapitation and their brains were rapidly extracted and frozen in isopentane at -50° C. Sections were prepared with a cryostat at -20° C., from medulla to striatum (+1.7 from bregma) 600 μm-spaced, thaw-mounted on glass slides and stored at -80° C. until usage. KIAA1840 mRNA expression was analyzed using 3 antisens oligonucleotides designed using Helios ETC oligo design software (Helios Biosciences, Paris, France) on the mRNA sequence (XM-242139) of Rattus norvegicus similar to hypothetical protein FLJ21439 (LOC311372). Each oligonucleotide or a mix of the 3 oligonucleotides were used for the hybridization step and gave identical results. A mix of three sens oligonucleotides was used as a negative control.
[0161] In situ hybridization was performed as described in Moutsimilli et al. (2005) Briefly, oligonucleotides were labeled with [35S]-dATP (Amersham Biosciences) using terminal transferase (Amersham Biosciences) to a specific activity of 5×108 dpm/μg. The day of the experiment, slides were fixed in 4% formaldehyde in PBS, washed with PBS, rinsed with water, dehydrated in 70% ethanol and air-dried. Sections were then covered with 140 μl of hybridization medium (Helios Biosciences, Paris, France) containing 3-5×105 dpm of the labeled oligonucleotide mix. Slides were incubated overnight at 42° C., washed and exposed to a BAS-SR Fujifilm Imaging Plate for 5-10 days. The plates were scanned with a Fujifilm Biolmaging Analyzer BAS-5000 and analyzed with Multi Gauge Software (Fuji).
[0162] For double labeling experiments, brains were processed as for in situ hybridization. After the last wash step, sections were fixed in 4% paraformaldehyde in PBS and preincubated in PBS containing 6% goat serum and 0.1% triton. Sections were next incubated with mouse antibodies directed against Neu-N (Chemicon International, 1/250), in the same buffer, processed with biotinylated horse anti-mouse IgG antibodies and ABC reagents (Vector Laboratories, Burlingame, Calif.) and submitted to emulsion autoradiography. The labeling with the antisense probe in comparison with the Neu-N neuronal specific counterstaining was observed.
[0163] Bioinformatics: Functional domains were searched using bioinformatics tools available online at BABEL (http://babel.infobiogen.fr:1984/), Ressource Parisienne en Bioinformatique Structurale (http://bioserv.rpbs.jussieu.fr/RPBS) and PSORT (http://psort.nibb.ac.jp/). Psi-blast (www.ncbi.nlm.nih.gov) was used to look for homologous proteins or peptides. Alignment of homologous proteins was performed using CLUSTALW (http://www.ebi.ac.uk/clustalw/). Alteration of splicing sites was verified in the Alternative Splicing Database at http://rulai.cshl.edu/new_alt_exon_db2/HTML/score.html.
[0164] HCA is a method that allows to represent a protein sequence on a bidimensional scaffold that increases the density of the amino acids, and consequently, evidences local compacity of hydrophobic residues. They form clusters according to a connectivity that is the one of an alpha helix. It has been shown that the centers of the clusters and the centers of the secondary structures statistically match, (Woodcocks et al. 1992) and on the other hand the shape of a cluster is related to the nature of the secondary structure (Callebaut et al. 1997). HCA is a very efficient tool for recovery of highly divergent internal duplication of domains and for the detection of globular domain limits.
[0165] Results:
[0166] We selected a series of 91 families of European or North-African origins, all without mutations in the SPG7 gene and with a typical AR-HSP-TCC phenotype. Six of these families were previously reported as linked to SPG11 using a subset of polymorphic markers from the interval (Casali et al, 2004; Stevanin et al, 2006; Lossos et al, 2006). The other families were new. All available family members of 16 most informative families were genotyped using 34 microsatellite markers for linkage to three successive loci on chromosome 15 which have been associated with thin corpus callosum; SPG11, SPG21 and the locus for agenesis of corpus callosum with polyneuropathy (ACCPN). Positive multipoint LOD scores ranging from 0.60 to 3.85 and corresponding to the maximal expected values in the pedigrees were obtained in the 16 most informative families (FIGS. 1 and 2). Mutations in the ACCPN or SPG21 loci were excluded by direct sequencing in all families that showed positive linkage to these regions (data not shown). A significant combined multipoint LOD score of 28.1 was reached in the 3.3 cM interval flanked by markers D15S778 and D15S659 in the linked kindreds (FIGS. 1 and 2). Haplotype reconstructions identified two critical recombination events that allowed to restrict the candidate interval to 6.6 cM between markers D15S1044 and D15S123. The 3.2 cM of the D15S778-D15S659 interval was considered to be the region most likely containing the responsible gene on the basis of homozygosity in all consanguineous patients of two significantly linked families; family FSP221 linked to SPG11 with a maximal LOD score of 3.85 and family FSP672 linked to the same locus with a 2.6 LOD score value (FIGS. 3 and 4). In addition, a genome wide screen performed in family FSP221 at a resolution of 10 cM on all chromosomes only identified three other possible locations with multipoint lod scores of 2.2 to 2.5 that were excluded using 18 additional microsatellite markers (data not shown), therefore highly supporting linkage to SPG11.
[0167] The narrowed interval contained 40 genes in accordance with the National Center for Biotechnology Information (NCBI) and the Ensembl databases. Two were excluded in previous studies (SEMA6D and MAP1A, Stevanin et al, 2006). We evaluated 16 additional genes from the interval as candidates for SPG11, prioritizing those with a known or putative function in mitochondrial metabolism, intra-cellular trafficking or cytoskeleton integrity (FIG. 5). All coding and non-coding exons as well as their splicing sites with at least 50 bp of intronic sequences on each side were sequenced on genomic DNA of 5 index patients from 5 linked families. No mutations were found in 15 genes but sequence variations were found in the KIAA1840 gene. We then screened one affected member from the 16 linked families as well as of the uninformative kindreds and checked all other members of the families, when available, for sequence variations. 43 different mutations were identified in 47 families, including the 16 linked ones, 31 at the homozygous state, (FIGS. 5 to 9). They were either nonsense mutations (n=13), deletions (n=17), insertions (n=7) or splice site mutations (n=6) in the coding sequence, and resulted in an abnormally truncated protein or predicted to alter the splicing of the messenger RNA in all cases. In two families (FSP670 and ITA28VAC, FIG. 8), we found a missense change (R945G or R815M) affecting a nucleotide of the 5'-splice site consensus and predicted to alter the splicing of the mRNA. This could be confirmed in family FSP670 by the analysis of mRNA from one patient (c.2833A>G, r.2834+1--2834+65ins, p.R945GfsX950). Four mutations affected the intronic part of the consensus sequence for the acceptor splicing site (see Table 2) that also likely affect the splicing of the mRNA. The mutations segregated completely in the families with the disease and were not found on at least 140 chromosomes from unrelated control individuals of European and North-African origin suggesting that these mutations were not polymorphisms. Only 4 mutations were found in more than one pedigree (FIGS. 6 and 7). A c.6100C>T substitution that replaces an arginine by a stop codon in exon 32 (R2034X), shortening the protein from 2443 to 2034 amino acids (SEQ ID NO:160), was identified, in the homozygous state, in 4 Algerian, 3 Tunisian and 2 Moroccan consanguineous kindreds (FIG. 6). A 5 bp deletion in exon 3 (c.529--533delATATT) leading to a frameshift and a stop codon at aa 178 (SEQ ID NO:150) was found at the homozygous state in all patients of 3 Portuguese families and at the heterozygous state in one Brazilian kindred (FIG. 7). Interestingly, alleles at close flanking markers were partially similar in families with identical mutations (when it could be tested) suggesting founder effects in North-Africa and Portugal for these mutations. The c.733--734del AT mutation was also found in 4 Tunisian pedigrees, sharing partial common haplotypes (data not shown) and one French kindred. Finally, the c.1951C>T variant was found at the heterozygous state in 2 Italian and one Kindred from Romania for which we are extending the pedigrees to check for haplotype conservation.
[0168] No mutations were found in 44 families, suggesting that the responsible mutations were either in non-coding regions of KIAA1840 or in another unidentified gene.
[0169] SPG11 mutations were thus found in the majority of the families with the typical AR-HSP-TCC studied here (47/91). Most families originated from the Mediterranean basin. Complete examination of 22 affected members (Stevanin et al, 2007), 12 men and 10 women, showed a mean age of 24.8±9.5 years ranging from 12 to 49. Onset of the disease always occurred before age 24 years (mean age 11.8±5.5 years; range 2-23) and consisted in either spastic gait (57%, 12/21) or cognitive impairment (19%, 4/21), sometimes diagnosed as mental retardation. After about 10 years of evolution, the full-blown clinical picture consisted in progressive and severe spastic paraplegia with distal wasting and cognitive problems. In several cases (n=6), cognitive dysfunction clearly worsened with disease progression. Cerebral imaging showed a thin corpus callosum, but also periventricular white matter changes and cortical atrophy, in the majority of the patients. Pseudo-bulbar dysarthria was frequent (54%, n=12) and dystonic voice was noted in one patient. Interestingly, although a few patients had normal electromyographic recordings, peripheral neuropathy was frequent (72%, 13 out of 18 patients) and was mostly associated with pure motor changes. Additional signs, such as optic atrophy, retinitis pigmentosa, mild cerebellar signs, cataract, and clinodactily were occasionally observed, a finding that expands the clinical spectrum of this entity.
[0170] The human KIAA1840 gene contains 40 exons spanning 101 Kbases of genomic DNA on chromosome 15q21.1. The full length transcript encodes a predicted protein of 2443 amino acids of unknown function called spatacsin for SPAsticity with Thin or Atrophied Corpus callosum Syndrome proteIN. The sequence of spatacsin is strongly conserved through evolution with orthologues in mammalians and other vertebrates: human KIAA1840 shares 85% identity with the homologous protein in dog, 76 and 73% with the mouse and rat homologues and 59% with the chicken homologue, all of similar sizes. Less similarity was found with homologous proteins of smaller sizes from fugu (44%), tetraodon (39%), and drosophila (22%).
[0171] Neither the gene nor the predicted protein it encodes in many species show any significant sequence similarity to known cDNA or protein sequences. We then looked for protein motifs and domains (FIG. 3). Four putative transmembrane domains were predicted by various algorithms (aa 163-194, 200-240, 1239-1267 and 1471-1493). A glycosyl hydrolase F1 signature was also detected (aa 482-490). This motif is based on a conserved glutamic acid residue which has been shown in the beta-glucosidase of various bacteria and plants and mammalian lactase-phlorizin hydrolase, an integral membrane glycoprotein that splits lactose in the small intestine. Interestingly, this protein is assigned to the aromatic compound dioxygenase superfamily because of a 22% identity with the consensus sequence between aa 2104-2381. A leucine zipper (aa 611 to 632), involved in dimerization of many gene-regulatory proteins (C/EBP, CREB, CRE-BP1, ATFs and Jun/AP1 family of transcription factors) and a Myb domain (aa 1766 to 1774), involved in the DNA-binding of drosophila and vertebrate myb and related proteins, were also identified. Interestingly, there is a 47% identity, over 44 aa, with thymosyl-like peptides, small peptides which play an important role in the organization of the cytoskeleton; these peptides, bind to and sequester actin monomers, thereby inhibiting actin polymerization (Low and Golstein 1985). Furthermore, a probable coiled-coil domain of 33 residues from 1556 to 1590 was also present and such domains are reported in structural or motor proteins such as spectrin, laminin, dynein or neurofilament proteins.
[0172] We then looked at the structure of the predicted protein. The level of hydrophobicity (34.2%) over the entire sequence was typical of a globular protein. Because of it's size, a succession of globular domains is likely and we tried to identify them by the identification of inter domain regions, corresponding to a low density of hydrophobic clusters with the DomHCA software (Prat-Albeau et al, 2006). Except a small linker located between positions 1410 and 1440, no domain separation was evidenced. From the HCA plots, one of the putative transmembrane regions was confirmed at amino acids 200 to 240 on spatacsin from 5 vertebrates, but it was lacking in the homologous sequences from tetraodon and drosophila, as these last two sequences presented a shortened N-terminal domain. A thorough analysis of putative duplication highlighted two structurally similar regions (aa 560-700 and 2250-2390) in all vertebrate homologues of the protein with 19% sequence identity in human sequences (FIG. 10). Amino acid proportion shows a non standard distribution in some cases: high amount of leucines (13.8% vs 9.6% in standard reference databases), a low level of methionines (1.9% instead of 2.38%) and glycines (3.9% vs 6.93% in Swiss Prot). The proportion of cysteins was over 2 fold higher (2.9%) compared to the mean in databases but did not gave rise to disulfide bridges, according to the predictions of the CysState software (Mucchielli-Girgi, 2002). Cluster shapes claim for a mainly helical behavior of this protein, which is confirmed by standard prediction tools.
[0173] The spatacsin protein, fused with GFP, had a diffuse cytosolic and nuclear distribution that sometimes excluded the nucleus of COS-7 cells. In rare cases (<5%), spatacsin formed small perinuclear dots or aggresome-like structures in cells with high expression levels after 4 days post-transfection that did not colocalized with the mitochondrial marker Cox2 or the Golgi marker alpha-COP.
[0174] Previous expression profiling of the SPG11 gene showed that it is expressed ubiquitously at low levels in mouse tissues, including the brain (Nagase et al, 2001). Ubiquitous low level expression, even in structures apparently not related to the phenotype, has been shown for other genes responsible for neurodegenerative diseases (Paisan-Ruiz et al, 2004). We successfully amplified seven overlapping cDNA fragments from the KIAA1840 mRNA extracted from human cerebral cortex and used them to probe human adult multiple-tissue northern blots. At least three alternative transcripts were detected in all structures of adult brain. The full-length transcript (˜8 Kb) was most highly expressed in the cerebellum, the 5.5-Kb transcript in the cerebral cortex (FIG. 11).
[0175] When the temporal and regional expression of the mouse KIAA1840 mRNA was investigated by in situ hybridization in rat brain, it was undetectable in newborn rats (P1). It was detected in the cerebellum, however, from P6 to P21. At adulthood (P68), expression was found throughout the brain. Expression was generally low, but stronger signals were observed in the pineal gland, the edges of the lateral ventricles, the granular layer of the cerebellum and the hippocampus. In contrast to human adult northern blots, only a weak expression was detected in the cerebral cortex. Understanding the function of spatacsin in these structures would help to explain the major features of the disease phenotype: e.g., expression in the hippocampus could be related to the cognitive impairment observed in the patients. In addition, whether the labeling of the edges of the lateral ventricles, where oligodendrocyte progenitors are located, is related to the white matter changes in patients remains to be investigated.
[0176] Our study identified the gene responsible for spastic paraplegia with thin corpus callosum linked to SPG11, KIAA1840. This is supported by four pieces of evidence; first, we have excluded 17 out of the 40 genes assigned to the SPG11 candidate interval; second, we have identified 43 different mutations segregating in 47 families, 16 of which linked previously to the SPG11 locus, and not found in at least 140 control chromosomes; third, all, these mutations were leading to a truncated protein and/or abnormally spliced mRNA, and fourth all mutated families presented with the typical AR-HSP-TCC phenotype or at least a compatible phenotype in 2 families in which cerebral imaging was not available. Mutations in KIAA1840 affected 47 of 91 AR-HSP-TCC families in this study making this genetic entity very frequent among AR-HSP-TCC (52%), 75% was estimated in a previous study (Stevanin et al, 2006), but also among recessive spastic paraplegias. At least another gene might however exist as previously shown (Lossos et al, 2006; Stevanin et al, 2006; Casali et al, 2004).
[0177] This gene has a widespread low level expression, including in the brain where it is more strongly expressed in the cerebellum, the cerebral cortex, the hippocampus, the pineal gland and the edges of the ventricles. Spastic paraplegias are supposed to results from a dying back mechanism of the exons and mitochondrial metabolism or axonal transport has been implicated in several genetic entities of HSP (Crosby et al, 2002). Indeed, three causative genes identified in AR-HSP have been implicated in defective intracellular trafficking: mutations in the mitochondrial metalloprotease protein paraplegin impair axonal transport in SPG7; spartin (SPG20) mutations affect endosomal trafficking and microtubule dynamics; maspardin (SPG21) mutations may interfere with endosomal/trans-Golgi vesicle transportation. Although, the function of spatacsin remains unknown, given it's basal expression in all tissues and it's high conservation in all species, this protein might have a crucial function which might explain the degeneration of the corticospinal tracts which might rely on the post-translational modifications or modeling/carriage of other proteins involved in axonal transport, mitochondrial metabolism as well as cerebral development. The presence of at least one transmembrane domain suggests that spatacsin may act as a receptor of a transporter.
[0178] All mutations identified so far in the KIAA1840 gene cause or are predicted to cause truncation of the protein, suggesting that pathogenicity results from loss of function. They are located in many exons, including exon 1 and exon 39 suggesting that the C-terminal domain of the protein has also an important function or effect on the structure of the protein. It is also conceivable that, given its position in the 5' splice site consensus sequence, the missense mutation R815M would also affect the transcription of the gene as demonstrated for mutation c.2833A>G, r.2834+1--2834+65ins, p.R945GfsX950. Similarly, the mutations found in the intronic part of the acceptor splicing sites in introns 4, 12, 13 and 34 (Table 2) are likely altering the splicing of the surrounding exons and therefore the synthesis and/or stability of the mRNA or protein. No tissues from patients were available yet, however, to validate this hypothesis.
[0179] The identification of the SPG11 gene will now improve the diagnostic procedure, as well as patient management, and permit more accurate genetic counseling. This is invaluable for patients and their families.
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[0217] Reid, E. Pure hereditary spastic paraplegia. J. Med. Genet. 34, 499-503 (1997).
Sequence CWU
1
18817751DNAhomo sapiens 1atggctgcag aggaaggggt cgcgagtgct gcttccgccg
gcggtagctg gggcaccgcg 60gccatggggc gggttctacc gatgctgttg gtgccagtcc
ccgccgaggc gatggggcag 120ctcggctccc gggcgcagct gcgcacacag ccggaggctc
tggggagcct gacggctgcg 180ggcagcctcc aagtgctttc tttgacgcct ggcagccggg
gcgggggtcg ctgctgcctg 240gagggcccct tctggcactt tctatgggag gattctcgta
acagcagcac accaactgaa 300aagcccaaac tgctcgctct tggtgaaaat tatgaactgc
ttatctatga atttaatttg 360aaagatggaa gatgtgatgc aaccattttg tatagctgta
gtagggaggc attgcaaaag 420ctcattgacg atcaagatat cagtatttcc ttattgtctt
tgagaatcct gtcatttcac 480aataacacat cattactgtt catcaacaaa tgtgtcatcc
tacatattat atttcctgaa 540agagatgctg caattagagt actcaactgt ttcacacttc
ccttgcctgc acaggcagtg 600gacatgatta ttgacacgca gctctgcaga ggaattcttt
ttgttttgag tagtttaggc 660tggatctaca tttttgatgt tgtggatggt acatatgtag
ctcatgtgga tttagcactt 720cacaaagaag acatgtgtaa tgagcagcaa caggagccag
ccaagatttc ttcatttact 780tcactgaaag tttctcaaga cctcgatgtt gcagtgattg
tcagctcctc caactccgca 840gttgctctta acttaaattt gtatttcagg caacacccag
gacacctact gtgtgaaaga 900atactagaag atcttcctat tcaaggacct aagggcgtag
atgaagatga tcctgttaac 960tctgcctaca acatgaaact ggccaagttt tccttccaaa
ttgataggtc ttggaaagcc 1020cagctatcat cattgaatga aacaataaag aactccaaac
tggaggtttc ctgttgtgct 1080ccatggttcc aggatatttt gcatttggag tcacctgaat
ctggtaacca cagtacaagt 1140gtgcagagct gggccttcat tccacaggac ataatgcatg
ggcaatataa tgttctacag 1200aaagatcatg ccaagaccag tgatccagga agatcatgga
aaataatgca catcagtgaa 1260caagaggaac ccatagagct taaatgtgtg tctgtgacag
gattcactgc actgtttact 1320tgggaagtgg aaaggatggg ctataccatt accctctggg
atttggagac ccagggcatg 1380cagtgttttt cccttggcac aaagtgtatt cctgtagaca
gtagtggaga ccagcagctg 1440tgctttgttt tgacagagaa tggactctct ctgattttgt
ttggtttgac tcaagaagag 1500tttttaaaca gactcatgat ccatggaagt gccagcactg
tggacactct ttgtcatctc 1560aatggctggg gaaggtgctc aattcccata catgcactag
aggccgggat agaaaatcgt 1620cagctggaca cagtaaattt ctttttgaag agcaaggaaa
atctttttaa tccatcctca 1680aaatcttctg tatctgatca gtttgatcac ttgtcatccc
atttatattt aagaaatgtg 1740gaagagctga taccagcatt ggatttactt tgctcggcaa
ttagagaaag ttattctgaa 1800ccccaaagca aacacttttc agaacaattg cttaatctta
cactgtcttt ccttaacaac 1860caaataaagg agcttttcat tcacactgaa gaactagatg
aacatctgca aaaaggagtg 1920aacattttga ctagctacat taatgaactt cgaaccttca
tgataaagtt tccttggaag 1980ctaacagatg ctatagatga atatgatgta catgaaaatg
tccccaaagt aaaggagagc 2040aatatatgga agaaactcag ctttgaggaa gttattgcca
gcgccatttt aaacaacaaa 2100ataccagagg cacagacttt cttcaggatt gatagtcatt
ctgctcaaaa acttgaggag 2160cttattggca taggcctaaa tttggtcttt gacaatttaa
aaaagaacaa tataaaggaa 2220gcctctgaac ttttgaagaa tatggggttt gatgtaaaag
gccaattgct caagatctgc 2280ttctatacaa ctaataaaaa tatacgtgac tttttggttg
aaattttaaa agaaaaaaat 2340tatttttctg aaaaagagaa aagaactata gacttcgtgc
atcaagttga gaagctttat 2400ttgggacatt tccaagaaaa tatgcaaatc cagtcatttc
ccaggtactg gataaaggaa 2460caagattttt tcaagcacaa gtctgttttg gactcattcc
tgaaatatga ttgtaaagat 2520gaatttaaca aacaggacca tagaattgtg ttaaattggg
ctctgtggtg ggatcaacta 2580acacaagaat ccatccttct ccccaggata agtccagaag
aatacaaatc atattcccct 2640gaagccctct ggagatacct cacagctcgc catgattggt
taaacattat cttatggatt 2700ggagaatttc aaacccagca tagttatgct tcacttcagc
agaacaaatg gccccttctg 2760actgttgatg ttattaacca gaatacttcc tgtaacaact
acatgaggaa tgaaatttta 2820gataagctgg ccaggaatgg ggtttttttg gcatctgaac
tggaagactt tgaatgcttc 2880ctcctaagac tgagccgtat tggaggtgta atacaggata
ccctccctgt tcaaaactac 2940aagaccaaag aaggttggga tttccattct caattcattc
tctattgttt ggagcacagt 3000ctgcagcatc ttctttatgt ctaccttgac tgttacaaac
ttagtcctga aaattgtccc 3060tttttggaaa aaaaagagtt acatgaagca cacccttggt
ttgaattttt agttcagtgt 3120cgacaagttg ccagtaactt aacagatccc aaactgatct
tccaggctag ccttgcaaat 3180gctcagattt tgattcccac caatcaggcc agtgtaagca
gtatgctatt ggaaggacat 3240accctcctgg cccttgctac tacaatgtat tctcctgggg
gtgtcagtca ggttgttcag 3300aatgaagaaa atgaaaactg tttgaagaaa gtggatcccc
agctattgaa gatggcatta 3360actccttacc ccaagctaaa aactgctctc ttcccacagt
gcactcctcc tagtgtcctg 3420ccatctgata ttacaatcta ccaccttatt cagtcattat
caccctttga tcctagcaga 3480ttgtttggct ggcagtctgc taacacacta gctataggag
atgcatggag tcatctccca 3540catttctcta gccctgacct ggttaataaa tatgctatag
tggaacgtct gaattttgct 3600tattatttac ataatgggcg gccatcattt gcatttggta
cttttctggt ccaggaatta 3660atcaagagca agactcccaa gcagctgatc cagcaagtag
gcaatgaagc ctatgttata 3720gggctctcct ccttccacat accttcaata ggagctgcat
gtgtttgttt cttagaattg 3780cttggccttg acagcctcaa gctcagagtt gatatgaaag
tggccaatat aattttgagc 3840tacaagtgca gaaatgaaga tgctcagtac agctttatca
gagagtctgt agccgaaaaa 3900ctatctaaac tagctgatgg tgaaaagaca accacagaag
aattgcttgt tctcttagaa 3960gaaggtacat ggaacagcat tcagcaacag gaaataaaga
ggttatccag tgaatctagc 4020agccaatggg cattagtggt gcagttctgc aggctacaca
atatgaaact aagcatatct 4080taccttagag aatgtgccaa agcaaatgat tggctgcagt
tcattattca cagccaactc 4140cacaactacc acccagcaga ggtgaaatcc cttatccagt
acttcagccc agtcattcaa 4200gaccacttaa ggctggcttt tgagaacttg ccctcagtgc
ccacctccaa aatggacagc 4260gatcaagtct gcaataagtg cccccaggaa cttcaaggaa
gcaaacaaga gatgaccgat 4320ttatttgaaa ttctgctcca atgctcagag gagccagact
cctggcactg gcttctggtt 4380gaagcagtga aacaacaggc ccctatcctc agtgttctgg
cctcatgtct ccagggtgcc 4440agtgccattt cttgtctctg tgtttggatc atcacttctg
tggaggacaa tgttgcaact 4500gaagcaatgg gacacattca ggactcaaca gaggaccata
cctggaacct tgaggatctt 4560tcagtcatct ggagaacatt attaacaaga caaaagagca
aaactctcat cagaggtttc 4620cagcttttct ttaaggattc cccgttacta ctggtgatgg
agatgtatga actgtgtatg 4680ttcttcagga attataaaga agctgaagct aaacttctgg
agtttcagaa gagccttgaa 4740acgcttaaca cagcagccac aaaggtccac cctgtcatcc
ctgccatgtg gctggaggat 4800caggtgtgtt tccttttgaa gcttatgcta cagcagtgta
agacccagta tgagctgggg 4860aagcttttac agctctttgt tgaaagagag catctcttct
ctgatggtcc agatgtgaaa 4920aagctttgca tcctttgcca gattttgaag gatacatcca
tagccattaa tcatacaatt 4980attaccagct acagcattga gaatcttcag catgaatgta
gatctatttt ggaaagactg 5040cagacagatg gacaattcgc tttggccagg agggtagcag
aattagctga gttacctgtg 5100gacaacttgg ttattaaaga gataacacag gaaatgcaga
ccctaaaaca cattgaacag 5160tggtcactaa aacaagcaag aattgacttc tggaaaaaat
gccatgagaa ttttaagaaa 5220aattcaattt caagcaaagc agcttcttcc tttttctcaa
cccaggccca tgtggcatgt 5280gagcacccaa ctggatggag cagcatggag gagcgccatc
tgctgctcac cttggcaggg 5340cactggcttg cccaggagga cgtggtgccc ttggataagc
tggaggagct ggagaagcag 5400atctggctgt gccgcatcac ccagcacact cttggaagaa
atcaggagga aacagagccc 5460agattttctc gacagatctc aactagtggt gaactttcct
ttgatagttt agccagtgag 5520ttttccttct ccaagttggc tgctctgaac acatcaaaat
acttagaact taacagcctt 5580ccatccaaag agacatgcga gaatagattg gattggaaag
agcaggagtc actaaacttt 5640ttgattgggc gcctactgga tgatggctgt gtgcatgaag
caagtagagt atgccggtat 5700tttcattttt ataatccaga tgtcgccttg gtattgcact
gcagagcact ggcctcaggg 5760gaagctagta tggaggatct gcacccagag atccatgctc
tcctacaaag tgctgagctg 5820cttgaggaag aagcacccga cattccccta aggagagtcc
acagcacttc aagtctggat 5880agtcagaagt ttgtgacagt gccctccagt aatgaagtgg
taactaacct ggaagtgctg 5940acaagcaaat gcctccatgg gaagaactac tgtcgacagg
tcctctgtct gtatgatctt 6000gccaaggagt tgggctgttc ctacacagat gttgctgctc
aggatggtga agccatgctc 6060cggaaaatct tggcctctca gcagcctgac cgatgcaaac
gagcccaggc cttcatcagc 6120acacagggcc ttaagccaga tactgtggct gaactcgtgg
cagaagaggt gacacgggag 6180ctgcttactt catcacaggg aacaggacat aagcagatgt
tcaacccaac agaggaaagc 6240cagacatttc ttcagctgac cactctgtgt caagaccgca
cattggtagg catgaagttg 6300ttggataaga tttcctccgt tccccatggg gaactgtctt
gcaccacaga gctcctgatc 6360ctggcccatc attgcttcac cctgacgtgc cacatggagg
gcatcatccg agtcctacag 6420gccgcccaca tgctcacaga taaccacctg gcccccagtg
aggagtatgg gctggtggta 6480cggctcctca ctggcattgg aaggtacaac gagatgacat
acatatttga tttgctgcat 6540aaaaagcact actttgaagt gctaatgagg aagaagttgg
atccgagtgg taccctgaaa 6600acagccctgc tggactacat caaacgctgc cgtcctggag
acagtgaaaa gcacaatatg 6660attgccctgt gcttcagcat gtgccgggag attggcgaga
accacgaggc agctgcccgc 6720atccaactga aattgattga gtctcagccc tgggaggaca
gcctcaagga tgggcaccag 6780ctgaaacaac tgctgctgaa ggccctgact ctgatgttgg
atgcagcaga gagttatgcc 6840aaggactcct gtgtgcgaca ggcccagcac tgtcagcggc
tcaccaagtt gataactctg 6900cagattcact ttctgaacac tggccagaac acaatgctca
tcaacttggg ccgccacaag 6960ctgatggact gtattctggc cctacctcgg ttctaccagg
cttctattgt ggctgaggcc 7020tacgattttg ttccagattg ggctgaaatt ttataccagc
aagtgattct taaaggagac 7080tttaattact tggaagaatt taagcagcaa aggttattaa
agtccagtat atttgaagag 7140atttccaaaa aatataaaca acatcagcct actgacatgg
tcatggaaaa cctgaagaaa 7200ttactcacat attgtgaaga tgtttacctg tattacaagt
tggcatacga acacaagttt 7260tatgaaattg taaatgtgct tctgaaggac cctcagacag
gttgctgtct aaaggacatg 7320ctagcaggtt agatgatttc ataggtgtct gttttcttgt
actgttagca gattctgaca 7380gatgtgatga gaagaagaat gcattggaga tctttgctaa
agttgaacaa tcccggtact 7440gtaccatatc agtcctttgt gggtagtagg tagcaagtaa
gaaacttttc aggaggaaat 7500tcctatttaa aatagattga ttttagatga ttgttcatcc
acaccatttt atatagatac 7560tagtattaag atcaaaagct tcctcttcct caggacagct
tctactttag atgatccaat 7620aatgattaaa gaatacctgt acctgcagat tccagtttca
aagaaattta attattattt 7680acacagttaa ggaacaggtg atacattttc atttgttaga
aactgatctt tctgtaataa 7740aatagatttt c
775122443PRThomo sapiens 2Met Ala Ala Glu Glu Gly
Val Ala Ser Ala Ala Ser Ala Gly Gly Ser1 5
10 15Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met
Leu Leu Val Pro 20 25 30Val
Pro Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35
40 45Thr Gln Pro Glu Ala Leu Gly Ser Leu
Thr Ala Ala Gly Ser Leu Gln 50 55
60Val Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu65
70 75 80Glu Gly Pro Phe Trp
His Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser 85
90 95Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu
Gly Glu Asn Tyr Glu 100 105
110Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr
115 120 125Ile Leu Tyr Ser Cys Ser Arg
Glu Ala Leu Gln Lys Leu Ile Asp Asp 130 135
140Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe
His145 150 155 160Asn Asn
Thr Ser Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile
165 170 175Ile Phe Pro Glu Arg Asp Ala
Ala Ile Arg Val Leu Asn Cys Phe Thr 180 185
190Leu Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr
Gln Leu 195 200 205Cys Arg Gly Ile
Leu Phe Val Leu Ser Ser Leu Gly Trp Ile Tyr Ile 210
215 220Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val
Asp Leu Ala Leu225 230 235
240His Lys Glu Asp Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile
245 250 255Ser Ser Phe Thr Ser
Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val 260
265 270Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn
Leu Asn Leu Tyr 275 280 285Phe Arg
Gln His Pro Gly His Leu Leu Cys Glu Arg Ile Leu Glu Asp 290
295 300Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu
Asp Asp Pro Val Asn305 310 315
320Ser Ala Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg
325 330 335Ser Trp Lys Ala
Gln Leu Ser Ser Leu Asn Glu Thr Ile Lys Asn Ser 340
345 350Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe
Gln Asp Ile Leu His 355 360 365Leu
Glu Ser Pro Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370
375 380Ala Phe Ile Pro Gln Asp Ile Met His Gly
Gln Tyr Asn Val Leu Gln385 390 395
400Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile
Met 405 410 415His Ile Ser
Glu Gln Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val 420
425 430Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu
Val Glu Arg Met Gly Tyr 435 440
445Thr Ile Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Phe Ser 450
455 460Leu Gly Thr Lys Cys Ile Pro Val
Asp Ser Ser Gly Asp Gln Gln Leu465 470
475 480Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile
Leu Phe Gly Leu 485 490
495Thr Gln Glu Glu Phe Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser
500 505 510Thr Val Asp Thr Leu Cys
His Leu Asn Gly Trp Gly Arg Cys Ser Ile 515 520
525Pro Ile His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu
Asp Thr 530 535 540Val Asn Phe Phe Leu
Lys Ser Lys Glu Asn Leu Phe Asn Pro Ser Ser545 550
555 560Lys Ser Ser Val Ser Asp Gln Phe Asp His
Leu Ser Ser His Leu Tyr 565 570
575Leu Arg Asn Val Glu Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser
580 585 590Ala Ile Arg Glu Ser
Tyr Ser Glu Pro Gln Ser Lys His Phe Ser Glu 595
600 605Gln Leu Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn
Gln Ile Lys Glu 610 615 620Leu Phe Ile
His Thr Glu Glu Leu Asp Glu His Leu Gln Lys Gly Val625
630 635 640Asn Ile Leu Thr Ser Tyr Ile
Asn Glu Leu Arg Thr Phe Met Ile Lys 645
650 655Phe Pro Trp Lys Leu Thr Asp Ala Ile Asp Glu Tyr
Asp Val His Glu 660 665 670Asn
Val Pro Lys Val Lys Glu Ser Asn Ile Trp Lys Lys Leu Ser Phe 675
680 685Glu Glu Val Ile Ala Ser Ala Ile Leu
Asn Asn Lys Ile Pro Glu Ala 690 695
700Gln Thr Phe Phe Arg Ile Asp Ser His Ser Ala Gln Lys Leu Glu Glu705
710 715 720Leu Ile Gly Ile
Gly Leu Asn Leu Val Phe Asp Asn Leu Lys Lys Asn 725
730 735Asn Ile Lys Glu Ala Ser Glu Leu Leu Lys
Asn Met Gly Phe Asp Val 740 745
750Lys Gly Gln Leu Leu Lys Ile Cys Phe Tyr Thr Thr Asn Lys Asn Ile
755 760 765Arg Asp Phe Leu Val Glu Ile
Leu Lys Glu Lys Asn Tyr Phe Ser Glu 770 775
780Lys Glu Lys Arg Thr Ile Asp Phe Val His Gln Val Glu Lys Leu
Tyr785 790 795 800Leu Gly
His Phe Gln Glu Asn Met Gln Ile Gln Ser Phe Pro Arg Tyr
805 810 815Trp Ile Lys Glu Gln Asp Phe
Phe Lys His Lys Ser Val Leu Asp Ser 820 825
830Phe Leu Lys Tyr Asp Cys Lys Asp Glu Phe Asn Lys Gln Asp
His Arg 835 840 845Ile Val Leu Asn
Trp Ala Leu Trp Trp Asp Gln Leu Thr Gln Glu Ser 850
855 860Ile Leu Leu Pro Arg Ile Ser Pro Glu Glu Tyr Lys
Ser Tyr Ser Pro865 870 875
880Glu Ala Leu Trp Arg Tyr Leu Thr Ala Arg His Asp Trp Leu Asn Ile
885 890 895Ile Leu Trp Ile Gly
Glu Phe Gln Thr Gln His Ser Tyr Ala Ser Leu 900
905 910Gln Gln Asn Lys Trp Pro Leu Leu Thr Val Asp Val
Ile Asn Gln Asn 915 920 925Thr Ser
Cys Asn Asn Tyr Met Arg Asn Glu Ile Leu Asp Lys Leu Ala 930
935 940Arg Asn Gly Val Phe Leu Ala Ser Glu Leu Glu
Asp Phe Glu Cys Phe945 950 955
960Leu Leu Arg Leu Ser Arg Ile Gly Gly Val Ile Gln Asp Thr Leu Pro
965 970 975Val Gln Asn Tyr
Lys Thr Lys Glu Gly Trp Asp Phe His Ser Gln Phe 980
985 990Ile Leu Tyr Cys Leu Glu His Ser Leu Gln His
Leu Leu Tyr Val Tyr 995 1000
1005Leu Asp Cys Tyr Lys Leu Ser Pro Glu Asn Cys Pro Phe Leu Glu
1010 1015 1020Lys Lys Glu Leu His Glu
Ala His Pro Trp Phe Glu Phe Leu Val 1025 1030
1035Gln Cys Arg Gln Val Ala Ser Asn Leu Thr Asp Pro Lys Leu
Ile 1040 1045 1050Phe Gln Ala Ser Leu
Ala Asn Ala Gln Ile Leu Ile Pro Thr Asn 1055 1060
1065Gln Ala Ser Val Ser Ser Met Leu Leu Glu Gly His Thr
Leu Leu 1070 1075 1080Ala Leu Ala Thr
Thr Met Tyr Ser Pro Gly Gly Val Ser Gln Val 1085
1090 1095Val Gln Asn Glu Glu Asn Glu Asn Cys Leu Lys
Lys Val Asp Pro 1100 1105 1110Gln Leu
Leu Lys Met Ala Leu Thr Pro Tyr Pro Lys Leu Lys Thr 1115
1120 1125Ala Leu Phe Pro Gln Cys Thr Pro Pro Ser
Val Leu Pro Ser Asp 1130 1135 1140Ile
Thr Ile Tyr His Leu Ile Gln Ser Leu Ser Pro Phe Asp Pro 1145
1150 1155Ser Arg Leu Phe Gly Trp Gln Ser Ala
Asn Thr Leu Ala Ile Gly 1160 1165
1170Asp Ala Trp Ser His Leu Pro His Phe Ser Ser Pro Asp Leu Val
1175 1180 1185Asn Lys Tyr Ala Ile Val
Glu Arg Leu Asn Phe Ala Tyr Tyr Leu 1190 1195
1200His Asn Gly Arg Pro Ser Phe Ala Phe Gly Thr Phe Leu Val
Gln 1205 1210 1215Glu Leu Ile Lys Ser
Lys Thr Pro Lys Gln Leu Ile Gln Gln Val 1220 1225
1230Gly Asn Glu Ala Tyr Val Ile Gly Leu Ser Ser Phe His
Ile Pro 1235 1240 1245Ser Ile Gly Ala
Ala Cys Val Cys Phe Leu Glu Leu Leu Gly Leu 1250
1255 1260Asp Ser Leu Lys Leu Arg Val Asp Met Lys Val
Ala Asn Ile Ile 1265 1270 1275Leu Ser
Tyr Lys Cys Arg Asn Glu Asp Ala Gln Tyr Ser Phe Ile 1280
1285 1290Arg Glu Ser Val Ala Glu Lys Leu Ser Lys
Leu Ala Asp Gly Glu 1295 1300 1305Lys
Thr Thr Thr Glu Glu Leu Leu Val Leu Leu Glu Glu Gly Thr 1310
1315 1320Trp Asn Ser Ile Gln Gln Gln Glu Ile
Lys Arg Leu Ser Ser Glu 1325 1330
1335Ser Ser Ser Gln Trp Ala Leu Val Val Gln Phe Cys Arg Leu His
1340 1345 1350Asn Met Lys Leu Ser Ile
Ser Tyr Leu Arg Glu Cys Ala Lys Ala 1355 1360
1365Asn Asp Trp Leu Gln Phe Ile Ile His Ser Gln Leu His Asn
Tyr 1370 1375 1380His Pro Ala Glu Val
Lys Ser Leu Ile Gln Tyr Phe Ser Pro Val 1385 1390
1395Ile Gln Asp His Leu Arg Leu Ala Phe Glu Asn Leu Pro
Ser Val 1400 1405 1410Pro Thr Ser Lys
Met Asp Ser Asp Gln Val Cys Asn Lys Cys Pro 1415
1420 1425Gln Glu Leu Gln Gly Ser Lys Gln Glu Met Thr
Asp Leu Phe Glu 1430 1435 1440Ile Leu
Leu Gln Cys Ser Glu Glu Pro Asp Ser Trp His Trp Leu 1445
1450 1455Leu Val Glu Ala Val Lys Gln Gln Ala Pro
Ile Leu Ser Val Leu 1460 1465 1470Ala
Ser Cys Leu Gln Gly Ala Ser Ala Ile Ser Cys Leu Cys Val 1475
1480 1485Trp Ile Ile Thr Ser Val Glu Asp Asn
Val Ala Thr Glu Ala Met 1490 1495
1500Gly His Ile Gln Asp Ser Thr Glu Asp His Thr Trp Asn Leu Glu
1505 1510 1515Asp Leu Ser Val Ile Trp
Arg Thr Leu Leu Thr Arg Gln Lys Ser 1520 1525
1530Lys Thr Leu Ile Arg Gly Phe Gln Leu Phe Phe Lys Asp Ser
Pro 1535 1540 1545Leu Leu Leu Val Met
Glu Met Tyr Glu Leu Cys Met Phe Phe Arg 1550 1555
1560Asn Tyr Lys Glu Ala Glu Ala Lys Leu Leu Glu Phe Gln
Lys Ser 1565 1570 1575Leu Glu Thr Leu
Asn Thr Ala Ala Thr Lys Val His Pro Val Ile 1580
1585 1590Pro Ala Met Trp Leu Glu Asp Gln Val Cys Phe
Leu Leu Lys Leu 1595 1600 1605Met Leu
Gln Gln Cys Lys Thr Gln Tyr Glu Leu Gly Lys Leu Leu 1610
1615 1620Gln Leu Phe Val Glu Arg Glu His Leu Phe
Ser Asp Gly Pro Asp 1625 1630 1635Val
Lys Lys Leu Cys Ile Leu Cys Gln Ile Leu Lys Asp Thr Ser 1640
1645 1650Ile Ala Ile Asn His Thr Ile Ile Thr
Ser Tyr Ser Ile Glu Asn 1655 1660
1665Leu Gln His Glu Cys Arg Ser Ile Leu Glu Arg Leu Gln Thr Asp
1670 1675 1680Gly Gln Phe Ala Leu Ala
Arg Arg Val Ala Glu Leu Ala Glu Leu 1685 1690
1695Pro Val Asp Asn Leu Val Ile Lys Glu Ile Thr Gln Glu Met
Gln 1700 1705 1710Thr Leu Lys His Ile
Glu Gln Trp Ser Leu Lys Gln Ala Arg Ile 1715 1720
1725Asp Phe Trp Lys Lys Cys His Glu Asn Phe Lys Lys Asn
Ser Ile 1730 1735 1740Ser Ser Lys Ala
Ala Ser Ser Phe Phe Ser Thr Gln Ala His Val 1745
1750 1755Ala Cys Glu His Pro Thr Gly Trp Ser Ser Met
Glu Glu Arg His 1760 1765 1770Leu Leu
Leu Thr Leu Ala Gly His Trp Leu Ala Gln Glu Asp Val 1775
1780 1785Val Pro Leu Asp Lys Leu Glu Glu Leu Glu
Lys Gln Ile Trp Leu 1790 1795 1800Cys
Arg Ile Thr Gln His Thr Leu Gly Arg Asn Gln Glu Glu Thr 1805
1810 1815Glu Pro Arg Phe Ser Arg Gln Ile Ser
Thr Ser Gly Glu Leu Ser 1820 1825
1830Phe Asp Ser Leu Ala Ser Glu Phe Ser Phe Ser Lys Leu Ala Ala
1835 1840 1845Leu Asn Thr Ser Lys Tyr
Leu Glu Leu Asn Ser Leu Pro Ser Lys 1850 1855
1860Glu Thr Cys Glu Asn Arg Leu Asp Trp Lys Glu Gln Glu Ser
Leu 1865 1870 1875Asn Phe Leu Ile Gly
Arg Leu Leu Asp Asp Gly Cys Val His Glu 1880 1885
1890Ala Ser Arg Val Cys Arg Tyr Phe His Phe Tyr Asn Pro
Asp Val 1895 1900 1905Ala Leu Val Leu
His Cys Arg Ala Leu Ala Ser Gly Glu Ala Ser 1910
1915 1920Met Glu Asp Leu His Pro Glu Ile His Ala Leu
Leu Gln Ser Ala 1925 1930 1935Glu Leu
Leu Glu Glu Glu Ala Pro Asp Ile Pro Leu Arg Arg Val 1940
1945 1950His Ser Thr Ser Ser Leu Asp Ser Gln Lys
Phe Val Thr Val Pro 1955 1960 1965Ser
Ser Asn Glu Val Val Thr Asn Leu Glu Val Leu Thr Ser Lys 1970
1975 1980Cys Leu His Gly Lys Asn Tyr Cys Arg
Gln Val Leu Cys Leu Tyr 1985 1990
1995Asp Leu Ala Lys Glu Leu Gly Cys Ser Tyr Thr Asp Val Ala Ala
2000 2005 2010Gln Asp Gly Glu Ala Met
Leu Arg Lys Ile Leu Ala Ser Gln Gln 2015 2020
2025Pro Asp Arg Cys Lys Arg Ala Gln Ala Phe Ile Ser Thr Gln
Gly 2030 2035 2040Leu Lys Pro Asp Thr
Val Ala Glu Leu Val Ala Glu Glu Val Thr 2045 2050
2055Arg Glu Leu Leu Thr Ser Ser Gln Gly Thr Gly His Lys
Gln Met 2060 2065 2070Phe Asn Pro Thr
Glu Glu Ser Gln Thr Phe Leu Gln Leu Thr Thr 2075
2080 2085Leu Cys Gln Asp Arg Thr Leu Val Gly Met Lys
Leu Leu Asp Lys 2090 2095 2100Ile Ser
Ser Val Pro His Gly Glu Leu Ser Cys Thr Thr Glu Leu 2105
2110 2115Leu Ile Leu Ala His His Cys Phe Thr Leu
Thr Cys His Met Glu 2120 2125 2130Gly
Ile Ile Arg Val Leu Gln Ala Ala His Met Leu Thr Asp Asn 2135
2140 2145His Leu Ala Pro Ser Glu Glu Tyr Gly
Leu Val Val Arg Leu Leu 2150 2155
2160Thr Gly Ile Gly Arg Tyr Asn Glu Met Thr Tyr Ile Phe Asp Leu
2165 2170 2175Leu His Lys Lys His Tyr
Phe Glu Val Leu Met Arg Lys Lys Leu 2180 2185
2190Asp Pro Ser Gly Thr Leu Lys Thr Ala Leu Leu Asp Tyr Ile
Lys 2195 2200 2205Arg Cys Arg Pro Gly
Asp Ser Glu Lys His Asn Met Ile Ala Leu 2210 2215
2220Cys Phe Ser Met Cys Arg Glu Ile Gly Glu Asn His Glu
Ala Ala 2225 2230 2235Ala Arg Ile Gln
Leu Lys Leu Ile Glu Ser Gln Pro Trp Glu Asp 2240
2245 2250Ser Leu Lys Asp Gly His Gln Leu Lys Gln Leu
Leu Leu Lys Ala 2255 2260 2265Leu Thr
Leu Met Leu Asp Ala Ala Glu Ser Tyr Ala Lys Asp Ser 2270
2275 2280Cys Val Arg Gln Ala Gln His Cys Gln Arg
Leu Thr Lys Leu Ile 2285 2290 2295Thr
Leu Gln Ile His Phe Leu Asn Thr Gly Gln Asn Thr Met Leu 2300
2305 2310Ile Asn Leu Gly Arg His Lys Leu Met
Asp Cys Ile Leu Ala Leu 2315 2320
2325Pro Arg Phe Tyr Gln Ala Ser Ile Val Ala Glu Ala Tyr Asp Phe
2330 2335 2340Val Pro Asp Trp Ala Glu
Ile Leu Tyr Gln Gln Val Ile Leu Lys 2345 2350
2355Gly Asp Phe Asn Tyr Leu Glu Glu Phe Lys Gln Gln Arg Leu
Leu 2360 2365 2370Lys Ser Ser Ile Phe
Glu Glu Ile Ser Lys Lys Tyr Lys Gln His 2375 2380
2385Gln Pro Thr Asp Met Val Met Glu Asn Leu Lys Lys Leu
Leu Thr 2390 2395 2400Tyr Cys Glu Asp
Val Tyr Leu Tyr Tyr Lys Leu Ala Tyr Glu His 2405
2410 2415Lys Phe Tyr Glu Ile Val Asn Val Leu Leu Lys
Asp Pro Gln Thr 2420 2425 2430Gly Cys
Cys Leu Lys Asp Met Leu Ala Gly 2435
2440320DNAArtificialprimer 3ccacaggaaa cgaatggaat
20420DNAArtificialprimer 4ggttctgtga ggaaaccacg
20520DNAArtificialprimer
5cagggacatt gtaggccatc
20620DNAArtificialprimer 6ccagttgtaa aattgtgacc
20720DNAArtificialprimer 7tcccagctcc caaaactaaa
20820DNAArtificialprimer
8tcaatcaaca cttctaccac
20922DNAArtificialprimer 9caggttcttt cttgtggcat ca
221025DNAArtificialprimer 10cgaggatatt tttaacctct
tatca 251124DNAArtificialprimer
11gttaggcata cttacaaaac tggc
241225DNAArtificialprimer 12cgaggatatt tttaacctct tatca
251320DNAArtificialprimer 13gaacatcttt gccctggttt
201420DNAArtificialprimer
14ctgtgacagg tgttaagtta
201520DNAArtificialprimer 15caggcactga ggcagaagta
201620DNAArtificialprimer 16atctaataca agacagtctc
201726DNAArtificialprimer
17aaaaatcaat tcctaaatca taatcc
261820DNAArtificialprimer 18tagtactgaa gtattgagta
201924DNAArtificialprimer 19tcttttaaag ccaaaaaggg
taaa 242020DNAArtificialprimer
20ttaagtaatg ttcttgggca
202121DNAArtificialprimer 21cccaggacta atcatgaagg a
212220DNAArtificialprimer 22atccccaaac cgataaaacc
202321DNAArtificialprimer
23cggtgtgtct tccactagct c
212423DNAArtificialprimer 24gttacataaa tgtataatcc ctg
232520DNAArtificialprimer 25acccagccat tctcagtgtt
202623DNAArtificialprimer
26cattttaaga ctttatggat tac
232720DNAArtificialprimer 27cacagcgaga tcctgtctca
202821DNAArtificialprimer 28cctcactgta agatgatgcc
c 212925DNAArtificialprimer
29cctttaaata ctacagtggt gcaga
253020DNAArtificialprimer 30tgtgggcatg atttggtcta
203122DNAArtificialprimer 31ccaactgttg agatggagaa
aa 223220DNAArtificialprimer
32acctgctcaa ggacaaatgc
203320DNAArtificialprimer 33tttgaagtat cccagggtgg
203420DNAArtificialprimer 34ccaccattcc ccaaagataa
203520DNAArtificialprimer
35ttacctggat ttggctttgg
203620DNAArtificialprimer 36cctggcttct aaaagtggcc
203722DNAArtificialprimer 37tgcaatccag aaacttgaga
ga 223821DNAArtificialprimer
38aagcacaaca tccaaatcct t
213920DNAArtificialprimer 39atgttggcag gaactccatc
204020DNAArtificialprimer 40ctcctttgga gcaacctctg
204120DNAArtificialprimer
41ttccaacagg aaagcacaca
204220DNAArtificialprimer 42caacaggaaa gcacacatgc
204320DNAArtificialprimer 43cagctacttg ggaggctgag
204420DNAArtificialprimer
44gtgtggctgt gacctcactc
204520DNAArtificialprimer 45gcattagaag gggcactgaa
204620DNAArtificialprimer 46aacatggctg ggatgtttct
204720DNAArtificialprimer
47ctcacaacgg tattcacccc
204820DNAArtificialprimer 48ttcctggttg gcctatgatg
204923DNAArtificialprimer 49aagggtttaa gataatttgg
gga 235020DNAArtificialprimer
50aatgccaaac acacacctga
205122DNAArtificialprimer 51ggattcttga tactgctttg cc
225220DNAArtificialprimer 52ctcaaagcag aggcaaggag
205320DNAArtificialprimer
53ctgagcccca catttttgtt
205420DNAArtificialprimer 54caagtgctca atagccccat
205525DNAArtificialprimer 55gctaactgcc cttaatagag
taaaa 255620DNAArtificialprimer
56aaagggtaca gcgtcagcat
205720DNAArtificialprimer 57cttgccccag attgcataat
205823DNAArtificialprimer 58tccaaaaagt acgtaaaatc
cca 235922DNAArtificialprimer
59cagcaaaagg gtaatagcag tg
226020DNAArtificialprimer 60cccaaatgta gtaaatggcg
206123DNAArtificialprimer 61tttgaaagag cagaaagcta
tgg 236221DNAArtificialprimer
62tgaaggggtt gtcacacttt t
216322DNAArtificialprimer 63ttgtggcaaa agaaaatttg tg
226420DNAArtificialprimer 64gagaatgcag gctcagttcc
206520DNAArtificialprimer
65atgtggaact gagcctgcat
206623DNAArtificialprimer 66cgacttgcat tttaaagaac ctg
236725DNAArtificialprimer 67ttgtttccag atcatgaaga
atatg 256820DNAArtificialprimer
68tcagatagct gaccacagcc
206924DNAArtificialprimer 69tccctcttaa ggagaaaaac actg
247020DNAArtificialprimer 70accgggccga gatataaaat
207125DNAArtificialprimer
71gctagtttgt cttagaacca gaaca
257223DNAArtificialprimer 72ttttgggttg tctcactatc aca
237324DNAArtificialprimer 73aaggaacata gccagttctg
tttt 247421DNAArtificialprimer
74tgcgaactat ttttcctttg g
217523DNAArtificialprimer 75tgcaacttct caggtacaca tct
237620DNAArtificialprimer 76aggctagagt gcagtggcat
207720DNAArtificialprimer
77agtcagctta agggaagcgg
207822DNAArtificialprimer 78gaagataacc attttctccc ca
227920DNAArtificialprimer 79ttgtgagtgt ttggggagaa
208021DNAArtificialprimer
80ggggatttag tgaaaacacc a
218124DNAArtificialprimer 81tttgttggag aatacactgt gctt
248225DNAArtificialprimer 82catgtctaca caacagaaag
aatgc 258321DNAArtificialprimer
83aaaaggcacc atacagcttt g
218420DNAArtificialprimer 84ggaaacacat gctggaacct
208522DNAArtificialprimer 85cttctgtctg cttcttggtc
tt 228622DNAArtificialprimer
86tatcatcatt atctgttgtt gg
228720DNAArtificialprimer 87ttaggtgatc ccactggctc
208820DNAArtificialprimer 88cccaggagtt caaggctgta
208920DNAArtificialprimer
89ctgaggaggg cttgtttttg
209025DNAArtificialprimer 90tctgtaactt gtttactccc agttg
259120DNAArtificialprimer 91gatcacacca ctgcattcca
209220DNAArtificialprimer
92ggcacctgta gtcccagcta
209320DNAArtificialprimer 93tgaggtggga ggatctcttg
209420DNAArtificialprimer 94gatgtgttca gagcagccaa
209520DNAArtificialprimer
95taagctggag gagctggaga
209620DNAArtificialprimer 96ttgttgtccc cttaacttgg
209720DNAArtificialprimer 97caataggcca agggtttcaa
209820DNAArtificialprimer
98tataactcct gctggagggc
209920DNAArtificialprimer 99ggtagcctgg aaattagccc
2010020DNAArtificialprimer 100tgaaccagaa
tctgaagcca
2010120DNAArtificialprimer 101ttttgtcctt gggctctttc
2010220DNAArtificialprimer 102cctggttctg
tcactagccc
2010320DNAArtificialprimer 103aattagccag ggtggtgaca
2010420DNAArtificialprimer 104cccacaaagg
actgatatgg
2010520DNAArtificialprimer 105aaggaccctc agacaggttg
2010620DNAArtificialprimer 106tcctttaagg
cagacaaggg
2010724DNAArtificialprimer 107accaggtcaa ctaaactgtt ctct
2410823DNAArtificialprimer 108tatgctgaaa
gaccacctgt aga
2310920DNAArtificialprimer 109caggagcagt agtaacacaa
2011020DNAArtificialprimer 110aaagggtaca
gcgtcagcat
2011121DNAArtificialprimer 111gcaggtaata agcctgcaga a
2111220DNAArtificialprimer 112cccccttcct
agctgctatt
2011325DNAArtificialprimer 113tgttcaaaat agttccatta caaaa
2511422DNAArtificialprimer 114tttcttccaa
ggttttcttc ca
2211521DNAArtificialprimer 115tttgcaaaag tgcttgattt t
2111620DNAArtificialprimer 116tgcaggctca
gttccacata
2011720DNAArtificialprimer 117ggaatgatgc ctttttctcc
2011820DNAArtificialprimer 118tctcacactt
gccttctgga
2011920DNAArtificialprimer 119aatcatcgcc tgagcaaaat
2012020DNAArtificialprimer 120ccagtgactg
atccaaagca
2012121DNAArtificialprimer 121ccctcttaag gagaaaaaca c
2112220DNAArtificialprimer 122cagccttatc
ctctgctctt
2012320DNAArtificialprimer 123tggaaaaggg gagcagacta
2012421DNAArtificialprimer 124tgcgaactat
ttttcctttg g
2112520DNAArtificialprimer 125gaggaggcca caaatcacat
2012620DNAArtificialprimer 126gccttagacc
tcgtcacacc
2012723DNAArtificialprimer 127tgctcaggtt ttgacttttt ctc
2312820DNAArtificialprimer 128tttcactgat
ggcaagatgc
2012920DNAArtificialprimer 129accaccccca cctctaattc
2013020DNAArtificialprimer 130ctacacaaca
gaaagaatgc
2013121DNAArtificialprimer 131ccagctgaaa ctgaaagttg g
2113220DNAArtificialprimer 132ctgggtactt
acttcaggct
2013320DNAArtificialprimer 133cactgtgccc tgccttatta
2013420DNAArtificialprimer 134tgtgcctgag
taaccgagtg
2013520DNAArtificialprimer 135tcccagattt ggaggttttg
2013624DNAArtificialprimer 136tgcattttaa
tttcctaact accc
2413720DNAArtificialprimer 137gctgtagtgg cattttattg
2013820DNAArtificialprimer 138cctgggtgac
agagcaagac
2013920DNAArtificialprimer 139agctgcagag ctccataagc
2014020DNAArtificialprimer 140taggcatcca
gagcaggaac
2014120DNAArtificialprimer 141ggcatctgaa agcaaccact
2014220DNAArtificialprimer 142ccctccattt
tcccaagagt
2014320DNAArtificialprimer 143ggggtgaata ccgttgtgag
2014420DNAArtificialprimer 144acctctgggt
tccatgagtg
2014520DNAArtificialprimer 145agactgctcc tctgcactcc
2014621DNAArtificialprimer 146ccgggattgt
tcaactttag c
2114720DNAArtificialprimer 147cagtatctta acctgtacat
2014821DNAArtificialprimer 148ccgggattgt
tcaactttag c 2114940PRTHomo
sapiensmisc_feature(40)..(40)Xaa can be any naturally occurring amino
acid 149Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser1
5 10 15Trp Gly Thr Ala
Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20
25 30Val Pro Ala Glu Ala Met Gly Xaa 35
40150178PRTHomo sapiensmisc_feature(178)..(178)Xaa can be any
naturally occurring amino acid 150Met Ala Ala Glu Glu Gly Val Ala Ser Ala
Ala Ser Ala Gly Gly Ser1 5 10
15Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro
20 25 30Val Pro Ala Glu Ala Met
Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40
45Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser
Leu Gln 50 55 60Val Leu Ser Leu Thr
Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu65 70
75 80Glu Gly Pro Phe Trp His Phe Leu Trp Glu
Asp Ser Arg Asn Ser Ser 85 90
95Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu
100 105 110Leu Leu Ile Tyr Glu
Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115
120 125Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys
Leu Ile Asp Asp 130 135 140Gln Asp Ile
Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His145
150 155 160Asn Asn Thr Ser Leu Leu Phe
Ile Asn Lys Cys Val Ile Leu His Ile 165
170 175Ser Xaa151246PRTHomo
sapiensmisc_feature(246)..(246)Xaa can be any naturally occurring amino
acid 151Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser1
5 10 15Trp Gly Thr Ala
Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20
25 30Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser
Arg Ala Gln Leu Arg 35 40 45Thr
Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50
55 60Val Leu Ser Leu Thr Pro Gly Ser Arg Gly
Gly Gly Arg Cys Cys Leu65 70 75
80Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser
Ser 85 90 95Thr Pro Thr
Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100
105 110Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp
Gly Arg Cys Asp Ala Thr 115 120
125Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130
135 140Gln Asp Ile Ser Ile Ser Leu Leu
Ser Leu Arg Ile Leu Ser Phe His145 150
155 160Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val
Ile Leu His Ile 165 170
175Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr
180 185 190Leu Pro Leu Pro Ala Gln
Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200
205Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile
Tyr Ile 210 215 220Phe Asp Val Val Asp
Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu225 230
235 240His Lys Glu Asp Val Xaa
245152415PRTHomo sapiensmisc_feature(415)..(415)Xaa can be any naturally
occurring amino acid 152Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser
Ala Gly Gly Ser1 5 10
15Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro
20 25 30Val Pro Ala Glu Ala Met Gly
Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40
45Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu
Gln 50 55 60Val Leu Ser Leu Thr Pro
Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu65 70
75 80Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp
Ser Arg Asn Ser Ser 85 90
95Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu
100 105 110Leu Leu Ile Tyr Glu Phe
Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115 120
125Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile
Asp Asp 130 135 140Gln Asp Ile Ser Ile
Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His145 150
155 160Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys
Cys Val Ile Leu His Ile 165 170
175Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr
180 185 190Leu Pro Leu Pro Ala
Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195
200 205Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly
Trp Ile Tyr Ile 210 215 220Phe Asp Val
Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu225
230 235 240His Lys Glu Asp Met Cys Asn
Glu Gln Gln Gln Glu Pro Ala Lys Ile 245
250 255Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu
Asp Val Ala Val 260 265 270Ile
Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275
280 285Phe Arg Gln His Pro Gly His Leu Leu
Cys Glu Arg Ile Leu Glu Asp 290 295
300Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn305
310 315 320Ser Ala Tyr Asn
Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg 325
330 335Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn
Glu Thr Ile Lys Asn Ser 340 345
350Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His
355 360 365Leu Glu Ser Pro Glu Ser Gly
Asn His Ser Thr Ser Val Gln Ser Trp 370 375
380Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu
Gln385 390 395 400Lys Ile
Met Pro Arg Pro Val Ile Gln Glu Asp His Gly Lys Xaa 405
410 415153412PRTHomo
sapiensmisc_feature(412)..(412)Xaa can be any naturally occurring amino
acid 153Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser1
5 10 15Trp Gly Thr Ala
Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20
25 30Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser
Arg Ala Gln Leu Arg 35 40 45Thr
Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50
55 60Val Leu Ser Leu Thr Pro Gly Ser Arg Gly
Gly Gly Arg Cys Cys Leu65 70 75
80Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser
Ser 85 90 95Thr Pro Thr
Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100
105 110Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp
Gly Arg Cys Asp Ala Thr 115 120
125Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130
135 140Gln Asp Ile Ser Ile Ser Leu Leu
Ser Leu Arg Ile Leu Ser Phe His145 150
155 160Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val
Ile Leu His Ile 165 170
175Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr
180 185 190Leu Pro Leu Pro Ala Gln
Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200
205Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile
Tyr Ile 210 215 220Phe Asp Val Val Asp
Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu225 230
235 240His Lys Glu Asp Met Cys Asn Glu Gln Gln
Gln Glu Pro Ala Lys Ile 245 250
255Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val
260 265 270Ile Val Ser Ser Ser
Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275
280 285Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg
Ile Leu Glu Asp 290 295 300Leu Pro Ile
Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn305
310 315 320Ser Ala Tyr Asn Met Lys Leu
Ala Lys Phe Ser Phe Gln Ile Asp Arg 325
330 335Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr
Ile Lys Asn Ser 340 345 350Lys
Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355
360 365Leu Glu Ser Pro Glu Ser Gly Asn His
Ser Thr Ser Val Gln Ser Trp 370 375
380Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln385
390 395 400Lys Asp His Ala
Lys Thr Ser Asp Pro Gly Arg Xaa 405
410154556PRTHomo sapiensmisc_feature(556)..(556)Xaa can be any naturally
occurring amino acid 154Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser
Ala Gly Gly Ser1 5 10
15Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro
20 25 30Val Pro Ala Glu Ala Met Gly
Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40
45Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu
Gln 50 55 60Val Leu Ser Leu Thr Pro
Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu65 70
75 80Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp
Ser Arg Asn Ser Ser 85 90
95Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu
100 105 110Leu Leu Ile Tyr Glu Phe
Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115 120
125Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile
Asp Asp 130 135 140Gln Asp Ile Ser Ile
Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His145 150
155 160Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys
Cys Val Ile Leu His Ile 165 170
175Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr
180 185 190Leu Pro Leu Pro Ala
Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195
200 205Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly
Trp Ile Tyr Ile 210 215 220Phe Asp Val
Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu225
230 235 240His Lys Glu Asp Met Cys Asn
Glu Gln Gln Gln Glu Pro Ala Lys Ile 245
250 255Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu
Asp Val Ala Val 260 265 270Ile
Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275
280 285Phe Arg Gln His Pro Gly His Leu Leu
Cys Glu Arg Ile Leu Glu Asp 290 295
300Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn305
310 315 320Ser Ala Tyr Asn
Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg 325
330 335Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn
Glu Thr Ile Lys Asn Ser 340 345
350Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His
355 360 365Leu Glu Ser Pro Glu Ser Gly
Asn His Ser Thr Ser Val Gln Ser Trp 370 375
380Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu
Gln385 390 395 400Lys Asp
His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met
405 410 415His Ile Ser Glu Gln Glu Glu
Pro Ile Glu Leu Lys Cys Val Ser Val 420 425
430Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met
Gly Tyr 435 440 445Thr Ile Thr Leu
Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450
455 460Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly
Asp Gln Gln Leu465 470 475
480Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu
485 490 495Thr Gln Glu Glu Phe
Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser 500
505 510Thr Val Asp Thr Leu Ser Ser Gln Trp Leu Gly Lys
Val Leu Asn Ser 515 520 525His Thr
Cys Thr Arg Gly Arg Asp Arg Lys Ser Ser Ala Gly His Ser 530
535 540Lys Phe Leu Phe Glu Glu Gln Gly Lys Ser Phe
Xaa545 550 555155651PRTHomo
sapiensmisc_feature(651)..(651)Xaa can be any naturally occurring amino
acid 155Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser1
5 10 15Trp Gly Thr Ala
Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20
25 30Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser
Arg Ala Gln Leu Arg 35 40 45Thr
Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50
55 60Val Leu Ser Leu Thr Pro Gly Ser Arg Gly
Gly Gly Arg Cys Cys Leu65 70 75
80Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser
Ser 85 90 95Thr Pro Thr
Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100
105 110Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp
Gly Arg Cys Asp Ala Thr 115 120
125Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130
135 140Gln Asp Ile Ser Ile Ser Leu Leu
Ser Leu Arg Ile Leu Ser Phe His145 150
155 160Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val
Ile Leu His Ile 165 170
175Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr
180 185 190Leu Pro Leu Pro Ala Gln
Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200
205Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile
Tyr Ile 210 215 220Phe Asp Val Val Asp
Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu225 230
235 240His Lys Glu Asp Met Cys Asn Glu Gln Gln
Gln Glu Pro Ala Lys Ile 245 250
255Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val
260 265 270Ile Val Ser Ser Ser
Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275
280 285Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg
Ile Leu Glu Asp 290 295 300Leu Pro Ile
Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn305
310 315 320Ser Ala Tyr Asn Met Lys Leu
Ala Lys Phe Ser Phe Gln Ile Asp Arg 325
330 335Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr
Ile Lys Asn Ser 340 345 350Lys
Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355
360 365Leu Glu Ser Pro Glu Ser Gly Asn His
Ser Thr Ser Val Gln Ser Trp 370 375
380Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln385
390 395 400Lys Asp His Ala
Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met 405
410 415His Ile Ser Glu Gln Glu Glu Pro Ile Glu
Leu Lys Cys Val Ser Val 420 425
430Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met Gly Tyr
435 440 445Thr Ile Thr Leu Trp Asp Leu
Glu Thr Gln Gly Met Gln Cys Ser Ser 450 455
460Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly Asp Gln Gln
Leu465 470 475 480Cys Phe
Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu
485 490 495Thr Gln Glu Glu Phe Leu Asn
Arg Leu Met Ile His Gly Ser Ala Ser 500 505
510Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly Arg Cys
Ser Ile 515 520 525Pro Ile His Ala
Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530
535 540Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu Phe
Asn Pro Ser Ser545 550 555
560Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu Tyr
565 570 575Leu Arg Asn Val Glu
Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580
585 590Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln Ser Lys
His Phe Ser Glu 595 600 605Gln Leu
Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610
615 620Leu Phe Ile His Thr Glu Glu Leu Asp Glu His
Leu Gln Lys Gly Val625 630 635
640Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Xaa 645
650156733PRTHomo sapiensmisc_feature(733)..(733)Xaa can be
any naturally occurring amino acid 156Met Ala Ala Glu Glu Gly Val Ala Ser
Ala Ala Ser Ala Gly Gly Ser1 5 10
15Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val
Pro 20 25 30Val Pro Ala Glu
Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35
40 45Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala
Gly Ser Leu Gln 50 55 60Val Leu Ser
Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu65 70
75 80Glu Gly Pro Phe Trp His Phe Leu
Trp Glu Asp Ser Arg Asn Ser Ser 85 90
95Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn
Tyr Glu 100 105 110Leu Leu Ile
Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115
120 125Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln
Lys Leu Ile Asp Asp 130 135 140Gln Asp
Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His145
150 155 160Asn Asn Thr Ser Leu Leu Phe
Ile Asn Lys Cys Val Ile Leu His Ile 165
170 175Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu
Asn Cys Phe Thr 180 185 190Leu
Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195
200 205Cys Arg Gly Ile Leu Phe Val Leu Ser
Ser Leu Gly Trp Ile Tyr Ile 210 215
220Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu225
230 235 240His Lys Glu Asp
Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile 245
250 255Ser Ser Phe Thr Ser Leu Lys Val Ser Gln
Asp Leu Asp Val Ala Val 260 265
270Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr
275 280 285Phe Arg Gln His Pro Gly His
Leu Leu Cys Glu Arg Ile Leu Glu Asp 290 295
300Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val
Asn305 310 315 320Ser Ala
Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg
325 330 335Ser Trp Lys Ala Gln Leu Ser
Ser Leu Asn Glu Thr Ile Lys Asn Ser 340 345
350Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile
Leu His 355 360 365Leu Glu Ser Pro
Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370
375 380Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr
Asn Val Leu Gln385 390 395
400Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met
405 410 415His Ile Ser Glu Gln
Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val 420
425 430Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu
Arg Met Gly Tyr 435 440 445Thr Ile
Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450
455 460Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser
Gly Asp Gln Gln Leu465 470 475
480Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu
485 490 495Thr Gln Glu Glu
Phe Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser 500
505 510Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp
Gly Arg Cys Ser Ile 515 520 525Pro
Ile His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530
535 540Val Asn Phe Phe Leu Lys Ser Lys Glu Asn
Leu Phe Asn Pro Ser Ser545 550 555
560Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu
Tyr 565 570 575Leu Arg Asn
Val Glu Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580
585 590Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln
Ser Lys His Phe Ser Glu 595 600
605Gln Leu Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610
615 620Leu Phe Ile His Thr Glu Glu Leu
Asp Glu His Leu Gln Lys Gly Val625 630
635 640Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Arg Thr
Phe Met Ile Lys 645 650
655Phe Pro Trp Lys Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu
660 665 670Asn Val Pro Lys Val Lys
Glu Ser Asn Ile Trp Lys Lys Leu Ser Phe 675 680
685Glu Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys Ile Pro
Glu Ala 690 695 700Gln Thr Phe Phe Arg
Ile Asp Ser His Ser Ala Gln Lys Leu Glu Glu705 710
715 720Leu Ile Gly Ile Gly Leu Asn Leu Val Phe
Asp Asn Xaa 725 730157953PRTHomo
sapiensmisc_feature(953)..(953)Xaa can be any naturally occurring amino
acid 157Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser1
5 10 15Trp Gly Thr Ala
Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20
25 30Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser
Arg Ala Gln Leu Arg 35 40 45Thr
Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50
55 60Val Leu Ser Leu Thr Pro Gly Ser Arg Gly
Gly Gly Arg Cys Cys Leu65 70 75
80Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser
Ser 85 90 95Thr Pro Thr
Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100
105 110Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp
Gly Arg Cys Asp Ala Thr 115 120
125Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130
135 140Gln Asp Ile Ser Ile Ser Leu Leu
Ser Leu Arg Ile Leu Ser Phe His145 150
155 160Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val
Ile Leu His Ile 165 170
175Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr
180 185 190Leu Pro Leu Pro Ala Gln
Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200
205Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile
Tyr Ile 210 215 220Phe Asp Val Val Asp
Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu225 230
235 240His Lys Glu Asp Met Cys Asn Glu Gln Gln
Gln Glu Pro Ala Lys Ile 245 250
255Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val
260 265 270Ile Val Ser Ser Ser
Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275
280 285Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg
Ile Leu Glu Asp 290 295 300Leu Pro Ile
Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn305
310 315 320Ser Ala Tyr Asn Met Lys Leu
Ala Lys Phe Ser Phe Gln Ile Asp Arg 325
330 335Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr
Ile Lys Asn Ser 340 345 350Lys
Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355
360 365Leu Glu Ser Pro Glu Ser Gly Asn His
Ser Thr Ser Val Gln Ser Trp 370 375
380Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln385
390 395 400Lys Asp His Ala
Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met 405
410 415His Ile Ser Glu Gln Glu Glu Pro Ile Glu
Leu Lys Cys Val Ser Val 420 425
430Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met Gly Tyr
435 440 445Thr Ile Thr Leu Trp Asp Leu
Glu Thr Gln Gly Met Gln Cys Ser Ser 450 455
460Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly Asp Gln Gln
Leu465 470 475 480Cys Phe
Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu
485 490 495Thr Gln Glu Glu Phe Leu Asn
Arg Leu Met Ile His Gly Ser Ala Ser 500 505
510Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly Arg Cys
Ser Ile 515 520 525Pro Ile His Ala
Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530
535 540Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu Phe
Asn Pro Ser Ser545 550 555
560Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu Tyr
565 570 575Leu Arg Asn Val Glu
Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580
585 590Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln Ser Lys
His Phe Ser Glu 595 600 605Gln Leu
Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610
615 620Leu Phe Ile His Thr Glu Glu Leu Asp Glu His
Leu Gln Lys Gly Val625 630 635
640Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Arg Thr Phe Met Ile Lys
645 650 655Phe Pro Trp Lys
Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu 660
665 670Asn Val Pro Lys Val Lys Glu Ser Asn Ile Trp
Lys Lys Leu Ser Phe 675 680 685Glu
Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys Ile Pro Glu Ala 690
695 700Gln Thr Phe Phe Arg Ile Asp Ser His Ser
Ala Gln Lys Leu Glu Glu705 710 715
720Leu Ile Gly Ile Gly Leu Asn Leu Val Phe Asp Asn Leu Lys Lys
Asn 725 730 735Asn Ile Lys
Glu Ala Ser Glu Leu Leu Lys Asn Met Gly Phe Asp Val 740
745 750Lys Gly Gln Leu Leu Lys Ile Cys Phe Tyr
Thr Thr Asn Lys Asn Ile 755 760
765Arg Asp Phe Leu Val Glu Ile Leu Lys Glu Lys Asn Tyr Phe Ser Glu 770
775 780Lys Glu Lys Arg Thr Ile Asp Phe
Val His Gln Val Glu Lys Leu Tyr785 790
795 800Leu Gly His Phe Gln Glu Asn Met Gln Ile Gln Ser
Phe Pro Arg Tyr 805 810
815Trp Ile Lys Glu Gln Asp Phe Phe Lys His Lys Ser Val Leu Asp Ser
820 825 830Phe Leu Lys Tyr Asp Cys
Lys Asp Glu Phe Asn Lys Gln Asp His Arg 835 840
845Ile Val Leu Asn Trp Ala Leu Trp Trp Asp Gln Leu Thr Gln
Glu Ser 850 855 860Ile Leu Leu Pro Arg
Ile Ser Pro Glu Glu Tyr Lys Ser Tyr Ser Pro865 870
875 880Glu Ala Leu Trp Arg Tyr Leu Thr Ala Arg
His Asp Trp Leu Asn Ile 885 890
895Ile Leu Trp Ile Gly Glu Phe Gln Thr Gln His Ser Tyr Ala Ser Leu
900 905 910Gln Gln Asn Lys Trp
Pro Leu Leu Thr Val Asp Val Ile Asn Gln Asn 915
920 925Thr Ser Cys Asn Asn Tyr Met Arg Asn Glu Ile Leu
Asp Lys Leu Ala 930 935 940Arg Asn Gly
Gly Phe Phe Gly Ile Xaa945 950158953PRTHomo
sapiensmisc_feature(953)..(953)Xaa can be any naturally occurring amino
acid 158Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser1
5 10 15Trp Gly Thr Ala
Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20
25 30Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser
Arg Ala Gln Leu Arg 35 40 45Thr
Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50
55 60Val Leu Ser Leu Thr Pro Gly Ser Arg Gly
Gly Gly Arg Cys Cys Leu65 70 75
80Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser
Ser 85 90 95Thr Pro Thr
Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100
105 110Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp
Gly Arg Cys Asp Ala Thr 115 120
125Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130
135 140Gln Asp Ile Ser Ile Ser Leu Leu
Ser Leu Arg Ile Leu Ser Phe His145 150
155 160Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val
Ile Leu His Ile 165 170
175Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr
180 185 190Leu Pro Leu Pro Ala Gln
Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200
205Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile
Tyr Ile 210 215 220Phe Asp Val Val Asp
Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu225 230
235 240His Lys Glu Asp Met Cys Asn Glu Gln Gln
Gln Glu Pro Ala Lys Ile 245 250
255Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val
260 265 270Ile Val Ser Ser Ser
Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275
280 285Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg
Ile Leu Glu Asp 290 295 300Leu Pro Ile
Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn305
310 315 320Ser Ala Tyr Asn Met Lys Leu
Ala Lys Phe Ser Phe Gln Ile Asp Arg 325
330 335Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr
Ile Lys Asn Ser 340 345 350Lys
Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355
360 365Leu Glu Ser Pro Glu Ser Gly Asn His
Ser Thr Ser Val Gln Ser Trp 370 375
380Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln385
390 395 400Lys Asp His Ala
Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met 405
410 415His Ile Ser Glu Gln Glu Glu Pro Ile Glu
Leu Lys Cys Val Ser Val 420 425
430Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met Gly Tyr
435 440 445Thr Ile Thr Leu Trp Asp Leu
Glu Thr Gln Gly Met Gln Cys Ser Ser 450 455
460Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly Asp Gln Gln
Leu465 470 475 480Cys Phe
Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu
485 490 495Thr Gln Glu Glu Phe Leu Asn
Arg Leu Met Ile His Gly Ser Ala Ser 500 505
510Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly Arg Cys
Ser Ile 515 520 525Pro Ile His Ala
Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530
535 540Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu Phe
Asn Pro Ser Ser545 550 555
560Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu Tyr
565 570 575Leu Arg Asn Val Glu
Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580
585 590Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln Ser Lys
His Phe Ser Glu 595 600 605Gln Leu
Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610
615 620Leu Phe Ile His Thr Glu Glu Leu Asp Glu His
Leu Gln Lys Gly Val625 630 635
640Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Arg Thr Phe Met Ile Lys
645 650 655Phe Pro Trp Lys
Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu 660
665 670Asn Val Pro Lys Val Lys Glu Ser Asn Ile Trp
Lys Lys Leu Ser Phe 675 680 685Glu
Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys Ile Pro Glu Ala 690
695 700Gln Thr Phe Phe Arg Ile Asp Ser His Ser
Ala Gln Lys Leu Glu Glu705 710 715
720Leu Ile Gly Ile Gly Leu Asn Leu Val Phe Asp Asn Leu Lys Lys
Asn 725 730 735Asn Ile Lys
Glu Ala Ser Glu Leu Leu Lys Asn Met Gly Phe Asp Val 740
745 750Lys Gly Gln Leu Leu Lys Ile Cys Phe Tyr
Thr Thr Asn Lys Asn Ile 755 760
765Arg Asp Phe Leu Val Glu Ile Leu Lys Glu Lys Asn Tyr Phe Ser Glu 770
775 780Lys Glu Lys Arg Thr Ile Asp Phe
Val His Gln Val Glu Lys Leu Tyr785 790
795 800Leu Gly His Phe Gln Glu Asn Met Gln Ile Gln Ser
Phe Pro Arg Tyr 805 810
815Trp Ile Lys Glu Gln Asp Phe Phe Lys His Lys Ser Val Leu Asp Ser
820 825 830Phe Leu Lys Tyr Asp Cys
Lys Asp Glu Phe Asn Lys Gln Asp His Arg 835 840
845Ile Val Leu Asn Trp Ala Leu Trp Trp Asp Gln Leu Thr Gln
Glu Ser 850 855 860Ile Leu Leu Pro Arg
Ile Ser Pro Glu Glu Tyr Lys Ser Tyr Ser Pro865 870
875 880Glu Ala Leu Trp Arg Tyr Leu Thr Ala Arg
His Asp Trp Leu Asn Ile 885 890
895Ile Leu Trp Ile Gly Glu Phe Gln Thr Gln His Ser Tyr Ala Ser Leu
900 905 910Gln Gln Asn Lys Trp
Pro Leu Leu Thr Val Asp Val Ile Asn Gln Asn 915
920 925Thr Ser Cys Asn Asn Tyr Met Arg Asn Glu Ile Leu
Asp Lys Leu Ala 930 935 940Arg Asn Gly
Val Phe Phe Gly Ile Xaa945 9501591992PRTHomo
sapiensmisc_feature(1992)..(1992)Xaa can be any naturally occurring amino
acid 159Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser1
5 10 15Trp Gly Thr Ala
Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20
25 30Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser
Arg Ala Gln Leu Arg 35 40 45Thr
Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50
55 60Val Leu Ser Leu Thr Pro Gly Ser Arg Gly
Gly Gly Arg Cys Cys Leu65 70 75
80Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser
Ser 85 90 95Thr Pro Thr
Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100
105 110Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp
Gly Arg Cys Asp Ala Thr 115 120
125Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130
135 140Gln Asp Ile Ser Ile Ser Leu Leu
Ser Leu Arg Ile Leu Ser Phe His145 150
155 160Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val
Ile Leu His Ile 165 170
175Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr
180 185 190Leu Pro Leu Pro Ala Gln
Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200
205Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile
Tyr Ile 210 215 220Phe Asp Val Val Asp
Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu225 230
235 240His Lys Glu Asp Met Cys Asn Glu Gln Gln
Gln Glu Pro Ala Lys Ile 245 250
255Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val
260 265 270Ile Val Ser Ser Ser
Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275
280 285Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg
Ile Leu Glu Asp 290 295 300Leu Pro Ile
Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn305
310 315 320Ser Ala Tyr Asn Met Lys Leu
Ala Lys Phe Ser Phe Gln Ile Asp Arg 325
330 335Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr
Ile Lys Asn Ser 340 345 350Lys
Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355
360 365Leu Glu Ser Pro Glu Ser Gly Asn His
Ser Thr Ser Val Gln Ser Trp 370 375
380Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln385
390 395 400Lys Asp His Ala
Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met 405
410 415His Ile Ser Glu Gln Glu Glu Pro Ile Glu
Leu Lys Cys Val Ser Val 420 425
430Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met Gly Tyr
435 440 445Thr Ile Thr Leu Trp Asp Leu
Glu Thr Gln Gly Met Gln Cys Ser Ser 450 455
460Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly Asp Gln Gln
Leu465 470 475 480Cys Phe
Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu
485 490 495Thr Gln Glu Glu Phe Leu Asn
Arg Leu Met Ile His Gly Ser Ala Ser 500 505
510Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly Arg Cys
Ser Ile 515 520 525Pro Ile His Ala
Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530
535 540Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu Phe
Asn Pro Ser Ser545 550 555
560Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu Tyr
565 570 575Leu Arg Asn Val Glu
Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580
585 590Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln Ser Lys
His Phe Ser Glu 595 600 605Gln Leu
Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610
615 620Leu Phe Ile His Thr Glu Glu Leu Asp Glu His
Leu Gln Lys Gly Val625 630 635
640Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Arg Thr Phe Met Ile Lys
645 650 655Phe Pro Trp Lys
Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu 660
665 670Asn Val Pro Lys Val Lys Glu Ser Asn Ile Trp
Lys Lys Leu Ser Phe 675 680 685Glu
Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys Ile Pro Glu Ala 690
695 700Gln Thr Phe Phe Arg Ile Asp Ser His Ser
Ala Gln Lys Leu Glu Glu705 710 715
720Leu Ile Gly Ile Gly Leu Asn Leu Val Phe Asp Asn Leu Lys Lys
Asn 725 730 735Asn Ile Lys
Glu Ala Ser Glu Leu Leu Lys Asn Met Gly Phe Asp Val 740
745 750Lys Gly Gln Leu Leu Lys Ile Cys Phe Tyr
Thr Thr Asn Lys Asn Ile 755 760
765Arg Asp Phe Leu Val Glu Ile Leu Lys Glu Lys Asn Tyr Phe Ser Glu 770
775 780Lys Glu Lys Arg Thr Ile Asp Phe
Val His Gln Val Glu Lys Leu Tyr785 790
795 800Leu Gly His Phe Gln Glu Asn Met Gln Ile Gln Ser
Phe Pro Arg Tyr 805 810
815Trp Ile Lys Glu Gln Asp Phe Phe Lys His Lys Ser Val Leu Asp Ser
820 825 830Phe Leu Lys Tyr Asp Cys
Lys Asp Glu Phe Asn Lys Gln Asp His Arg 835 840
845Ile Val Leu Asn Trp Ala Leu Trp Trp Asp Gln Leu Thr Gln
Glu Ser 850 855 860Ile Leu Leu Pro Arg
Ile Ser Pro Glu Glu Tyr Lys Ser Tyr Ser Pro865 870
875 880Glu Ala Leu Trp Arg Tyr Leu Thr Ala Arg
His Asp Trp Leu Asn Ile 885 890
895Ile Leu Trp Ile Gly Glu Phe Gln Thr Gln His Ser Tyr Ala Ser Leu
900 905 910Gln Gln Asn Lys Trp
Pro Leu Leu Thr Val Asp Val Ile Asn Gln Asn 915
920 925Thr Ser Cys Asn Asn Tyr Met Arg Asn Glu Ile Leu
Asp Lys Leu Ala 930 935 940Arg Asn Gly
Val Phe Leu Ala Ser Glu Leu Glu Asp Phe Glu Cys Phe945
950 955 960Leu Leu Arg Leu Ser Arg Ile
Gly Gly Val Ile Gln Asp Thr Leu Pro 965
970 975Val Gln Asn Tyr Lys Thr Lys Glu Gly Trp Asp Phe
His Ser Gln Phe 980 985 990Ile
Leu Tyr Cys Leu Glu His Ser Leu Gln His Leu Leu Tyr Val Tyr 995
1000 1005Leu Asp Cys Tyr Lys Leu Ser Pro
Glu Asn Cys Pro Phe Leu Glu 1010 1015
1020Lys Lys Glu Leu His Glu Ala His Pro Trp Phe Glu Phe Leu Val
1025 1030 1035Gln Cys Arg Gln Val Ala
Ser Asn Leu Thr Asp Pro Lys Leu Ile 1040 1045
1050Phe Gln Ala Ser Leu Ala Asn Ala Gln Ile Leu Ile Pro Thr
Asn 1055 1060 1065Gln Ala Ser Val Ser
Ser Met Leu Leu Glu Gly His Thr Leu Leu 1070 1075
1080Ala Leu Ala Thr Thr Met Tyr Ser Pro Gly Gly Val Ser
Gln Val 1085 1090 1095Val Gln Asn Glu
Glu Asn Glu Asn Cys Leu Lys Lys Val Asp Pro 1100
1105 1110Gln Leu Leu Lys Met Ala Leu Thr Pro Tyr Pro
Lys Leu Lys Thr 1115 1120 1125Ala Leu
Phe Pro Gln Cys Thr Pro Pro Ser Val Leu Pro Ser Asp 1130
1135 1140Ile Thr Ile Tyr His Leu Ile Gln Ser Leu
Ser Pro Phe Asp Pro 1145 1150 1155Ser
Arg Leu Phe Gly Trp Gln Ser Ala Asn Thr Leu Ala Ile Gly 1160
1165 1170Asp Ala Trp Ser His Leu Pro His Phe
Ser Ser Pro Asp Leu Val 1175 1180
1185Asn Lys Tyr Ala Ile Val Glu Arg Leu Asn Phe Ala Tyr Tyr Leu
1190 1195 1200His Asn Gly Arg Pro Ser
Phe Ala Phe Gly Thr Phe Leu Val Gln 1205 1210
1215Glu Leu Ile Lys Ser Lys Thr Pro Lys Gln Leu Ile Gln Gln
Val 1220 1225 1230Gly Asn Glu Ala Tyr
Val Ile Gly Leu Ser Ser Phe His Ile Pro 1235 1240
1245Ser Ile Gly Ala Ala Cys Val Cys Phe Leu Glu Leu Leu
Gly Leu 1250 1255 1260Asp Ser Leu Lys
Leu Arg Val Asp Met Lys Val Ala Asn Ile Ile 1265
1270 1275Leu Ser Tyr Lys Cys Arg Asn Glu Asp Ala Gln
Tyr Ser Phe Ile 1280 1285 1290Arg Glu
Ser Val Ala Glu Lys Leu Ser Lys Leu Ala Asp Gly Glu 1295
1300 1305Lys Thr Thr Thr Glu Glu Leu Leu Val Leu
Leu Glu Glu Gly Thr 1310 1315 1320Trp
Asn Ser Ile Gln Gln Gln Glu Ile Lys Arg Leu Ser Ser Glu 1325
1330 1335Ser Ser Ser Gln Trp Ala Leu Val Val
Gln Phe Cys Arg Leu His 1340 1345
1350Asn Met Lys Leu Ser Ile Ser Tyr Leu Arg Glu Cys Ala Lys Ala
1355 1360 1365Asn Asp Trp Leu Gln Phe
Ile Ile His Ser Gln Leu His Asn Tyr 1370 1375
1380His Pro Ala Glu Val Lys Ser Leu Ile Gln Tyr Phe Ser Pro
Val 1385 1390 1395Ile Gln Asp His Leu
Arg Leu Ala Phe Glu Asn Leu Pro Ser Val 1400 1405
1410Pro Thr Ser Lys Met Asp Ser Asp Gln Val Cys Asn Lys
Cys Pro 1415 1420 1425Gln Glu Leu Gln
Gly Ser Lys Gln Glu Met Thr Asp Leu Phe Glu 1430
1435 1440Ile Leu Leu Gln Cys Ser Glu Glu Pro Asp Ser
Trp His Trp Leu 1445 1450 1455Leu Val
Glu Ala Val Lys Gln Gln Ala Pro Ile Leu Ser Val Leu 1460
1465 1470Ala Ser Cys Leu Gln Gly Ala Ser Ala Ile
Ser Cys Leu Cys Val 1475 1480 1485Trp
Ile Ile Thr Ser Val Glu Asp Asn Val Ala Thr Glu Ala Met 1490
1495 1500Gly His Ile Gln Asp Ser Thr Glu Asp
His Thr Trp Asn Leu Glu 1505 1510
1515Asp Leu Ser Val Ile Trp Arg Thr Leu Leu Thr Arg Gln Lys Ser
1520 1525 1530Lys Thr Leu Ile Arg Gly
Phe Gln Leu Phe Phe Lys Asp Ser Pro 1535 1540
1545Leu Leu Leu Val Met Glu Met Tyr Glu Leu Cys Met Phe Phe
Arg 1550 1555 1560Asn Tyr Lys Glu Ala
Glu Ala Lys Leu Leu Glu Phe Gln Lys Ser 1565 1570
1575Leu Glu Thr Leu Asn Thr Ala Ala Thr Lys Val His Pro
Val Ile 1580 1585 1590Pro Ala Met Trp
Leu Glu Asp Gln Val Cys Phe Leu Leu Lys Leu 1595
1600 1605Met Leu Gln Gln Cys Lys Thr Gln Tyr Glu Leu
Gly Lys Leu Leu 1610 1615 1620Gln Leu
Phe Val Glu Arg Glu His Leu Phe Ser Asp Gly Pro Asp 1625
1630 1635Val Lys Lys Leu Cys Ile Leu Cys Gln Ile
Leu Lys Asp Thr Ser 1640 1645 1650Ile
Ala Ile Asn His Thr Ile Ile Thr Ser Tyr Ser Ile Glu Asn 1655
1660 1665Leu Gln His Glu Cys Arg Ser Ile Leu
Glu Arg Leu Gln Thr Asp 1670 1675
1680Gly Gln Phe Ala Leu Ala Arg Arg Val Ala Glu Leu Ala Glu Leu
1685 1690 1695Pro Val Asp Asn Leu Val
Ile Lys Glu Ile Thr Gln Glu Met Gln 1700 1705
1710Thr Leu Lys His Ile Glu Gln Trp Ser Leu Lys Gln Ala Arg
Ile 1715 1720 1725Asp Phe Trp Lys Lys
Cys His Glu Asn Phe Lys Lys Asn Ser Ile 1730 1735
1740Ser Ser Lys Ala Ala Ser Ser Phe Phe Ser Thr Gln Ala
His Val 1745 1750 1755Ala Cys Glu His
Pro Thr Gly Trp Ser Ser Met Glu Glu Arg His 1760
1765 1770Leu Leu Leu Thr Leu Ala Gly His Trp Leu Ala
Gln Glu Asp Val 1775 1780 1785Val Pro
Leu Asp Lys Leu Glu Glu Leu Glu Lys Gln Ile Trp Leu 1790
1795 1800Cys Arg Ile Thr Gln His Thr Leu Gly Arg
Asn Gln Glu Glu Thr 1805 1810 1815Glu
Pro Arg Phe Ser Arg Gln Ile Ser Thr Ser Gly Glu Leu Ser 1820
1825 1830Phe Asp Ser Leu Ala Ser Glu Phe Ser
Phe Ser Lys Leu Ala Ala 1835 1840
1845Leu Asn Thr Ser Lys Tyr Leu Glu Leu Asn Ser Leu Pro Ser Lys
1850 1855 1860Glu Thr Cys Glu Asn Arg
Leu Asp Trp Lys Glu Gln Glu Ser Leu 1865 1870
1875Asn Phe Leu Ile Gly Arg Leu Leu Asp Asp Gly Cys Val His
Glu 1880 1885 1890Ala Ser Arg Val Cys
Arg Tyr Phe His Phe Tyr Asn Pro Asp Val 1895 1900
1905Ala Leu Val Leu His Cys Arg Ala Leu Ala Ser Gly Glu
Ala Ser 1910 1915 1920Met Glu Asp Leu
His Pro Glu Ile His Ala Leu Leu Gln Ser Ala 1925
1930 1935Glu Leu Leu Glu Glu Glu Ala Pro Asp Ile Pro
Leu Arg Arg Val 1940 1945 1950His Ser
Thr Ser Ser Leu Asp Ser Gln Lys Phe Val Thr Val Pro 1955
1960 1965Ser Ser Asn Glu Val Val Thr Asn Leu Glu
Val Leu Thr Ser Lys 1970 1975 1980Cys
Leu His Gly Lys Asn Tyr Cys Xaa 1985
19901602034PRTHomo sapiensmisc_feature(2034)..(2034)Xaa can be any
naturally occurring amino acid 160Met Ala Ala Glu Glu Gly Val Ala Ser Ala
Ala Ser Ala Gly Gly Ser1 5 10
15Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro
20 25 30Val Pro Ala Glu Ala Met
Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40
45Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser
Leu Gln 50 55 60Val Leu Ser Leu Thr
Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu65 70
75 80Glu Gly Pro Phe Trp His Phe Leu Trp Glu
Asp Ser Arg Asn Ser Ser 85 90
95Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu
100 105 110Leu Leu Ile Tyr Glu
Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115
120 125Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys
Leu Ile Asp Asp 130 135 140Gln Asp Ile
Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His145
150 155 160Asn Asn Thr Ser Leu Leu Phe
Ile Asn Lys Cys Val Ile Leu His Ile 165
170 175Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu
Asn Cys Phe Thr 180 185 190Leu
Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195
200 205Cys Arg Gly Ile Leu Phe Val Leu Ser
Ser Leu Gly Trp Ile Tyr Ile 210 215
220Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu225
230 235 240His Lys Glu Asp
Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile 245
250 255Ser Ser Phe Thr Ser Leu Lys Val Ser Gln
Asp Leu Asp Val Ala Val 260 265
270Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr
275 280 285Phe Arg Gln His Pro Gly His
Leu Leu Cys Glu Arg Ile Leu Glu Asp 290 295
300Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val
Asn305 310 315 320Ser Ala
Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg
325 330 335Ser Trp Lys Ala Gln Leu Ser
Ser Leu Asn Glu Thr Ile Lys Asn Ser 340 345
350Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile
Leu His 355 360 365Leu Glu Ser Pro
Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370
375 380Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr
Asn Val Leu Gln385 390 395
400Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met
405 410 415His Ile Ser Glu Gln
Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val 420
425 430Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu
Arg Met Gly Tyr 435 440 445Thr Ile
Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450
455 460Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser
Gly Asp Gln Gln Leu465 470 475
480Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu
485 490 495Thr Gln Glu Glu
Phe Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser 500
505 510Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp
Gly Arg Cys Ser Ile 515 520 525Pro
Ile His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530
535 540Val Asn Phe Phe Leu Lys Ser Lys Glu Asn
Leu Phe Asn Pro Ser Ser545 550 555
560Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu
Tyr 565 570 575Leu Arg Asn
Val Glu Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580
585 590Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln
Ser Lys His Phe Ser Glu 595 600
605Gln Leu Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610
615 620Leu Phe Ile His Thr Glu Glu Leu
Asp Glu His Leu Gln Lys Gly Val625 630
635 640Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Arg Thr
Phe Met Ile Lys 645 650
655Phe Pro Trp Lys Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu
660 665 670Asn Val Pro Lys Val Lys
Glu Ser Asn Ile Trp Lys Lys Leu Ser Phe 675 680
685Glu Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys Ile Pro
Glu Ala 690 695 700Gln Thr Phe Phe Arg
Ile Asp Ser His Ser Ala Gln Lys Leu Glu Glu705 710
715 720Leu Ile Gly Ile Gly Leu Asn Leu Val Phe
Asp Asn Leu Lys Lys Asn 725 730
735Asn Ile Lys Glu Ala Ser Glu Leu Leu Lys Asn Met Gly Phe Asp Val
740 745 750Lys Gly Gln Leu Leu
Lys Ile Cys Phe Tyr Thr Thr Asn Lys Asn Ile 755
760 765Arg Asp Phe Leu Val Glu Ile Leu Lys Glu Lys Asn
Tyr Phe Ser Glu 770 775 780Lys Glu Lys
Arg Thr Ile Asp Phe Val His Gln Val Glu Lys Leu Tyr785
790 795 800Leu Gly His Phe Gln Glu Asn
Met Gln Ile Gln Ser Phe Pro Arg Tyr 805
810 815Trp Ile Lys Glu Gln Asp Phe Phe Lys His Lys Ser
Val Leu Asp Ser 820 825 830Phe
Leu Lys Tyr Asp Cys Lys Asp Glu Phe Asn Lys Gln Asp His Arg 835
840 845Ile Val Leu Asn Trp Ala Leu Trp Trp
Asp Gln Leu Thr Gln Glu Ser 850 855
860Ile Leu Leu Pro Arg Ile Ser Pro Glu Glu Tyr Lys Ser Tyr Ser Pro865
870 875 880Glu Ala Leu Trp
Arg Tyr Leu Thr Ala Arg His Asp Trp Leu Asn Ile 885
890 895Ile Leu Trp Ile Gly Glu Phe Gln Thr Gln
His Ser Tyr Ala Ser Leu 900 905
910Gln Gln Asn Lys Trp Pro Leu Leu Thr Val Asp Val Ile Asn Gln Asn
915 920 925Thr Ser Cys Asn Asn Tyr Met
Arg Asn Glu Ile Leu Asp Lys Leu Ala 930 935
940Arg Asn Gly Val Phe Leu Ala Ser Glu Leu Glu Asp Phe Glu Cys
Phe945 950 955 960Leu Leu
Arg Leu Ser Arg Ile Gly Gly Val Ile Gln Asp Thr Leu Pro
965 970 975Val Gln Asn Tyr Lys Thr Lys
Glu Gly Trp Asp Phe His Ser Gln Phe 980 985
990Ile Leu Tyr Cys Leu Glu His Ser Leu Gln His Leu Leu Tyr
Val Tyr 995 1000 1005Leu Asp Cys
Tyr Lys Leu Ser Pro Glu Asn Cys Pro Phe Leu Glu 1010
1015 1020Lys Lys Glu Leu His Glu Ala His Pro Trp Phe
Glu Phe Leu Val 1025 1030 1035Gln Cys
Arg Gln Val Ala Ser Asn Leu Thr Asp Pro Lys Leu Ile 1040
1045 1050Phe Gln Ala Ser Leu Ala Asn Ala Gln Ile
Leu Ile Pro Thr Asn 1055 1060 1065Gln
Ala Ser Val Ser Ser Met Leu Leu Glu Gly His Thr Leu Leu 1070
1075 1080Ala Leu Ala Thr Thr Met Tyr Ser Pro
Gly Gly Val Ser Gln Val 1085 1090
1095Val Gln Asn Glu Glu Asn Glu Asn Cys Leu Lys Lys Val Asp Pro
1100 1105 1110Gln Leu Leu Lys Met Ala
Leu Thr Pro Tyr Pro Lys Leu Lys Thr 1115 1120
1125Ala Leu Phe Pro Gln Cys Thr Pro Pro Ser Val Leu Pro Ser
Asp 1130 1135 1140Ile Thr Ile Tyr His
Leu Ile Gln Ser Leu Ser Pro Phe Asp Pro 1145 1150
1155Ser Arg Leu Phe Gly Trp Gln Ser Ala Asn Thr Leu Ala
Ile Gly 1160 1165 1170Asp Ala Trp Ser
His Leu Pro His Phe Ser Ser Pro Asp Leu Val 1175
1180 1185Asn Lys Tyr Ala Ile Val Glu Arg Leu Asn Phe
Ala Tyr Tyr Leu 1190 1195 1200His Asn
Gly Arg Pro Ser Phe Ala Phe Gly Thr Phe Leu Val Gln 1205
1210 1215Glu Leu Ile Lys Ser Lys Thr Pro Lys Gln
Leu Ile Gln Gln Val 1220 1225 1230Gly
Asn Glu Ala Tyr Val Ile Gly Leu Ser Ser Phe His Ile Pro 1235
1240 1245Ser Ile Gly Ala Ala Cys Val Cys Phe
Leu Glu Leu Leu Gly Leu 1250 1255
1260Asp Ser Leu Lys Leu Arg Val Asp Met Lys Val Ala Asn Ile Ile
1265 1270 1275Leu Ser Tyr Lys Cys Arg
Asn Glu Asp Ala Gln Tyr Ser Phe Ile 1280 1285
1290Arg Glu Ser Val Ala Glu Lys Leu Ser Lys Leu Ala Asp Gly
Glu 1295 1300 1305Lys Thr Thr Thr Glu
Glu Leu Leu Val Leu Leu Glu Glu Gly Thr 1310 1315
1320Trp Asn Ser Ile Gln Gln Gln Glu Ile Lys Arg Leu Ser
Ser Glu 1325 1330 1335Ser Ser Ser Gln
Trp Ala Leu Val Val Gln Phe Cys Arg Leu His 1340
1345 1350Asn Met Lys Leu Ser Ile Ser Tyr Leu Arg Glu
Cys Ala Lys Ala 1355 1360 1365Asn Asp
Trp Leu Gln Phe Ile Ile His Ser Gln Leu His Asn Tyr 1370
1375 1380His Pro Ala Glu Val Lys Ser Leu Ile Gln
Tyr Phe Ser Pro Val 1385 1390 1395Ile
Gln Asp His Leu Arg Leu Ala Phe Glu Asn Leu Pro Ser Val 1400
1405 1410Pro Thr Ser Lys Met Asp Ser Asp Gln
Val Cys Asn Lys Cys Pro 1415 1420
1425Gln Glu Leu Gln Gly Ser Lys Gln Glu Met Thr Asp Leu Phe Glu
1430 1435 1440Ile Leu Leu Gln Cys Ser
Glu Glu Pro Asp Ser Trp His Trp Leu 1445 1450
1455Leu Val Glu Ala Val Lys Gln Gln Ala Pro Ile Leu Ser Val
Leu 1460 1465 1470Ala Ser Cys Leu Gln
Gly Ala Ser Ala Ile Ser Cys Leu Cys Val 1475 1480
1485Trp Ile Ile Thr Ser Val Glu Asp Asn Val Ala Thr Glu
Ala Met 1490 1495 1500Gly His Ile Gln
Asp Ser Thr Glu Asp His Thr Trp Asn Leu Glu 1505
1510 1515Asp Leu Ser Val Ile Trp Arg Thr Leu Leu Thr
Arg Gln Lys Ser 1520 1525 1530Lys Thr
Leu Ile Arg Gly Phe Gln Leu Phe Phe Lys Asp Ser Pro 1535
1540 1545Leu Leu Leu Val Met Glu Met Tyr Glu Leu
Cys Met Phe Phe Arg 1550 1555 1560Asn
Tyr Lys Glu Ala Glu Ala Lys Leu Leu Glu Phe Gln Lys Ser 1565
1570 1575Leu Glu Thr Leu Asn Thr Ala Ala Thr
Lys Val His Pro Val Ile 1580 1585
1590Pro Ala Met Trp Leu Glu Asp Gln Val Cys Phe Leu Leu Lys Leu
1595 1600 1605Met Leu Gln Gln Cys Lys
Thr Gln Tyr Glu Leu Gly Lys Leu Leu 1610 1615
1620Gln Leu Phe Val Glu Arg Glu His Leu Phe Ser Asp Gly Pro
Asp 1625 1630 1635Val Lys Lys Leu Cys
Ile Leu Cys Gln Ile Leu Lys Asp Thr Ser 1640 1645
1650Ile Ala Ile Asn His Thr Ile Ile Thr Ser Tyr Ser Ile
Glu Asn 1655 1660 1665Leu Gln His Glu
Cys Arg Ser Ile Leu Glu Arg Leu Gln Thr Asp 1670
1675 1680Gly Gln Phe Ala Leu Ala Arg Arg Val Ala Glu
Leu Ala Glu Leu 1685 1690 1695Pro Val
Asp Asn Leu Val Ile Lys Glu Ile Thr Gln Glu Met Gln 1700
1705 1710Thr Leu Lys His Ile Glu Gln Trp Ser Leu
Lys Gln Ala Arg Ile 1715 1720 1725Asp
Phe Trp Lys Lys Cys His Glu Asn Phe Lys Lys Asn Ser Ile 1730
1735 1740Ser Ser Lys Ala Ala Ser Ser Phe Phe
Ser Thr Gln Ala His Val 1745 1750
1755Ala Cys Glu His Pro Thr Gly Trp Ser Ser Met Glu Glu Arg His
1760 1765 1770Leu Leu Leu Thr Leu Ala
Gly His Trp Leu Ala Gln Glu Asp Val 1775 1780
1785Val Pro Leu Asp Lys Leu Glu Glu Leu Glu Lys Gln Ile Trp
Leu 1790 1795 1800Cys Arg Ile Thr Gln
His Thr Leu Gly Arg Asn Gln Glu Glu Thr 1805 1810
1815Glu Pro Arg Phe Ser Arg Gln Ile Ser Thr Ser Gly Glu
Leu Ser 1820 1825 1830Phe Asp Ser Leu
Ala Ser Glu Phe Ser Phe Ser Lys Leu Ala Ala 1835
1840 1845Leu Asn Thr Ser Lys Tyr Leu Glu Leu Asn Ser
Leu Pro Ser Lys 1850 1855 1860Glu Thr
Cys Glu Asn Arg Leu Asp Trp Lys Glu Gln Glu Ser Leu 1865
1870 1875Asn Phe Leu Ile Gly Arg Leu Leu Asp Asp
Gly Cys Val His Glu 1880 1885 1890Ala
Ser Arg Val Cys Arg Tyr Phe His Phe Tyr Asn Pro Asp Val 1895
1900 1905Ala Leu Val Leu His Cys Arg Ala Leu
Ala Ser Gly Glu Ala Ser 1910 1915
1920Met Glu Asp Leu His Pro Glu Ile His Ala Leu Leu Gln Ser Ala
1925 1930 1935Glu Leu Leu Glu Glu Glu
Ala Pro Asp Ile Pro Leu Arg Arg Val 1940 1945
1950His Ser Thr Ser Ser Leu Asp Ser Gln Lys Phe Val Thr Val
Pro 1955 1960 1965Ser Ser Asn Glu Val
Val Thr Asn Leu Glu Val Leu Thr Ser Lys 1970 1975
1980Cys Leu His Gly Lys Asn Tyr Cys Arg Gln Val Leu Cys
Leu Tyr 1985 1990 1995Asp Leu Ala Lys
Glu Leu Gly Cys Ser Tyr Thr Asp Val Ala Ala 2000
2005 2010Gln Asp Gly Glu Ala Met Leu Arg Lys Ile Leu
Ala Ser Gln Gln 2015 2020 2025Pro Asp
Arg Cys Lys Xaa 20301612172PRTHomo
sapiensmisc_feature(2172)..(2172)Xaa can be any naturally occurring amino
acid 161Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser1
5 10 15Trp Gly Thr Ala
Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20
25 30Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser
Arg Ala Gln Leu Arg 35 40 45Thr
Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50
55 60Val Leu Ser Leu Thr Pro Gly Ser Arg Gly
Gly Gly Arg Cys Cys Leu65 70 75
80Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser
Ser 85 90 95Thr Pro Thr
Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100
105 110Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp
Gly Arg Cys Asp Ala Thr 115 120
125Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130
135 140Gln Asp Ile Ser Ile Ser Leu Leu
Ser Leu Arg Ile Leu Ser Phe His145 150
155 160Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val
Ile Leu His Ile 165 170
175Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr
180 185 190Leu Pro Leu Pro Ala Gln
Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200
205Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile
Tyr Ile 210 215 220Phe Asp Val Val Asp
Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu225 230
235 240His Lys Glu Asp Met Cys Asn Glu Gln Gln
Gln Glu Pro Ala Lys Ile 245 250
255Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val
260 265 270Ile Val Ser Ser Ser
Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275
280 285Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg
Ile Leu Glu Asp 290 295 300Leu Pro Ile
Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn305
310 315 320Ser Ala Tyr Asn Met Lys Leu
Ala Lys Phe Ser Phe Gln Ile Asp Arg 325
330 335Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr
Ile Lys Asn Ser 340 345 350Lys
Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355
360 365Leu Glu Ser Pro Glu Ser Gly Asn His
Ser Thr Ser Val Gln Ser Trp 370 375
380Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln385
390 395 400Lys Asp His Ala
Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met 405
410 415His Ile Ser Glu Gln Glu Glu Pro Ile Glu
Leu Lys Cys Val Ser Val 420 425
430Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met Gly Tyr
435 440 445Thr Ile Thr Leu Trp Asp Leu
Glu Thr Gln Gly Met Gln Cys Ser Ser 450 455
460Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly Asp Gln Gln
Leu465 470 475 480Cys Phe
Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu
485 490 495Thr Gln Glu Glu Phe Leu Asn
Arg Leu Met Ile His Gly Ser Ala Ser 500 505
510Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly Arg Cys
Ser Ile 515 520 525Pro Ile His Ala
Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530
535 540Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu Phe
Asn Pro Ser Ser545 550 555
560Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu Tyr
565 570 575Leu Arg Asn Val Glu
Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580
585 590Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln Ser Lys
His Phe Ser Glu 595 600 605Gln Leu
Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610
615 620Leu Phe Ile His Thr Glu Glu Leu Asp Glu His
Leu Gln Lys Gly Val625 630 635
640Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Arg Thr Phe Met Ile Lys
645 650 655Phe Pro Trp Lys
Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu 660
665 670Asn Val Pro Lys Val Lys Glu Ser Asn Ile Trp
Lys Lys Leu Ser Phe 675 680 685Glu
Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys Ile Pro Glu Ala 690
695 700Gln Thr Phe Phe Arg Ile Asp Ser His Ser
Ala Gln Lys Leu Glu Glu705 710 715
720Leu Ile Gly Ile Gly Leu Asn Leu Val Phe Asp Asn Leu Lys Lys
Asn 725 730 735Asn Ile Lys
Glu Ala Ser Glu Leu Leu Lys Asn Met Gly Phe Asp Val 740
745 750Lys Gly Gln Leu Leu Lys Ile Cys Phe Tyr
Thr Thr Asn Lys Asn Ile 755 760
765Arg Asp Phe Leu Val Glu Ile Leu Lys Glu Lys Asn Tyr Phe Ser Glu 770
775 780Lys Glu Lys Arg Thr Ile Asp Phe
Val His Gln Val Glu Lys Leu Tyr785 790
795 800Leu Gly His Phe Gln Glu Asn Met Gln Ile Gln Ser
Phe Pro Arg Tyr 805 810
815Trp Ile Lys Glu Gln Asp Phe Phe Lys His Lys Ser Val Leu Asp Ser
820 825 830Phe Leu Lys Tyr Asp Cys
Lys Asp Glu Phe Asn Lys Gln Asp His Arg 835 840
845Ile Val Leu Asn Trp Ala Leu Trp Trp Asp Gln Leu Thr Gln
Glu Ser 850 855 860Ile Leu Leu Pro Arg
Ile Ser Pro Glu Glu Tyr Lys Ser Tyr Ser Pro865 870
875 880Glu Ala Leu Trp Arg Tyr Leu Thr Ala Arg
His Asp Trp Leu Asn Ile 885 890
895Ile Leu Trp Ile Gly Glu Phe Gln Thr Gln His Ser Tyr Ala Ser Leu
900 905 910Gln Gln Asn Lys Trp
Pro Leu Leu Thr Val Asp Val Ile Asn Gln Asn 915
920 925Thr Ser Cys Asn Asn Tyr Met Arg Asn Glu Ile Leu
Asp Lys Leu Ala 930 935 940Arg Asn Gly
Val Phe Leu Ala Ser Glu Leu Glu Asp Phe Glu Cys Phe945
950 955 960Leu Leu Arg Leu Ser Arg Ile
Gly Gly Val Ile Gln Asp Thr Leu Pro 965
970 975Val Gln Asn Tyr Lys Thr Lys Glu Gly Trp Asp Phe
His Ser Gln Phe 980 985 990Ile
Leu Tyr Cys Leu Glu His Ser Leu Gln His Leu Leu Tyr Val Tyr 995
1000 1005Leu Asp Cys Tyr Lys Leu Ser Pro
Glu Asn Cys Pro Phe Leu Glu 1010 1015
1020Lys Lys Glu Leu His Glu Ala His Pro Trp Phe Glu Phe Leu Val
1025 1030 1035Gln Cys Arg Gln Val Ala
Ser Asn Leu Thr Asp Pro Lys Leu Ile 1040 1045
1050Phe Gln Ala Ser Leu Ala Asn Ala Gln Ile Leu Ile Pro Thr
Asn 1055 1060 1065Gln Ala Ser Val Ser
Ser Met Leu Leu Glu Gly His Thr Leu Leu 1070 1075
1080Ala Leu Ala Thr Thr Met Tyr Ser Pro Gly Gly Val Ser
Gln Val 1085 1090 1095Val Gln Asn Glu
Glu Asn Glu Asn Cys Leu Lys Lys Val Asp Pro 1100
1105 1110Gln Leu Leu Lys Met Ala Leu Thr Pro Tyr Pro
Lys Leu Lys Thr 1115 1120 1125Ala Leu
Phe Pro Gln Cys Thr Pro Pro Ser Val Leu Pro Ser Asp 1130
1135 1140Ile Thr Ile Tyr His Leu Ile Gln Ser Leu
Ser Pro Phe Asp Pro 1145 1150 1155Ser
Arg Leu Phe Gly Trp Gln Ser Ala Asn Thr Leu Ala Ile Gly 1160
1165 1170Asp Ala Trp Ser His Leu Pro His Phe
Ser Ser Pro Asp Leu Val 1175 1180
1185Asn Lys Tyr Ala Ile Val Glu Arg Leu Asn Phe Ala Tyr Tyr Leu
1190 1195 1200His Asn Gly Arg Pro Ser
Phe Ala Phe Gly Thr Phe Leu Val Gln 1205 1210
1215Glu Leu Ile Lys Ser Lys Thr Pro Lys Gln Leu Ile Gln Gln
Val 1220 1225 1230Gly Asn Glu Ala Tyr
Val Ile Gly Leu Ser Ser Phe His Ile Pro 1235 1240
1245Ser Ile Gly Ala Ala Cys Val Cys Phe Leu Glu Leu Leu
Gly Leu 1250 1255 1260Asp Ser Leu Lys
Leu Arg Val Asp Met Lys Val Ala Asn Ile Ile 1265
1270 1275Leu Ser Tyr Lys Cys Arg Asn Glu Asp Ala Gln
Tyr Ser Phe Ile 1280 1285 1290Arg Glu
Ser Val Ala Glu Lys Leu Ser Lys Leu Ala Asp Gly Glu 1295
1300 1305Lys Thr Thr Thr Glu Glu Leu Leu Val Leu
Leu Glu Glu Gly Thr 1310 1315 1320Trp
Asn Ser Ile Gln Gln Gln Glu Ile Lys Arg Leu Ser Ser Glu 1325
1330 1335Ser Ser Ser Gln Trp Ala Leu Val Val
Gln Phe Cys Arg Leu His 1340 1345
1350Asn Met Lys Leu Ser Ile Ser Tyr Leu Arg Glu Cys Ala Lys Ala
1355 1360 1365Asn Asp Trp Leu Gln Phe
Ile Ile His Ser Gln Leu His Asn Tyr 1370 1375
1380His Pro Ala Glu Val Lys Ser Leu Ile Gln Tyr Phe Ser Pro
Val 1385 1390 1395Ile Gln Asp His Leu
Arg Leu Ala Phe Glu Asn Leu Pro Ser Val 1400 1405
1410Pro Thr Ser Lys Met Asp Ser Asp Gln Val Cys Asn Lys
Cys Pro 1415 1420 1425Gln Glu Leu Gln
Gly Ser Lys Gln Glu Met Thr Asp Leu Phe Glu 1430
1435 1440Ile Leu Leu Gln Cys Ser Glu Glu Pro Asp Ser
Trp His Trp Leu 1445 1450 1455Leu Val
Glu Ala Val Lys Gln Gln Ala Pro Ile Leu Ser Val Leu 1460
1465 1470Ala Ser Cys Leu Gln Gly Ala Ser Ala Ile
Ser Cys Leu Cys Val 1475 1480 1485Trp
Ile Ile Thr Ser Val Glu Asp Asn Val Ala Thr Glu Ala Met 1490
1495 1500Gly His Ile Gln Asp Ser Thr Glu Asp
His Thr Trp Asn Leu Glu 1505 1510
1515Asp Leu Ser Val Ile Trp Arg Thr Leu Leu Thr Arg Gln Lys Ser
1520 1525 1530Lys Thr Leu Ile Arg Gly
Phe Gln Leu Phe Phe Lys Asp Ser Pro 1535 1540
1545Leu Leu Leu Val Met Glu Met Tyr Glu Leu Cys Met Phe Phe
Arg 1550 1555 1560Asn Tyr Lys Glu Ala
Glu Ala Lys Leu Leu Glu Phe Gln Lys Ser 1565 1570
1575Leu Glu Thr Leu Asn Thr Ala Ala Thr Lys Val His Pro
Val Ile 1580 1585 1590Pro Ala Met Trp
Leu Glu Asp Gln Val Cys Phe Leu Leu Lys Leu 1595
1600 1605Met Leu Gln Gln Cys Lys Thr Gln Tyr Glu Leu
Gly Lys Leu Leu 1610 1615 1620Gln Leu
Phe Val Glu Arg Glu His Leu Phe Ser Asp Gly Pro Asp 1625
1630 1635Val Lys Lys Leu Cys Ile Leu Cys Gln Ile
Leu Lys Asp Thr Ser 1640 1645 1650Ile
Ala Ile Asn His Thr Ile Ile Thr Ser Tyr Ser Ile Glu Asn 1655
1660 1665Leu Gln His Glu Cys Arg Ser Ile Leu
Glu Arg Leu Gln Thr Asp 1670 1675
1680Gly Gln Phe Ala Leu Ala Arg Arg Val Ala Glu Leu Ala Glu Leu
1685 1690 1695Pro Val Asp Asn Leu Val
Ile Lys Glu Ile Thr Gln Glu Met Gln 1700 1705
1710Thr Leu Lys His Ile Glu Gln Trp Ser Leu Lys Gln Ala Arg
Ile 1715 1720 1725Asp Phe Trp Lys Lys
Cys His Glu Asn Phe Lys Lys Asn Ser Ile 1730 1735
1740Ser Ser Lys Ala Ala Ser Ser Phe Phe Ser Thr Gln Ala
His Val 1745 1750 1755Ala Cys Glu His
Pro Thr Gly Trp Ser Ser Met Glu Glu Arg His 1760
1765 1770Leu Leu Leu Thr Leu Ala Gly His Trp Leu Ala
Gln Glu Asp Val 1775 1780 1785Val Pro
Leu Asp Lys Leu Glu Glu Leu Glu Lys Gln Ile Trp Leu 1790
1795 1800Cys Arg Ile Thr Gln His Thr Leu Gly Arg
Asn Gln Glu Glu Thr 1805 1810 1815Glu
Pro Arg Phe Ser Arg Gln Ile Ser Thr Ser Gly Glu Leu Ser 1820
1825 1830Phe Asp Ser Leu Ala Ser Glu Phe Ser
Phe Ser Lys Leu Ala Ala 1835 1840
1845Leu Asn Thr Ser Lys Tyr Leu Glu Leu Asn Ser Leu Pro Ser Lys
1850 1855 1860Glu Thr Cys Glu Asn Arg
Leu Asp Trp Lys Glu Gln Glu Ser Leu 1865 1870
1875Asn Phe Leu Ile Gly Arg Leu Leu Asp Asp Gly Cys Val His
Glu 1880 1885 1890Ala Ser Arg Val Cys
Arg Tyr Phe His Phe Tyr Asn Pro Asp Val 1895 1900
1905Ala Leu Val Leu His Cys Arg Ala Leu Ala Ser Gly Glu
Ala Ser 1910 1915 1920Met Glu Asp Leu
His Pro Glu Ile His Ala Leu Leu Gln Ser Ala 1925
1930 1935Glu Leu Leu Glu Glu Glu Ala Pro Asp Ile Pro
Leu Arg Arg Val 1940 1945 1950His Ser
Thr Ser Ser Leu Asp Ser Gln Lys Phe Val Thr Val Pro 1955
1960 1965Ser Ser Asn Glu Val Val Thr Asn Leu Glu
Val Leu Thr Ser Lys 1970 1975 1980Cys
Leu His Gly Lys Asn Tyr Cys Arg Gln Val Leu Cys Leu Tyr 1985
1990 1995Asp Leu Ala Lys Glu Leu Gly Cys Ser
Tyr Thr Asp Val Ala Ala 2000 2005
2010Gln Asp Gly Glu Ala Met Leu Arg Lys Ile Leu Ala Ser Gln Gln
2015 2020 2025Pro Asp Arg Cys Lys Arg
Ala Gln Ala Phe Ile Ser Thr Gln Gly 2030 2035
2040Leu Lys Pro Asp Thr Val Ala Glu Leu Val Ala Glu Glu Val
Thr 2045 2050 2055Arg Glu Leu Leu Thr
Ser Ser Gln Gly Thr Gly His Lys Gln Met 2060 2065
2070Phe Asn Pro Thr Glu Glu Ser Gln Thr Phe Leu Gln Leu
Thr Thr 2075 2080 2085Leu Cys Gln Asp
Arg Thr Leu Val Gly Met Lys Leu Leu Asp Lys 2090
2095 2100Ile Ser Ser Val Pro His Gly Glu Leu Ser Cys
Thr Thr Glu Leu 2105 2110 2115Leu Ile
Leu Ala His His Cys Phe Thr Leu Thr Cys His Met Glu 2120
2125 2130Gly Ile Ile Arg Val Leu Gln Ala Ala His
Met Leu Thr Asp Asn 2135 2140 2145His
Leu Pro Pro Val Arg Ser Met Gly Trp Trp Tyr Gly Ser Ser 2150
2155 2160Leu Ala Leu Glu Gly Thr Thr Arg Xaa
2165 21701622260PRTHomo
sapiensmisc_feature(2260)..(2260)Xaa can be any naturally occurring amino
acid 162Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser1
5 10 15Trp Gly Thr Ala
Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20
25 30Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser
Arg Ala Gln Leu Arg 35 40 45Thr
Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50
55 60Val Leu Ser Leu Thr Pro Gly Ser Arg Gly
Gly Gly Arg Cys Cys Leu65 70 75
80Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser
Ser 85 90 95Thr Pro Thr
Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100
105 110Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp
Gly Arg Cys Asp Ala Thr 115 120
125Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130
135 140Gln Asp Ile Ser Ile Ser Leu Leu
Ser Leu Arg Ile Leu Ser Phe His145 150
155 160Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val
Ile Leu His Ile 165 170
175Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr
180 185 190Leu Pro Leu Pro Ala Gln
Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200
205Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile
Tyr Ile 210 215 220Phe Asp Val Val Asp
Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu225 230
235 240His Lys Glu Asp Met Cys Asn Glu Gln Gln
Gln Glu Pro Ala Lys Ile 245 250
255Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val
260 265 270Ile Val Ser Ser Ser
Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275
280 285Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg
Ile Leu Glu Asp 290 295 300Leu Pro Ile
Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn305
310 315 320Ser Ala Tyr Asn Met Lys Leu
Ala Lys Phe Ser Phe Gln Ile Asp Arg 325
330 335Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr
Ile Lys Asn Ser 340 345 350Lys
Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355
360 365Leu Glu Ser Pro Glu Ser Gly Asn His
Ser Thr Ser Val Gln Ser Trp 370 375
380Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln385
390 395 400Lys Asp His Ala
Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met 405
410 415His Ile Ser Glu Gln Glu Glu Pro Ile Glu
Leu Lys Cys Val Ser Val 420 425
430Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met Gly Tyr
435 440 445Thr Ile Thr Leu Trp Asp Leu
Glu Thr Gln Gly Met Gln Cys Ser Ser 450 455
460Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly Asp Gln Gln
Leu465 470 475 480Cys Phe
Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu
485 490 495Thr Gln Glu Glu Phe Leu Asn
Arg Leu Met Ile His Gly Ser Ala Ser 500 505
510Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly Arg Cys
Ser Ile 515 520 525Pro Ile His Ala
Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530
535 540Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu Phe
Asn Pro Ser Ser545 550 555
560Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu Tyr
565 570 575Leu Arg Asn Val Glu
Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580
585 590Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln Ser Lys
His Phe Ser Glu 595 600 605Gln Leu
Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610
615 620Leu Phe Ile His Thr Glu Glu Leu Asp Glu His
Leu Gln Lys Gly Val625 630 635
640Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Arg Thr Phe Met Ile Lys
645 650 655Phe Pro Trp Lys
Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu 660
665 670Asn Val Pro Lys Val Lys Glu Ser Asn Ile Trp
Lys Lys Leu Ser Phe 675 680 685Glu
Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys Ile Pro Glu Ala 690
695 700Gln Thr Phe Phe Arg Ile Asp Ser His Ser
Ala Gln Lys Leu Glu Glu705 710 715
720Leu Ile Gly Ile Gly Leu Asn Leu Val Phe Asp Asn Leu Lys Lys
Asn 725 730 735Asn Ile Lys
Glu Ala Ser Glu Leu Leu Lys Asn Met Gly Phe Asp Val 740
745 750Lys Gly Gln Leu Leu Lys Ile Cys Phe Tyr
Thr Thr Asn Lys Asn Ile 755 760
765Arg Asp Phe Leu Val Glu Ile Leu Lys Glu Lys Asn Tyr Phe Ser Glu 770
775 780Lys Glu Lys Arg Thr Ile Asp Phe
Val His Gln Val Glu Lys Leu Tyr785 790
795 800Leu Gly His Phe Gln Glu Asn Met Gln Ile Gln Ser
Phe Pro Arg Tyr 805 810
815Trp Ile Lys Glu Gln Asp Phe Phe Lys His Lys Ser Val Leu Asp Ser
820 825 830Phe Leu Lys Tyr Asp Cys
Lys Asp Glu Phe Asn Lys Gln Asp His Arg 835 840
845Ile Val Leu Asn Trp Ala Leu Trp Trp Asp Gln Leu Thr Gln
Glu Ser 850 855 860Ile Leu Leu Pro Arg
Ile Ser Pro Glu Glu Tyr Lys Ser Tyr Ser Pro865 870
875 880Glu Ala Leu Trp Arg Tyr Leu Thr Ala Arg
His Asp Trp Leu Asn Ile 885 890
895Ile Leu Trp Ile Gly Glu Phe Gln Thr Gln His Ser Tyr Ala Ser Leu
900 905 910Gln Gln Asn Lys Trp
Pro Leu Leu Thr Val Asp Val Ile Asn Gln Asn 915
920 925Thr Ser Cys Asn Asn Tyr Met Arg Asn Glu Ile Leu
Asp Lys Leu Ala 930 935 940Arg Asn Gly
Val Phe Leu Ala Ser Glu Leu Glu Asp Phe Glu Cys Phe945
950 955 960Leu Leu Arg Leu Ser Arg Ile
Gly Gly Val Ile Gln Asp Thr Leu Pro 965
970 975Val Gln Asn Tyr Lys Thr Lys Glu Gly Trp Asp Phe
His Ser Gln Phe 980 985 990Ile
Leu Tyr Cys Leu Glu His Ser Leu Gln His Leu Leu Tyr Val Tyr 995
1000 1005Leu Asp Cys Tyr Lys Leu Ser Pro
Glu Asn Cys Pro Phe Leu Glu 1010 1015
1020Lys Lys Glu Leu His Glu Ala His Pro Trp Phe Glu Phe Leu Val
1025 1030 1035Gln Cys Arg Gln Val Ala
Ser Asn Leu Thr Asp Pro Lys Leu Ile 1040 1045
1050Phe Gln Ala Ser Leu Ala Asn Ala Gln Ile Leu Ile Pro Thr
Asn 1055 1060 1065Gln Ala Ser Val Ser
Ser Met Leu Leu Glu Gly His Thr Leu Leu 1070 1075
1080Ala Leu Ala Thr Thr Met Tyr Ser Pro Gly Gly Val Ser
Gln Val 1085 1090 1095Val Gln Asn Glu
Glu Asn Glu Asn Cys Leu Lys Lys Val Asp Pro 1100
1105 1110Gln Leu Leu Lys Met Ala Leu Thr Pro Tyr Pro
Lys Leu Lys Thr 1115 1120 1125Ala Leu
Phe Pro Gln Cys Thr Pro Pro Ser Val Leu Pro Ser Asp 1130
1135 1140Ile Thr Ile Tyr His Leu Ile Gln Ser Leu
Ser Pro Phe Asp Pro 1145 1150 1155Ser
Arg Leu Phe Gly Trp Gln Ser Ala Asn Thr Leu Ala Ile Gly 1160
1165 1170Asp Ala Trp Ser His Leu Pro His Phe
Ser Ser Pro Asp Leu Val 1175 1180
1185Asn Lys Tyr Ala Ile Val Glu Arg Leu Asn Phe Ala Tyr Tyr Leu
1190 1195 1200His Asn Gly Arg Pro Ser
Phe Ala Phe Gly Thr Phe Leu Val Gln 1205 1210
1215Glu Leu Ile Lys Ser Lys Thr Pro Lys Gln Leu Ile Gln Gln
Val 1220 1225 1230Gly Asn Glu Ala Tyr
Val Ile Gly Leu Ser Ser Phe His Ile Pro 1235 1240
1245Ser Ile Gly Ala Ala Cys Val Cys Phe Leu Glu Leu Leu
Gly Leu 1250 1255 1260Asp Ser Leu Lys
Leu Arg Val Asp Met Lys Val Ala Asn Ile Ile 1265
1270 1275Leu Ser Tyr Lys Cys Arg Asn Glu Asp Ala Gln
Tyr Ser Phe Ile 1280 1285 1290Arg Glu
Ser Val Ala Glu Lys Leu Ser Lys Leu Ala Asp Gly Glu 1295
1300 1305Lys Thr Thr Thr Glu Glu Leu Leu Val Leu
Leu Glu Glu Gly Thr 1310 1315 1320Trp
Asn Ser Ile Gln Gln Gln Glu Ile Lys Arg Leu Ser Ser Glu 1325
1330 1335Ser Ser Ser Gln Trp Ala Leu Val Val
Gln Phe Cys Arg Leu His 1340 1345
1350Asn Met Lys Leu Ser Ile Ser Tyr Leu Arg Glu Cys Ala Lys Ala
1355 1360 1365Asn Asp Trp Leu Gln Phe
Ile Ile His Ser Gln Leu His Asn Tyr 1370 1375
1380His Pro Ala Glu Val Lys Ser Leu Ile Gln Tyr Phe Ser Pro
Val 1385 1390 1395Ile Gln Asp His Leu
Arg Leu Ala Phe Glu Asn Leu Pro Ser Val 1400 1405
1410Pro Thr Ser Lys Met Asp Ser Asp Gln Val Cys Asn Lys
Cys Pro 1415 1420 1425Gln Glu Leu Gln
Gly Ser Lys Gln Glu Met Thr Asp Leu Phe Glu 1430
1435 1440Ile Leu Leu Gln Cys Ser Glu Glu Pro Asp Ser
Trp His Trp Leu 1445 1450 1455Leu Val
Glu Ala Val Lys Gln Gln Ala Pro Ile Leu Ser Val Leu 1460
1465 1470Ala Ser Cys Leu Gln Gly Ala Ser Ala Ile
Ser Cys Leu Cys Val 1475 1480 1485Trp
Ile Ile Thr Ser Val Glu Asp Asn Val Ala Thr Glu Ala Met 1490
1495 1500Gly His Ile Gln Asp Ser Thr Glu Asp
His Thr Trp Asn Leu Glu 1505 1510
1515Asp Leu Ser Val Ile Trp Arg Thr Leu Leu Thr Arg Gln Lys Ser
1520 1525 1530Lys Thr Leu Ile Arg Gly
Phe Gln Leu Phe Phe Lys Asp Ser Pro 1535 1540
1545Leu Leu Leu Val Met Glu Met Tyr Glu Leu Cys Met Phe Phe
Arg 1550 1555 1560Asn Tyr Lys Glu Ala
Glu Ala Lys Leu Leu Glu Phe Gln Lys Ser 1565 1570
1575Leu Glu Thr Leu Asn Thr Ala Ala Thr Lys Val His Pro
Val Ile 1580 1585 1590Pro Ala Met Trp
Leu Glu Asp Gln Val Cys Phe Leu Leu Lys Leu 1595
1600 1605Met Leu Gln Gln Cys Lys Thr Gln Tyr Glu Leu
Gly Lys Leu Leu 1610 1615 1620Gln Leu
Phe Val Glu Arg Glu His Leu Phe Ser Asp Gly Pro Asp 1625
1630 1635Val Lys Lys Leu Cys Ile Leu Cys Gln Ile
Leu Lys Asp Thr Ser 1640 1645 1650Ile
Ala Ile Asn His Thr Ile Ile Thr Ser Tyr Ser Ile Glu Asn 1655
1660 1665Leu Gln His Glu Cys Arg Ser Ile Leu
Glu Arg Leu Gln Thr Asp 1670 1675
1680Gly Gln Phe Ala Leu Ala Arg Arg Val Ala Glu Leu Ala Glu Leu
1685 1690 1695Pro Val Asp Asn Leu Val
Ile Lys Glu Ile Thr Gln Glu Met Gln 1700 1705
1710Thr Leu Lys His Ile Glu Gln Trp Ser Leu Lys Gln Ala Arg
Ile 1715 1720 1725Asp Phe Trp Lys Lys
Cys His Glu Asn Phe Lys Lys Asn Ser Ile 1730 1735
1740Ser Ser Lys Ala Ala Ser Ser Phe Phe Ser Thr Gln Ala
His Val 1745 1750 1755Ala Cys Glu His
Pro Thr Gly Trp Ser Ser Met Glu Glu Arg His 1760
1765 1770Leu Leu Leu Thr Leu Ala Gly His Trp Leu Ala
Gln Glu Asp Val 1775 1780 1785Val Pro
Leu Asp Lys Leu Glu Glu Leu Glu Lys Gln Ile Trp Leu 1790
1795 1800Cys Arg Ile Thr Gln His Thr Leu Gly Arg
Asn Gln Glu Glu Thr 1805 1810 1815Glu
Pro Arg Phe Ser Arg Gln Ile Ser Thr Ser Gly Glu Leu Ser 1820
1825 1830Phe Asp Ser Leu Ala Ser Glu Phe Ser
Phe Ser Lys Leu Ala Ala 1835 1840
1845Leu Asn Thr Ser Lys Tyr Leu Glu Leu Asn Ser Leu Pro Ser Lys
1850 1855 1860Glu Thr Cys Glu Asn Arg
Leu Asp Trp Lys Glu Gln Glu Ser Leu 1865 1870
1875Asn Phe Leu Ile Gly Arg Leu Leu Asp Asp Gly Cys Val His
Glu 1880 1885 1890Ala Ser Arg Val Cys
Arg Tyr Phe His Phe Tyr Asn Pro Asp Val 1895 1900
1905Ala Leu Val Leu His Cys Arg Ala Leu Ala Ser Gly Glu
Ala Ser 1910 1915 1920Met Glu Asp Leu
His Pro Glu Ile His Ala Leu Leu Gln Ser Ala 1925
1930 1935Glu Leu Leu Glu Glu Glu Ala Pro Asp Ile Pro
Leu Arg Arg Val 1940 1945 1950His Ser
Thr Ser Ser Leu Asp Ser Gln Lys Phe Val Thr Val Pro 1955
1960 1965Ser Ser Asn Glu Val Val Thr Asn Leu Glu
Val Leu Thr Ser Lys 1970 1975 1980Cys
Leu His Gly Lys Asn Tyr Cys Arg Gln Val Leu Cys Leu Tyr 1985
1990 1995Asp Leu Ala Lys Glu Leu Gly Cys Ser
Tyr Thr Asp Val Ala Ala 2000 2005
2010Gln Asp Gly Glu Ala Met Leu Arg Lys Ile Leu Ala Ser Gln Gln
2015 2020 2025Pro Asp Arg Cys Lys Arg
Ala Gln Ala Phe Ile Ser Thr Gln Gly 2030 2035
2040Leu Lys Pro Asp Thr Val Ala Glu Leu Val Ala Glu Glu Val
Thr 2045 2050 2055Arg Glu Leu Leu Thr
Ser Ser Gln Gly Thr Gly His Lys Gln Met 2060 2065
2070Phe Asn Pro Thr Glu Glu Ser Gln Thr Phe Leu Gln Leu
Thr Thr 2075 2080 2085Leu Cys Gln Asp
Arg Thr Leu Val Gly Met Lys Leu Leu Asp Lys 2090
2095 2100Ile Ser Ser Val Pro His Gly Glu Leu Ser Cys
Thr Thr Glu Leu 2105 2110 2115Leu Ile
Leu Ala His His Cys Phe Thr Leu Thr Cys His Met Glu 2120
2125 2130Gly Ile Ile Arg Val Leu Gln Ala Ala His
Met Leu Thr Asp Asn 2135 2140 2145His
Leu Ala Pro Ser Glu Glu Tyr Gly Leu Val Val Arg Leu Leu 2150
2155 2160Thr Gly Ile Gly Arg Tyr Asn Glu Met
Thr Tyr Ile Phe Asp Leu 2165 2170
2175Leu His Lys Lys His Tyr Phe Glu Val Leu Met Arg Lys Lys Leu
2180 2185 2190Asp Pro Ser Gly Thr Leu
Lys Thr Ala Leu Leu Asp Tyr Ile Lys 2195 2200
2205Arg Cys Arg Pro Gly Asp Ser Glu Lys His Asn Met Ile Ala
Leu 2210 2215 2220Cys Phe Ser Met Cys
Arg Glu Ile Gly Glu Asn His Glu Ala Ala 2225 2230
2235Ala Arg Ile Gln Leu Lys Leu Ser Leu Ser Pro Gly Arg
Thr Ala 2240 2245 2250Ser Arg Met Gly
Thr Ser Xaa 2255 22601632338PRTHomo
sapiensmisc_feature(2338)..(2338)Xaa can be any naturally occurring amino
acid 163Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser1
5 10 15Trp Gly Thr Ala
Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20
25 30Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser
Arg Ala Gln Leu Arg 35 40 45Thr
Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50
55 60Val Leu Ser Leu Thr Pro Gly Ser Arg Gly
Gly Gly Arg Cys Cys Leu65 70 75
80Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser
Ser 85 90 95Thr Pro Thr
Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100
105 110Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp
Gly Arg Cys Asp Ala Thr 115 120
125Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130
135 140Gln Asp Ile Ser Ile Ser Leu Leu
Ser Leu Arg Ile Leu Ser Phe His145 150
155 160Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val
Ile Leu His Ile 165 170
175Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr
180 185 190Leu Pro Leu Pro Ala Gln
Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200
205Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile
Tyr Ile 210 215 220Phe Asp Val Val Asp
Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu225 230
235 240His Lys Glu Asp Met Cys Asn Glu Gln Gln
Gln Glu Pro Ala Lys Ile 245 250
255Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val
260 265 270Ile Val Ser Ser Ser
Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275
280 285Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg
Ile Leu Glu Asp 290 295 300Leu Pro Ile
Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn305
310 315 320Ser Ala Tyr Asn Met Lys Leu
Ala Lys Phe Ser Phe Gln Ile Asp Arg 325
330 335Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr
Ile Lys Asn Ser 340 345 350Lys
Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355
360 365Leu Glu Ser Pro Glu Ser Gly Asn His
Ser Thr Ser Val Gln Ser Trp 370 375
380Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln385
390 395 400Lys Asp His Ala
Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met 405
410 415His Ile Ser Glu Gln Glu Glu Pro Ile Glu
Leu Lys Cys Val Ser Val 420 425
430Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met Gly Tyr
435 440 445Thr Ile Thr Leu Trp Asp Leu
Glu Thr Gln Gly Met Gln Cys Ser Ser 450 455
460Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly Asp Gln Gln
Leu465 470 475 480Cys Phe
Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu
485 490 495Thr Gln Glu Glu Phe Leu Asn
Arg Leu Met Ile His Gly Ser Ala Ser 500 505
510Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly Arg Cys
Ser Ile 515 520 525Pro Ile His Ala
Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530
535 540Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu Phe
Asn Pro Ser Ser545 550 555
560Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu Tyr
565 570 575Leu Arg Asn Val Glu
Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580
585 590Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln Ser Lys
His Phe Ser Glu 595 600 605Gln Leu
Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610
615 620Leu Phe Ile His Thr Glu Glu Leu Asp Glu His
Leu Gln Lys Gly Val625 630 635
640Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Arg Thr Phe Met Ile Lys
645 650 655Phe Pro Trp Lys
Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu 660
665 670Asn Val Pro Lys Val Lys Glu Ser Asn Ile Trp
Lys Lys Leu Ser Phe 675 680 685Glu
Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys Ile Pro Glu Ala 690
695 700Gln Thr Phe Phe Arg Ile Asp Ser His Ser
Ala Gln Lys Leu Glu Glu705 710 715
720Leu Ile Gly Ile Gly Leu Asn Leu Val Phe Asp Asn Leu Lys Lys
Asn 725 730 735Asn Ile Lys
Glu Ala Ser Glu Leu Leu Lys Asn Met Gly Phe Asp Val 740
745 750Lys Gly Gln Leu Leu Lys Ile Cys Phe Tyr
Thr Thr Asn Lys Asn Ile 755 760
765Arg Asp Phe Leu Val Glu Ile Leu Lys Glu Lys Asn Tyr Phe Ser Glu 770
775 780Lys Glu Lys Arg Thr Ile Asp Phe
Val His Gln Val Glu Lys Leu Tyr785 790
795 800Leu Gly His Phe Gln Glu Asn Met Gln Ile Gln Ser
Phe Pro Arg Tyr 805 810
815Trp Ile Lys Glu Gln Asp Phe Phe Lys His Lys Ser Val Leu Asp Ser
820 825 830Phe Leu Lys Tyr Asp Cys
Lys Asp Glu Phe Asn Lys Gln Asp His Arg 835 840
845Ile Val Leu Asn Trp Ala Leu Trp Trp Asp Gln Leu Thr Gln
Glu Ser 850 855 860Ile Leu Leu Pro Arg
Ile Ser Pro Glu Glu Tyr Lys Ser Tyr Ser Pro865 870
875 880Glu Ala Leu Trp Arg Tyr Leu Thr Ala Arg
His Asp Trp Leu Asn Ile 885 890
895Ile Leu Trp Ile Gly Glu Phe Gln Thr Gln His Ser Tyr Ala Ser Leu
900 905 910Gln Gln Asn Lys Trp
Pro Leu Leu Thr Val Asp Val Ile Asn Gln Asn 915
920 925Thr Ser Cys Asn Asn Tyr Met Arg Asn Glu Ile Leu
Asp Lys Leu Ala 930 935 940Arg Asn Gly
Val Phe Leu Ala Ser Glu Leu Glu Asp Phe Glu Cys Phe945
950 955 960Leu Leu Arg Leu Ser Arg Ile
Gly Gly Val Ile Gln Asp Thr Leu Pro 965
970 975Val Gln Asn Tyr Lys Thr Lys Glu Gly Trp Asp Phe
His Ser Gln Phe 980 985 990Ile
Leu Tyr Cys Leu Glu His Ser Leu Gln His Leu Leu Tyr Val Tyr 995
1000 1005Leu Asp Cys Tyr Lys Leu Ser Pro
Glu Asn Cys Pro Phe Leu Glu 1010 1015
1020Lys Lys Glu Leu His Glu Ala His Pro Trp Phe Glu Phe Leu Val
1025 1030 1035Gln Cys Arg Gln Val Ala
Ser Asn Leu Thr Asp Pro Lys Leu Ile 1040 1045
1050Phe Gln Ala Ser Leu Ala Asn Ala Gln Ile Leu Ile Pro Thr
Asn 1055 1060 1065Gln Ala Ser Val Ser
Ser Met Leu Leu Glu Gly His Thr Leu Leu 1070 1075
1080Ala Leu Ala Thr Thr Met Tyr Ser Pro Gly Gly Val Ser
Gln Val 1085 1090 1095Val Gln Asn Glu
Glu Asn Glu Asn Cys Leu Lys Lys Val Asp Pro 1100
1105 1110Gln Leu Leu Lys Met Ala Leu Thr Pro Tyr Pro
Lys Leu Lys Thr 1115 1120 1125Ala Leu
Phe Pro Gln Cys Thr Pro Pro Ser Val Leu Pro Ser Asp 1130
1135 1140Ile Thr Ile Tyr His Leu Ile Gln Ser Leu
Ser Pro Phe Asp Pro 1145 1150 1155Ser
Arg Leu Phe Gly Trp Gln Ser Ala Asn Thr Leu Ala Ile Gly 1160
1165 1170Asp Ala Trp Ser His Leu Pro His Phe
Ser Ser Pro Asp Leu Val 1175 1180
1185Asn Lys Tyr Ala Ile Val Glu Arg Leu Asn Phe Ala Tyr Tyr Leu
1190 1195 1200His Asn Gly Arg Pro Ser
Phe Ala Phe Gly Thr Phe Leu Val Gln 1205 1210
1215Glu Leu Ile Lys Ser Lys Thr Pro Lys Gln Leu Ile Gln Gln
Val 1220 1225 1230Gly Asn Glu Ala Tyr
Val Ile Gly Leu Ser Ser Phe His Ile Pro 1235 1240
1245Ser Ile Gly Ala Ala Cys Val Cys Phe Leu Glu Leu Leu
Gly Leu 1250 1255 1260Asp Ser Leu Lys
Leu Arg Val Asp Met Lys Val Ala Asn Ile Ile 1265
1270 1275Leu Ser Tyr Lys Cys Arg Asn Glu Asp Ala Gln
Tyr Ser Phe Ile 1280 1285 1290Arg Glu
Ser Val Ala Glu Lys Leu Ser Lys Leu Ala Asp Gly Glu 1295
1300 1305Lys Thr Thr Thr Glu Glu Leu Leu Val Leu
Leu Glu Glu Gly Thr 1310 1315 1320Trp
Asn Ser Ile Gln Gln Gln Glu Ile Lys Arg Leu Ser Ser Glu 1325
1330 1335Ser Ser Ser Gln Trp Ala Leu Val Val
Gln Phe Cys Arg Leu His 1340 1345
1350Asn Met Lys Leu Ser Ile Ser Tyr Leu Arg Glu Cys Ala Lys Ala
1355 1360 1365Asn Asp Trp Leu Gln Phe
Ile Ile His Ser Gln Leu His Asn Tyr 1370 1375
1380His Pro Ala Glu Val Lys Ser Leu Ile Gln Tyr Phe Ser Pro
Val 1385 1390 1395Ile Gln Asp His Leu
Arg Leu Ala Phe Glu Asn Leu Pro Ser Val 1400 1405
1410Pro Thr Ser Lys Met Asp Ser Asp Gln Val Cys Asn Lys
Cys Pro 1415 1420 1425Gln Glu Leu Gln
Gly Ser Lys Gln Glu Met Thr Asp Leu Phe Glu 1430
1435 1440Ile Leu Leu Gln Cys Ser Glu Glu Pro Asp Ser
Trp His Trp Leu 1445 1450 1455Leu Val
Glu Ala Val Lys Gln Gln Ala Pro Ile Leu Ser Val Leu 1460
1465 1470Ala Ser Cys Leu Gln Gly Ala Ser Ala Ile
Ser Cys Leu Cys Val 1475 1480 1485Trp
Ile Ile Thr Ser Val Glu Asp Asn Val Ala Thr Glu Ala Met 1490
1495 1500Gly His Ile Gln Asp Ser Thr Glu Asp
His Thr Trp Asn Leu Glu 1505 1510
1515Asp Leu Ser Val Ile Trp Arg Thr Leu Leu Thr Arg Gln Lys Ser
1520 1525 1530Lys Thr Leu Ile Arg Gly
Phe Gln Leu Phe Phe Lys Asp Ser Pro 1535 1540
1545Leu Leu Leu Val Met Glu Met Tyr Glu Leu Cys Met Phe Phe
Arg 1550 1555 1560Asn Tyr Lys Glu Ala
Glu Ala Lys Leu Leu Glu Phe Gln Lys Ser 1565 1570
1575Leu Glu Thr Leu Asn Thr Ala Ala Thr Lys Val His Pro
Val Ile 1580 1585 1590Pro Ala Met Trp
Leu Glu Asp Gln Val Cys Phe Leu Leu Lys Leu 1595
1600 1605Met Leu Gln Gln Cys Lys Thr Gln Tyr Glu Leu
Gly Lys Leu Leu 1610 1615 1620Gln Leu
Phe Val Glu Arg Glu His Leu Phe Ser Asp Gly Pro Asp 1625
1630 1635Val Lys Lys Leu Cys Ile Leu Cys Gln Ile
Leu Lys Asp Thr Ser 1640 1645 1650Ile
Ala Ile Asn His Thr Ile Ile Thr Ser Tyr Ser Ile Glu Asn 1655
1660 1665Leu Gln His Glu Cys Arg Ser Ile Leu
Glu Arg Leu Gln Thr Asp 1670 1675
1680Gly Gln Phe Ala Leu Ala Arg Arg Val Ala Glu Leu Ala Glu Leu
1685 1690 1695Pro Val Asp Asn Leu Val
Ile Lys Glu Ile Thr Gln Glu Met Gln 1700 1705
1710Thr Leu Lys His Ile Glu Gln Trp Ser Leu Lys Gln Ala Arg
Ile 1715 1720 1725Asp Phe Trp Lys Lys
Cys His Glu Asn Phe Lys Lys Asn Ser Ile 1730 1735
1740Ser Ser Lys Ala Ala Ser Ser Phe Phe Ser Thr Gln Ala
His Val 1745 1750 1755Ala Cys Glu His
Pro Thr Gly Trp Ser Ser Met Glu Glu Arg His 1760
1765 1770Leu Leu Leu Thr Leu Ala Gly His Trp Leu Ala
Gln Glu Asp Val 1775 1780 1785Val Pro
Leu Asp Lys Leu Glu Glu Leu Glu Lys Gln Ile Trp Leu 1790
1795 1800Cys Arg Ile Thr Gln His Thr Leu Gly Arg
Asn Gln Glu Glu Thr 1805 1810 1815Glu
Pro Arg Phe Ser Arg Gln Ile Ser Thr Ser Gly Glu Leu Ser 1820
1825 1830Phe Asp Ser Leu Ala Ser Glu Phe Ser
Phe Ser Lys Leu Ala Ala 1835 1840
1845Leu Asn Thr Ser Lys Tyr Leu Glu Leu Asn Ser Leu Pro Ser Lys
1850 1855 1860Glu Thr Cys Glu Asn Arg
Leu Asp Trp Lys Glu Gln Glu Ser Leu 1865 1870
1875Asn Phe Leu Ile Gly Arg Leu Leu Asp Asp Gly Cys Val His
Glu 1880 1885 1890Ala Ser Arg Val Cys
Arg Tyr Phe His Phe Tyr Asn Pro Asp Val 1895 1900
1905Ala Leu Val Leu His Cys Arg Ala Leu Ala Ser Gly Glu
Ala Ser 1910 1915 1920Met Glu Asp Leu
His Pro Glu Ile His Ala Leu Leu Gln Ser Ala 1925
1930 1935Glu Leu Leu Glu Glu Glu Ala Pro Asp Ile Pro
Leu Arg Arg Val 1940 1945 1950His Ser
Thr Ser Ser Leu Asp Ser Gln Lys Phe Val Thr Val Pro 1955
1960 1965Ser Ser Asn Glu Val Val Thr Asn Leu Glu
Val Leu Thr Ser Lys 1970 1975 1980Cys
Leu His Gly Lys Asn Tyr Cys Arg Gln Val Leu Cys Leu Tyr 1985
1990 1995Asp Leu Ala Lys Glu Leu Gly Cys Ser
Tyr Thr Asp Val Ala Ala 2000 2005
2010Gln Asp Gly Glu Ala Met Leu Arg Lys Ile Leu Ala Ser Gln Gln
2015 2020 2025Pro Asp Arg Cys Lys Arg
Ala Gln Ala Phe Ile Ser Thr Gln Gly 2030 2035
2040Leu Lys Pro Asp Thr Val Ala Glu Leu Val Ala Glu Glu Val
Thr 2045 2050 2055Arg Glu Leu Leu Thr
Ser Ser Gln Gly Thr Gly His Lys Gln Met 2060 2065
2070Phe Asn Pro Thr Glu Glu Ser Gln Thr Phe Leu Gln Leu
Thr Thr 2075 2080 2085Leu Cys Gln Asp
Arg Thr Leu Val Gly Met Lys Leu Leu Asp Lys 2090
2095 2100Ile Ser Ser Val Pro His Gly Glu Leu Ser Cys
Thr Thr Glu Leu 2105 2110 2115Leu Ile
Leu Ala His His Cys Phe Thr Leu Thr Cys His Met Glu 2120
2125 2130Gly Ile Ile Arg Val Leu Gln Ala Ala His
Met Leu Thr Asp Asn 2135 2140 2145His
Leu Ala Pro Ser Glu Glu Tyr Gly Leu Val Val Arg Leu Leu 2150
2155 2160Thr Gly Ile Gly Arg Tyr Asn Glu Met
Thr Tyr Ile Phe Asp Leu 2165 2170
2175Leu His Lys Lys His Tyr Phe Glu Val Leu Met Arg Lys Lys Leu
2180 2185 2190Asp Pro Ser Gly Thr Leu
Lys Thr Ala Leu Leu Asp Tyr Ile Lys 2195 2200
2205Arg Cys Arg Pro Gly Asp Ser Glu Lys His Asn Met Ile Ala
Leu 2210 2215 2220Cys Phe Ser Met Cys
Arg Glu Ile Gly Glu Asn His Glu Ala Ala 2225 2230
2235Ala Arg Ile Gln Leu Lys Leu Ile Glu Ser Gln Pro Trp
Glu Asp 2240 2245 2250Ser Leu Lys Asp
Gly His Gln Leu Lys Gln Leu Leu Leu Lys Ala 2255
2260 2265Leu Thr Leu Met Leu Asp Ala Ala Glu Leu Cys
Gln Gly Leu Leu 2270 2275 2280Cys Ala
Thr Gly Pro Ala Leu Ser Ala Ala His Gln Val Asp Asn 2285
2290 2295Ser Ala Asp Ser Leu Ser Glu His Trp Pro
Glu His Asn Ala His 2300 2305 2310Gln
Leu Gly Pro Pro Gln Ala Asp Gly Leu Tyr Ser Gly Pro Thr 2315
2320 2325Ser Val Leu Pro Gly Phe Tyr Cys Gly
Xaa 2330 23351642349PRTHomo
sapiensmisc_feature(2349)..(2349)Xaa can be any naturally occurring amino
acid 164Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser1
5 10 15Trp Gly Thr Ala
Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20
25 30Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser
Arg Ala Gln Leu Arg 35 40 45Thr
Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50
55 60Val Leu Ser Leu Thr Pro Gly Ser Arg Gly
Gly Gly Arg Cys Cys Leu65 70 75
80Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser
Ser 85 90 95Thr Pro Thr
Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100
105 110Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp
Gly Arg Cys Asp Ala Thr 115 120
125Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130
135 140Gln Asp Ile Ser Ile Ser Leu Leu
Ser Leu Arg Ile Leu Ser Phe His145 150
155 160Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val
Ile Leu His Ile 165 170
175Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr
180 185 190Leu Pro Leu Pro Ala Gln
Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200
205Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile
Tyr Ile 210 215 220Phe Asp Val Val Asp
Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu225 230
235 240His Lys Glu Asp Met Cys Asn Glu Gln Gln
Gln Glu Pro Ala Lys Ile 245 250
255Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val
260 265 270Ile Val Ser Ser Ser
Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275
280 285Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg
Ile Leu Glu Asp 290 295 300Leu Pro Ile
Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn305
310 315 320Ser Ala Tyr Asn Met Lys Leu
Ala Lys Phe Ser Phe Gln Ile Asp Arg 325
330 335Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr
Ile Lys Asn Ser 340 345 350Lys
Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355
360 365Leu Glu Ser Pro Glu Ser Gly Asn His
Ser Thr Ser Val Gln Ser Trp 370 375
380Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln385
390 395 400Lys Asp His Ala
Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met 405
410 415His Ile Ser Glu Gln Glu Glu Pro Ile Glu
Leu Lys Cys Val Ser Val 420 425
430Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met Gly Tyr
435 440 445Thr Ile Thr Leu Trp Asp Leu
Glu Thr Gln Gly Met Gln Cys Ser Ser 450 455
460Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly Asp Gln Gln
Leu465 470 475 480Cys Phe
Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu
485 490 495Thr Gln Glu Glu Phe Leu Asn
Arg Leu Met Ile His Gly Ser Ala Ser 500 505
510Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly Arg Cys
Ser Ile 515 520 525Pro Ile His Ala
Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530
535 540Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu Phe
Asn Pro Ser Ser545 550 555
560Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu Tyr
565 570 575Leu Arg Asn Val Glu
Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580
585 590Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln Ser Lys
His Phe Ser Glu 595 600 605Gln Leu
Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610
615 620Leu Phe Ile His Thr Glu Glu Leu Asp Glu His
Leu Gln Lys Gly Val625 630 635
640Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Arg Thr Phe Met Ile Lys
645 650 655Phe Pro Trp Lys
Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu 660
665 670Asn Val Pro Lys Val Lys Glu Ser Asn Ile Trp
Lys Lys Leu Ser Phe 675 680 685Glu
Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys Ile Pro Glu Ala 690
695 700Gln Thr Phe Phe Arg Ile Asp Ser His Ser
Ala Gln Lys Leu Glu Glu705 710 715
720Leu Ile Gly Ile Gly Leu Asn Leu Val Phe Asp Asn Leu Lys Lys
Asn 725 730 735Asn Ile Lys
Glu Ala Ser Glu Leu Leu Lys Asn Met Gly Phe Asp Val 740
745 750Lys Gly Gln Leu Leu Lys Ile Cys Phe Tyr
Thr Thr Asn Lys Asn Ile 755 760
765Arg Asp Phe Leu Val Glu Ile Leu Lys Glu Lys Asn Tyr Phe Ser Glu 770
775 780Lys Glu Lys Arg Thr Ile Asp Phe
Val His Gln Val Glu Lys Leu Tyr785 790
795 800Leu Gly His Phe Gln Glu Asn Met Gln Ile Gln Ser
Phe Pro Arg Tyr 805 810
815Trp Ile Lys Glu Gln Asp Phe Phe Lys His Lys Ser Val Leu Asp Ser
820 825 830Phe Leu Lys Tyr Asp Cys
Lys Asp Glu Phe Asn Lys Gln Asp His Arg 835 840
845Ile Val Leu Asn Trp Ala Leu Trp Trp Asp Gln Leu Thr Gln
Glu Ser 850 855 860Ile Leu Leu Pro Arg
Ile Ser Pro Glu Glu Tyr Lys Ser Tyr Ser Pro865 870
875 880Glu Ala Leu Trp Arg Tyr Leu Thr Ala Arg
His Asp Trp Leu Asn Ile 885 890
895Ile Leu Trp Ile Gly Glu Phe Gln Thr Gln His Ser Tyr Ala Ser Leu
900 905 910Gln Gln Asn Lys Trp
Pro Leu Leu Thr Val Asp Val Ile Asn Gln Asn 915
920 925Thr Ser Cys Asn Asn Tyr Met Arg Asn Glu Ile Leu
Asp Lys Leu Ala 930 935 940Arg Asn Gly
Val Phe Leu Ala Ser Glu Leu Glu Asp Phe Glu Cys Phe945
950 955 960Leu Leu Arg Leu Ser Arg Ile
Gly Gly Val Ile Gln Asp Thr Leu Pro 965
970 975Val Gln Asn Tyr Lys Thr Lys Glu Gly Trp Asp Phe
His Ser Gln Phe 980 985 990Ile
Leu Tyr Cys Leu Glu His Ser Leu Gln His Leu Leu Tyr Val Tyr 995
1000 1005Leu Asp Cys Tyr Lys Leu Ser Pro
Glu Asn Cys Pro Phe Leu Glu 1010 1015
1020Lys Lys Glu Leu His Glu Ala His Pro Trp Phe Glu Phe Leu Val
1025 1030 1035Gln Cys Arg Gln Val Ala
Ser Asn Leu Thr Asp Pro Lys Leu Ile 1040 1045
1050Phe Gln Ala Ser Leu Ala Asn Ala Gln Ile Leu Ile Pro Thr
Asn 1055 1060 1065Gln Ala Ser Val Ser
Ser Met Leu Leu Glu Gly His Thr Leu Leu 1070 1075
1080Ala Leu Ala Thr Thr Met Tyr Ser Pro Gly Gly Val Ser
Gln Val 1085 1090 1095Val Gln Asn Glu
Glu Asn Glu Asn Cys Leu Lys Lys Val Asp Pro 1100
1105 1110Gln Leu Leu Lys Met Ala Leu Thr Pro Tyr Pro
Lys Leu Lys Thr 1115 1120 1125Ala Leu
Phe Pro Gln Cys Thr Pro Pro Ser Val Leu Pro Ser Asp 1130
1135 1140Ile Thr Ile Tyr His Leu Ile Gln Ser Leu
Ser Pro Phe Asp Pro 1145 1150 1155Ser
Arg Leu Phe Gly Trp Gln Ser Ala Asn Thr Leu Ala Ile Gly 1160
1165 1170Asp Ala Trp Ser His Leu Pro His Phe
Ser Ser Pro Asp Leu Val 1175 1180
1185Asn Lys Tyr Ala Ile Val Glu Arg Leu Asn Phe Ala Tyr Tyr Leu
1190 1195 1200His Asn Gly Arg Pro Ser
Phe Ala Phe Gly Thr Phe Leu Val Gln 1205 1210
1215Glu Leu Ile Lys Ser Lys Thr Pro Lys Gln Leu Ile Gln Gln
Val 1220 1225 1230Gly Asn Glu Ala Tyr
Val Ile Gly Leu Ser Ser Phe His Ile Pro 1235 1240
1245Ser Ile Gly Ala Ala Cys Val Cys Phe Leu Glu Leu Leu
Gly Leu 1250 1255 1260Asp Ser Leu Lys
Leu Arg Val Asp Met Lys Val Ala Asn Ile Ile 1265
1270 1275Leu Ser Tyr Lys Cys Arg Asn Glu Asp Ala Gln
Tyr Ser Phe Ile 1280 1285 1290Arg Glu
Ser Val Ala Glu Lys Leu Ser Lys Leu Ala Asp Gly Glu 1295
1300 1305Lys Thr Thr Thr Glu Glu Leu Leu Val Leu
Leu Glu Glu Gly Thr 1310 1315 1320Trp
Asn Ser Ile Gln Gln Gln Glu Ile Lys Arg Leu Ser Ser Glu 1325
1330 1335Ser Ser Ser Gln Trp Ala Leu Val Val
Gln Phe Cys Arg Leu His 1340 1345
1350Asn Met Lys Leu Ser Ile Ser Tyr Leu Arg Glu Cys Ala Lys Ala
1355 1360 1365Asn Asp Trp Leu Gln Phe
Ile Ile His Ser Gln Leu His Asn Tyr 1370 1375
1380His Pro Ala Glu Val Lys Ser Leu Ile Gln Tyr Phe Ser Pro
Val 1385 1390 1395Ile Gln Asp His Leu
Arg Leu Ala Phe Glu Asn Leu Pro Ser Val 1400 1405
1410Pro Thr Ser Lys Met Asp Ser Asp Gln Val Cys Asn Lys
Cys Pro 1415 1420 1425Gln Glu Leu Gln
Gly Ser Lys Gln Glu Met Thr Asp Leu Phe Glu 1430
1435 1440Ile Leu Leu Gln Cys Ser Glu Glu Pro Asp Ser
Trp His Trp Leu 1445 1450 1455Leu Val
Glu Ala Val Lys Gln Gln Ala Pro Ile Leu Ser Val Leu 1460
1465 1470Ala Ser Cys Leu Gln Gly Ala Ser Ala Ile
Ser Cys Leu Cys Val 1475 1480 1485Trp
Ile Ile Thr Ser Val Glu Asp Asn Val Ala Thr Glu Ala Met 1490
1495 1500Gly His Ile Gln Asp Ser Thr Glu Asp
His Thr Trp Asn Leu Glu 1505 1510
1515Asp Leu Ser Val Ile Trp Arg Thr Leu Leu Thr Arg Gln Lys Ser
1520 1525 1530Lys Thr Leu Ile Arg Gly
Phe Gln Leu Phe Phe Lys Asp Ser Pro 1535 1540
1545Leu Leu Leu Val Met Glu Met Tyr Glu Leu Cys Met Phe Phe
Arg 1550 1555 1560Asn Tyr Lys Glu Ala
Glu Ala Lys Leu Leu Glu Phe Gln Lys Ser 1565 1570
1575Leu Glu Thr Leu Asn Thr Ala Ala Thr Lys Val His Pro
Val Ile 1580 1585 1590Pro Ala Met Trp
Leu Glu Asp Gln Val Cys Phe Leu Leu Lys Leu 1595
1600 1605Met Leu Gln Gln Cys Lys Thr Gln Tyr Glu Leu
Gly Lys Leu Leu 1610 1615 1620Gln Leu
Phe Val Glu Arg Glu His Leu Phe Ser Asp Gly Pro Asp 1625
1630 1635Val Lys Lys Leu Cys Ile Leu Cys Gln Ile
Leu Lys Asp Thr Ser 1640 1645 1650Ile
Ala Ile Asn His Thr Ile Ile Thr Ser Tyr Ser Ile Glu Asn 1655
1660 1665Leu Gln His Glu Cys Arg Ser Ile Leu
Glu Arg Leu Gln Thr Asp 1670 1675
1680Gly Gln Phe Ala Leu Ala Arg Arg Val Ala Glu Leu Ala Glu Leu
1685 1690 1695Pro Val Asp Asn Leu Val
Ile Lys Glu Ile Thr Gln Glu Met Gln 1700 1705
1710Thr Leu Lys His Ile Glu Gln Trp Ser Leu Lys Gln Ala Arg
Ile 1715 1720 1725Asp Phe Trp Lys Lys
Cys His Glu Asn Phe Lys Lys Asn Ser Ile 1730 1735
1740Ser Ser Lys Ala Ala Ser Ser Phe Phe Ser Thr Gln Ala
His Val 1745 1750 1755Ala Cys Glu His
Pro Thr Gly Trp Ser Ser Met Glu Glu Arg His 1760
1765 1770Leu Leu Leu Thr Leu Ala Gly His Trp Leu Ala
Gln Glu Asp Val 1775 1780 1785Val Pro
Leu Asp Lys Leu Glu Glu Leu Glu Lys Gln Ile Trp Leu 1790
1795 1800Cys Arg Ile Thr Gln His Thr Leu Gly Arg
Asn Gln Glu Glu Thr 1805 1810 1815Glu
Pro Arg Phe Ser Arg Gln Ile Ser Thr Ser Gly Glu Leu Ser 1820
1825 1830Phe Asp Ser Leu Ala Ser Glu Phe Ser
Phe Ser Lys Leu Ala Ala 1835 1840
1845Leu Asn Thr Ser Lys Tyr Leu Glu Leu Asn Ser Leu Pro Ser Lys
1850 1855 1860Glu Thr Cys Glu Asn Arg
Leu Asp Trp Lys Glu Gln Glu Ser Leu 1865 1870
1875Asn Phe Leu Ile Gly Arg Leu Leu Asp Asp Gly Cys Val His
Glu 1880 1885 1890Ala Ser Arg Val Cys
Arg Tyr Phe His Phe Tyr Asn Pro Asp Val 1895 1900
1905Ala Leu Val Leu His Cys Arg Ala Leu Ala Ser Gly Glu
Ala Ser 1910 1915 1920Met Glu Asp Leu
His Pro Glu Ile His Ala Leu Leu Gln Ser Ala 1925
1930 1935Glu Leu Leu Glu Glu Glu Ala Pro Asp Ile Pro
Leu Arg Arg Val 1940 1945 1950His Ser
Thr Ser Ser Leu Asp Ser Gln Lys Phe Val Thr Val Pro 1955
1960 1965Ser Ser Asn Glu Val Val Thr Asn Leu Glu
Val Leu Thr Ser Lys 1970 1975 1980Cys
Leu His Gly Lys Asn Tyr Cys Arg Gln Val Leu Cys Leu Tyr 1985
1990 1995Asp Leu Ala Lys Glu Leu Gly Cys Ser
Tyr Thr Asp Val Ala Ala 2000 2005
2010Gln Asp Gly Glu Ala Met Leu Arg Lys Ile Leu Ala Ser Gln Gln
2015 2020 2025Pro Asp Arg Cys Lys Arg
Ala Gln Ala Phe Ile Ser Thr Gln Gly 2030 2035
2040Leu Lys Pro Asp Thr Val Ala Glu Leu Val Ala Glu Glu Val
Thr 2045 2050 2055Arg Glu Leu Leu Thr
Ser Ser Gln Gly Thr Gly His Lys Gln Met 2060 2065
2070Phe Asn Pro Thr Glu Glu Ser Gln Thr Phe Leu Gln Leu
Thr Thr 2075 2080 2085Leu Cys Gln Asp
Arg Thr Leu Val Gly Met Lys Leu Leu Asp Lys 2090
2095 2100Ile Ser Ser Val Pro His Gly Glu Leu Ser Cys
Thr Thr Glu Leu 2105 2110 2115Leu Ile
Leu Ala His His Cys Phe Thr Leu Thr Cys His Met Glu 2120
2125 2130Gly Ile Ile Arg Val Leu Gln Ala Ala His
Met Leu Thr Asp Asn 2135 2140 2145His
Leu Ala Pro Ser Glu Glu Tyr Gly Leu Val Val Arg Leu Leu 2150
2155 2160Thr Gly Ile Gly Arg Tyr Asn Glu Met
Thr Tyr Ile Phe Asp Leu 2165 2170
2175Leu His Lys Lys His Tyr Phe Glu Val Leu Met Arg Lys Lys Leu
2180 2185 2190Asp Pro Ser Gly Thr Leu
Lys Thr Ala Leu Leu Asp Tyr Ile Lys 2195 2200
2205Arg Cys Arg Pro Gly Asp Ser Glu Lys His Asn Met Ile Ala
Leu 2210 2215 2220Cys Phe Ser Met Cys
Arg Glu Ile Gly Glu Asn His Glu Ala Ala 2225 2230
2235Ala Arg Ile Gln Leu Lys Leu Ile Glu Ser Gln Pro Trp
Glu Asp 2240 2245 2250Ser Leu Lys Asp
Gly His Gln Leu Lys Gln Leu Leu Leu Lys Ala 2255
2260 2265Leu Thr Leu Met Leu Asp Ala Ala Glu Ser Tyr
Ala Lys Asp Ser 2270 2275 2280Cys Val
Arg Gln Ala Gln His Cys Gln Arg Leu Thr Lys Leu Ile 2285
2290 2295Thr Leu Gln Ile His Phe Leu Asn Thr Gly
Gln Asn Thr Met Leu 2300 2305 2310Ile
Asn Leu Gly Arg His Lys Leu Met Asp Cys Ile Leu Ala Leu 2315
2320 2325Pro Arg Phe Tyr Gln Ala Ser Ile Val
Ala Glu Ala Tyr Asp Phe 2330 2335
2340Cys Ser Arg Leu Gly Xaa 23451652443PRThomo sapiens 165Met Ala Ala
Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser1 5
10 15Trp Gly Thr Ala Ala Met Gly Arg Val
Leu Pro Met Leu Leu Val Pro 20 25
30Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg
35 40 45Thr Gln Pro Glu Ala Leu Gly
Ser Leu Thr Ala Ala Gly Ser Leu Gln 50 55
60Val Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu65
70 75 80Glu Gly Pro Phe
Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser 85
90 95Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala
Leu Gly Glu Asn Tyr Glu 100 105
110Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr
115 120 125Ile Leu Tyr Ser Cys Ser Arg
Glu Ala Leu Gln Lys Leu Ile Asp Asp 130 135
140Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe
His145 150 155 160Asn Asn
Thr Ser Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile
165 170 175Ile Phe Pro Glu Arg Asp Ala
Ala Ile Arg Val Leu Asn Cys Phe Thr 180 185
190Leu Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr
Gln Leu 195 200 205Cys Arg Gly Ile
Leu Phe Val Leu Ser Ser Leu Gly Trp Ile Tyr Ile 210
215 220Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val
Asp Leu Ala Leu225 230 235
240His Lys Glu Asp Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile
245 250 255Ser Ser Phe Thr Ser
Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val 260
265 270Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn
Leu Asn Leu Tyr 275 280 285Phe Arg
Gln His Pro Gly His Leu Leu Cys Glu Arg Ile Leu Glu Asp 290
295 300Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu
Asp Asp Pro Val Asn305 310 315
320Ser Ala Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg
325 330 335Ser Trp Lys Ala
Gln Leu Ser Ser Leu Asn Glu Thr Ile Lys Asn Ser 340
345 350Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe
Gln Asp Ile Leu His 355 360 365Leu
Glu Ser Pro Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370
375 380Ala Phe Ile Pro Gln Asp Ile Met His Gly
Gln Tyr Asn Val Leu Gln385 390 395
400Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile
Met 405 410 415His Ile Ser
Glu Gln Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val 420
425 430Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu
Val Glu Arg Met Gly Tyr 435 440
445Thr Ile Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450
455 460Leu Gly Thr Lys Cys Ile Pro Val
Asp Ser Ser Gly Asp Gln Gln Leu465 470
475 480Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile
Leu Phe Gly Leu 485 490
495Thr Gln Glu Glu Phe Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser
500 505 510Thr Val Asp Thr Leu Cys
His Leu Asn Gly Trp Gly Arg Cys Ser Ile 515 520
525Pro Ile His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu
Asp Thr 530 535 540Val Asn Phe Phe Leu
Lys Ser Lys Glu Asn Leu Phe Asn Pro Ser Ser545 550
555 560Lys Ser Ser Val Ser Asp Gln Phe Asp His
Leu Ser Ser His Leu Tyr 565 570
575Leu Arg Asn Val Glu Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser
580 585 590Ala Ile Arg Glu Ser
Tyr Ser Glu Pro Gln Ser Lys His Phe Ser Glu 595
600 605Gln Leu Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn
Gln Ile Lys Glu 610 615 620Leu Phe Ile
His Thr Glu Glu Leu Asp Glu His Leu Gln Lys Gly Val625
630 635 640Asn Ile Leu Thr Ser Tyr Ile
Asn Glu Leu Arg Thr Phe Met Ile Lys 645
650 655Phe Pro Trp Lys Leu Thr Asp Ala Ile Asp Glu Tyr
Asp Val His Glu 660 665 670Asn
Val Pro Lys Val Lys Glu Ser Asn Ile Trp Lys Lys Leu Ser Phe 675
680 685Glu Glu Val Ile Ala Ser Ala Ile Leu
Asn Asn Lys Ile Pro Glu Ala 690 695
700Gln Thr Phe Phe Arg Ile Asp Ser His Ser Ala Gln Lys Leu Glu Glu705
710 715 720Leu Ile Gly Ile
Gly Leu Asn Leu Val Phe Asp Asn Leu Lys Lys Asn 725
730 735Asn Ile Lys Glu Ala Ser Glu Leu Leu Lys
Asn Met Gly Phe Asp Val 740 745
750Lys Gly Gln Leu Leu Lys Ile Cys Phe Tyr Thr Thr Asn Lys Asn Ile
755 760 765Arg Asp Phe Leu Val Glu Ile
Leu Lys Glu Lys Asn Tyr Phe Ser Glu 770 775
780Lys Glu Lys Arg Thr Ile Asp Phe Val His Gln Val Glu Lys Leu
Tyr785 790 795 800Leu Gly
His Phe Gln Glu Asn Met Gln Ile Gln Ser Phe Pro Arg Tyr
805 810 815Trp Ile Lys Glu Gln Asp Phe
Phe Lys His Lys Ser Val Leu Asp Ser 820 825
830Phe Leu Lys Tyr Asp Cys Lys Asp Glu Phe Asn Lys Gln Asp
His Arg 835 840 845Ile Val Leu Asn
Trp Ala Leu Trp Trp Asp Gln Leu Thr Gln Glu Ser 850
855 860Ile Leu Leu Pro Arg Ile Ser Pro Glu Glu Tyr Lys
Ser Tyr Ser Pro865 870 875
880Glu Ala Leu Trp Arg Tyr Leu Thr Ala Arg His Asp Trp Leu Asn Ile
885 890 895Ile Leu Trp Ile Gly
Glu Phe Gln Thr Gln His Ser Tyr Ala Ser Leu 900
905 910Gln Gln Asn Lys Trp Pro Leu Leu Thr Val Asp Val
Ile Asn Gln Asn 915 920 925Thr Ser
Cys Asn Asn Tyr Met Arg Asn Glu Ile Leu Asp Lys Leu Ala 930
935 940Gly Asn Gly Val Phe Leu Ala Ser Glu Leu Glu
Asp Phe Glu Cys Phe945 950 955
960Leu Leu Arg Leu Ser Arg Ile Gly Gly Val Ile Gln Asp Thr Leu Pro
965 970 975Val Gln Asn Tyr
Lys Thr Lys Glu Gly Trp Asp Phe His Ser Gln Phe 980
985 990Ile Leu Tyr Cys Leu Glu His Ser Leu Gln His
Leu Leu Tyr Val Tyr 995 1000
1005Leu Asp Cys Tyr Lys Leu Ser Pro Glu Asn Cys Pro Phe Leu Glu
1010 1015 1020Lys Lys Glu Leu His Glu
Ala His Pro Trp Phe Glu Phe Leu Val 1025 1030
1035Gln Cys Arg Gln Val Ala Ser Asn Leu Thr Asp Pro Lys Leu
Ile 1040 1045 1050Phe Gln Ala Ser Leu
Ala Asn Ala Gln Ile Leu Ile Pro Thr Asn 1055 1060
1065Gln Ala Ser Val Ser Ser Met Leu Leu Glu Gly His Thr
Leu Leu 1070 1075 1080Ala Leu Ala Thr
Thr Met Tyr Ser Pro Gly Gly Val Ser Gln Val 1085
1090 1095Val Gln Asn Glu Glu Asn Glu Asn Cys Leu Lys
Lys Val Asp Pro 1100 1105 1110Gln Leu
Leu Lys Met Ala Leu Thr Pro Tyr Pro Lys Leu Lys Thr 1115
1120 1125Ala Leu Phe Pro Gln Cys Thr Pro Pro Ser
Val Leu Pro Ser Asp 1130 1135 1140Ile
Thr Ile Tyr His Leu Ile Gln Ser Leu Ser Pro Phe Asp Pro 1145
1150 1155Ser Arg Leu Phe Gly Trp Gln Ser Ala
Asn Thr Leu Ala Ile Gly 1160 1165
1170Asp Ala Trp Ser His Leu Pro His Phe Ser Ser Pro Asp Leu Val
1175 1180 1185Asn Lys Tyr Ala Ile Val
Glu Arg Leu Asn Phe Ala Tyr Tyr Leu 1190 1195
1200His Asn Gly Arg Pro Ser Phe Ala Phe Gly Thr Phe Leu Val
Gln 1205 1210 1215Glu Leu Ile Lys Ser
Lys Thr Pro Lys Gln Leu Ile Gln Gln Val 1220 1225
1230Gly Asn Glu Ala Tyr Val Ile Gly Leu Ser Ser Phe His
Ile Pro 1235 1240 1245Ser Ile Gly Ala
Ala Cys Val Cys Phe Leu Glu Leu Leu Gly Leu 1250
1255 1260Asp Ser Leu Lys Leu Arg Val Asp Met Lys Val
Ala Asn Ile Ile 1265 1270 1275Leu Ser
Tyr Lys Cys Arg Asn Glu Asp Ala Gln Tyr Ser Phe Ile 1280
1285 1290Arg Glu Ser Val Ala Glu Lys Leu Ser Lys
Leu Ala Asp Gly Glu 1295 1300 1305Lys
Thr Thr Thr Glu Glu Leu Leu Val Leu Leu Glu Glu Gly Thr 1310
1315 1320Trp Asn Ser Ile Gln Gln Gln Glu Ile
Lys Arg Leu Ser Ser Glu 1325 1330
1335Ser Ser Ser Gln Trp Ala Leu Val Val Gln Phe Cys Arg Leu His
1340 1345 1350Asn Met Lys Leu Ser Ile
Ser Tyr Leu Arg Glu Cys Ala Lys Ala 1355 1360
1365Asn Asp Trp Leu Gln Phe Ile Ile His Ser Gln Leu His Asn
Tyr 1370 1375 1380His Pro Ala Glu Val
Lys Ser Leu Ile Gln Tyr Phe Ser Pro Val 1385 1390
1395Ile Gln Asp His Leu Arg Leu Ala Phe Glu Asn Leu Pro
Ser Val 1400 1405 1410Pro Thr Ser Lys
Met Asp Ser Asp Gln Val Cys Asn Lys Cys Pro 1415
1420 1425Gln Glu Leu Gln Gly Ser Lys Gln Glu Met Thr
Asp Leu Phe Glu 1430 1435 1440Ile Leu
Leu Gln Cys Ser Glu Glu Pro Asp Ser Trp His Trp Leu 1445
1450 1455Leu Val Glu Ala Val Lys Gln Gln Ala Pro
Ile Leu Ser Val Leu 1460 1465 1470Ala
Ser Cys Leu Gln Gly Ala Ser Ala Ile Ser Cys Leu Cys Val 1475
1480 1485Trp Ile Ile Thr Ser Val Glu Asp Asn
Val Ala Thr Glu Ala Met 1490 1495
1500Gly His Ile Gln Asp Ser Thr Glu Asp His Thr Trp Asn Leu Glu
1505 1510 1515Asp Leu Ser Val Ile Trp
Arg Thr Leu Leu Thr Arg Gln Lys Ser 1520 1525
1530Lys Thr Leu Ile Arg Gly Phe Gln Leu Phe Phe Lys Asp Ser
Pro 1535 1540 1545Leu Leu Leu Val Met
Glu Met Tyr Glu Leu Cys Met Phe Phe Arg 1550 1555
1560Asn Tyr Lys Glu Ala Glu Ala Lys Leu Leu Glu Phe Gln
Lys Ser 1565 1570 1575Leu Glu Thr Leu
Asn Thr Ala Ala Thr Lys Val His Pro Val Ile 1580
1585 1590Pro Ala Met Trp Leu Glu Asp Gln Val Cys Phe
Leu Leu Lys Leu 1595 1600 1605Met Leu
Gln Gln Cys Lys Thr Gln Tyr Glu Leu Gly Lys Leu Leu 1610
1615 1620Gln Leu Phe Val Glu Arg Glu His Leu Phe
Ser Asp Gly Pro Asp 1625 1630 1635Val
Lys Lys Leu Cys Ile Leu Cys Gln Ile Leu Lys Asp Thr Ser 1640
1645 1650Ile Ala Ile Asn His Thr Ile Ile Thr
Ser Tyr Ser Ile Glu Asn 1655 1660
1665Leu Gln His Glu Cys Arg Ser Ile Leu Glu Arg Leu Gln Thr Asp
1670 1675 1680Gly Gln Phe Ala Leu Ala
Arg Arg Val Ala Glu Leu Ala Glu Leu 1685 1690
1695Pro Val Asp Asn Leu Val Ile Lys Glu Ile Thr Gln Glu Met
Gln 1700 1705 1710Thr Leu Lys His Ile
Glu Gln Trp Ser Leu Lys Gln Ala Arg Ile 1715 1720
1725Asp Phe Trp Lys Lys Cys His Glu Asn Phe Lys Lys Asn
Ser Ile 1730 1735 1740Ser Ser Lys Ala
Ala Ser Ser Phe Phe Ser Thr Gln Ala His Val 1745
1750 1755Ala Cys Glu His Pro Thr Gly Trp Ser Ser Met
Glu Glu Arg His 1760 1765 1770Leu Leu
Leu Thr Leu Ala Gly His Trp Leu Ala Gln Glu Asp Val 1775
1780 1785Val Pro Leu Asp Lys Leu Glu Glu Leu Glu
Lys Gln Ile Trp Leu 1790 1795 1800Cys
Arg Ile Thr Gln His Thr Leu Gly Arg Asn Gln Glu Glu Thr 1805
1810 1815Glu Pro Arg Phe Ser Arg Gln Ile Ser
Thr Ser Gly Glu Leu Ser 1820 1825
1830Phe Asp Ser Leu Ala Ser Glu Phe Ser Phe Ser Lys Leu Ala Ala
1835 1840 1845Leu Asn Thr Ser Lys Tyr
Leu Glu Leu Asn Ser Leu Pro Ser Lys 1850 1855
1860Glu Thr Cys Glu Asn Arg Leu Asp Trp Lys Glu Gln Glu Ser
Leu 1865 1870 1875Asn Phe Leu Ile Gly
Arg Leu Leu Asp Asp Gly Cys Val His Glu 1880 1885
1890Ala Ser Arg Val Cys Arg Tyr Phe His Phe Tyr Asn Pro
Asp Val 1895 1900 1905Ala Leu Val Leu
His Cys Arg Ala Leu Ala Ser Gly Glu Ala Ser 1910
1915 1920Met Glu Asp Leu His Pro Glu Ile His Ala Leu
Leu Gln Ser Ala 1925 1930 1935Glu Leu
Leu Glu Glu Glu Ala Pro Asp Ile Pro Leu Arg Arg Val 1940
1945 1950His Ser Thr Ser Ser Leu Asp Ser Gln Lys
Phe Val Thr Val Pro 1955 1960 1965Ser
Ser Asn Glu Val Val Thr Asn Leu Glu Val Leu Thr Ser Lys 1970
1975 1980Cys Leu His Gly Lys Asn Tyr Cys Arg
Gln Val Leu Cys Leu Tyr 1985 1990
1995Asp Leu Ala Lys Glu Leu Gly Cys Ser Tyr Thr Asp Val Ala Ala
2000 2005 2010Gln Asp Gly Glu Ala Met
Leu Arg Lys Ile Leu Ala Ser Gln Gln 2015 2020
2025Pro Asp Arg Cys Lys Arg Ala Gln Ala Phe Ile Ser Thr Gln
Gly 2030 2035 2040Leu Lys Pro Asp Thr
Val Ala Glu Leu Val Ala Glu Glu Val Thr 2045 2050
2055Arg Glu Leu Leu Thr Ser Ser Gln Gly Thr Gly His Lys
Gln Met 2060 2065 2070Phe Asn Pro Thr
Glu Glu Ser Gln Thr Phe Leu Gln Leu Thr Thr 2075
2080 2085Leu Cys Gln Asp Arg Thr Leu Val Gly Met Lys
Leu Leu Asp Lys 2090 2095 2100Ile Ser
Ser Val Pro His Gly Glu Leu Ser Cys Thr Thr Glu Leu 2105
2110 2115Leu Ile Leu Ala His His Cys Phe Thr Leu
Thr Cys His Met Glu 2120 2125 2130Gly
Ile Ile Arg Val Leu Gln Ala Ala His Met Leu Thr Asp Asn 2135
2140 2145His Leu Ala Pro Ser Glu Glu Tyr Gly
Leu Val Val Arg Leu Leu 2150 2155
2160Thr Gly Ile Gly Arg Tyr Asn Glu Met Thr Tyr Ile Phe Asp Leu
2165 2170 2175Leu His Lys Lys His Tyr
Phe Glu Val Leu Met Arg Lys Lys Leu 2180 2185
2190Asp Pro Ser Gly Thr Leu Lys Thr Ala Leu Leu Asp Tyr Ile
Lys 2195 2200 2205Arg Cys Arg Pro Gly
Asp Ser Glu Lys His Asn Met Ile Ala Leu 2210 2215
2220Cys Phe Ser Met Cys Arg Glu Ile Gly Glu Asn His Glu
Ala Ala 2225 2230 2235Ala Arg Ile Gln
Leu Lys Leu Ile Glu Ser Gln Pro Trp Glu Asp 2240
2245 2250Ser Leu Lys Asp Gly His Gln Leu Lys Gln Leu
Leu Leu Lys Ala 2255 2260 2265Leu Thr
Leu Met Leu Asp Ala Ala Glu Ser Tyr Ala Lys Asp Ser 2270
2275 2280Cys Val Arg Gln Ala Gln His Cys Gln Arg
Leu Thr Lys Leu Ile 2285 2290 2295Thr
Leu Gln Ile His Phe Leu Asn Thr Gly Gln Asn Thr Met Leu 2300
2305 2310Ile Asn Leu Gly Arg His Lys Leu Met
Asp Cys Ile Leu Ala Leu 2315 2320
2325Pro Arg Phe Tyr Gln Ala Ser Ile Val Ala Glu Ala Tyr Asp Phe
2330 2335 2340Val Pro Asp Trp Ala Glu
Ile Leu Tyr Gln Gln Val Ile Leu Lys 2345 2350
2355Gly Asp Phe Asn Tyr Leu Glu Glu Phe Lys Gln Gln Arg Leu
Leu 2360 2365 2370Lys Ser Ser Ile Phe
Glu Glu Ile Ser Lys Lys Tyr Lys Gln His 2375 2380
2385Gln Pro Thr Asp Met Val Met Glu Asn Leu Lys Lys Leu
Leu Thr 2390 2395 2400Tyr Cys Glu Asp
Val Tyr Leu Tyr Tyr Lys Leu Ala Tyr Glu His 2405
2410 2415Lys Phe Tyr Glu Ile Val Asn Val Leu Leu Lys
Asp Pro Gln Thr 2420 2425 2430Gly Cys
Cys Leu Lys Asp Met Leu Ala Gly 2435
2440166245PRThomo sapiens 166Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala
Ser Ala Gly Gly Ser1 5 10
15Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro
20 25 30Val Pro Ala Glu Ala Met Gly
Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40
45Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu
Gln 50 55 60Val Leu Ser Leu Thr Pro
Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu65 70
75 80Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp
Ser Arg Asn Ser Ser 85 90
95Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu
100 105 110Leu Leu Ile Tyr Glu Phe
Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115 120
125Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile
Asp Asp 130 135 140Gln Asp Ile Ser Ile
Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His145 150
155 160Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys
Cys Val Ile Leu His Ile 165 170
175Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr
180 185 190Leu Pro Leu Pro Ala
Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195
200 205Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly
Trp Ile Tyr Ile 210 215 220Phe Asp Val
Val Asp Gly Thr Tyr Val Ala Arg Gly Phe Ser Thr Ser225
230 235 240Gln Arg Arg His Val
245167427PRTHomo sapiens 167Met Ala Ala Glu Glu Gly Val Ala Ser Ala
Ala Ser Ala Gly Gly Ser1 5 10
15Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro
20 25 30Val Pro Ala Glu Ala Met
Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40
45Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser
Leu Gln 50 55 60Val Leu Ser Leu Thr
Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu65 70
75 80Glu Gly Pro Phe Trp His Phe Leu Trp Glu
Asp Ser Arg Asn Ser Ser 85 90
95Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu
100 105 110Leu Leu Ile Tyr Glu
Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115
120 125Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys
Leu Ile Asp Asp 130 135 140Gln Asp Ile
Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His145
150 155 160Asn Asn Thr Ser Leu Leu Phe
Ile Asn Lys Cys Val Ile Leu His Ile 165
170 175Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu
Asn Cys Phe Thr 180 185 190Leu
Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195
200 205Cys Arg Gly Ile Leu Phe Val Leu Ser
Ser Leu Gly Trp Ile Tyr Ile 210 215
220Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu225
230 235 240His Lys Glu Asp
Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile 245
250 255Ser Ser Phe Thr Ser Leu Lys Val Ser Gln
Asp Leu Asp Val Ala Val 260 265
270Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr
275 280 285Phe Arg Gln His Pro Gly His
Leu Leu Cys Glu Arg Ile Leu Glu Asp 290 295
300Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val
Asn305 310 315 320Ser Ala
Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg
325 330 335Ser Trp Lys Ala Gln Leu Ser
Ser Leu Asn Glu Thr Ile Lys Asn Ser 340 345
350Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile
Leu His 355 360 365Leu Glu Ser Pro
Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370
375 380Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr
Asn Val Leu Gln385 390 395
400Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met
405 410 415His Ile Ser Glu Gln
Glu Glu Pro Ile Glu Leu 420 425168555PRTHomo
sapiens 168Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly
Ser1 5 10 15Trp Gly Thr
Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20
25 30Val Pro Ala Glu Ala Met Gly Gln Leu Gly
Ser Arg Ala Gln Leu Arg 35 40
45Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50
55 60Val Leu Ser Leu Thr Pro Gly Ser Arg
Gly Gly Gly Arg Cys Cys Leu65 70 75
80Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn
Ser Ser 85 90 95Thr Pro
Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100
105 110Leu Leu Ile Tyr Glu Phe Asn Leu Lys
Asp Gly Arg Cys Asp Ala Thr 115 120
125Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp
130 135 140Gln Asp Ile Ser Ile Ser Leu
Leu Ser Leu Arg Ile Leu Ser Phe His145 150
155 160Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val
Ile Leu His Ile 165 170
175Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr
180 185 190Leu Pro Leu Pro Ala Gln
Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200
205Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile
Tyr Ile 210 215 220Phe Asp Val Val Asp
Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu225 230
235 240His Lys Glu Asp Met Cys Asn Glu Gln Gln
Gln Glu Pro Ala Lys Ile 245 250
255Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val
260 265 270Ile Val Ser Ser Ser
Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275
280 285Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg
Ile Leu Glu Asp 290 295 300Leu Pro Ile
Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn305
310 315 320Ser Ala Tyr Asn Met Lys Leu
Ala Lys Phe Ser Phe Gln Ile Asp Arg 325
330 335Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr
Ile Lys Asn Ser 340 345 350Lys
Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355
360 365Leu Glu Ser Pro Glu Ser Gly Asn His
Ser Thr Ser Val Gln Ser Trp 370 375
380Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln385
390 395 400Lys Asp His Ala
Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met 405
410 415His Ile Ser Glu Gln Glu Glu Pro Ile Glu
Leu Lys Cys Val Ser Val 420 425
430Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met Gly Tyr
435 440 445Thr Ile Thr Leu Trp Asp Leu
Glu Thr Gln Gly Met Gln Cys Ser Ser 450 455
460Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly Asp Gln Gln
Leu465 470 475 480Cys Phe
Val Leu Thr Glu Asn Gly Leu Ser Asp Phe Val Trp Phe Asp
485 490 495Ser Arg Arg Val Phe Lys Gln
Thr His Asp Pro Trp Lys Cys Gln His 500 505
510Cys Gly His Ser Leu Ser Ser Gln Trp Leu Gly Lys Val Leu
Asn Ser 515 520 525His Thr Cys Thr
Arg Gly Arg Asp Arg Lys Ser Ser Ala Gly His Ser 530
535 540Lys Phe Leu Phe Glu Glu Gln Gly Lys Ser Phe545
550 555169576PRTHomo sapiens 169Met Ala Ala
Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser1 5
10 15Trp Gly Thr Ala Ala Met Gly Arg Val
Leu Pro Met Leu Leu Val Pro 20 25
30Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg
35 40 45Thr Gln Pro Glu Ala Leu Gly
Ser Leu Thr Ala Ala Gly Ser Leu Gln 50 55
60Val Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu65
70 75 80Glu Gly Pro Phe
Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser 85
90 95Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala
Leu Gly Glu Asn Tyr Glu 100 105
110Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr
115 120 125Ile Leu Tyr Ser Cys Ser Arg
Glu Ala Leu Gln Lys Leu Ile Asp Asp 130 135
140Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe
His145 150 155 160Asn Asn
Thr Ser Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile
165 170 175Ile Phe Pro Glu Arg Asp Ala
Ala Ile Arg Val Leu Asn Cys Phe Thr 180 185
190Leu Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr
Gln Leu 195 200 205Cys Arg Gly Ile
Leu Phe Val Leu Ser Ser Leu Gly Trp Ile Tyr Ile 210
215 220Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val
Asp Leu Ala Leu225 230 235
240His Lys Glu Asp Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile
245 250 255Ser Ser Phe Thr Ser
Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val 260
265 270Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn
Leu Asn Leu Tyr 275 280 285Phe Arg
Gln His Pro Gly His Leu Leu Cys Glu Arg Ile Leu Glu Asp 290
295 300Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu
Asp Asp Pro Val Asn305 310 315
320Ser Ala Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg
325 330 335Ser Trp Lys Ala
Gln Leu Ser Ser Leu Asn Glu Thr Ile Lys Asn Ser 340
345 350Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe
Gln Asp Ile Leu His 355 360 365Leu
Glu Ser Pro Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370
375 380Ala Phe Ile Pro Gln Asp Ile Met His Gly
Gln Tyr Asn Val Leu Gln385 390 395
400Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile
Met 405 410 415His Ile Ser
Glu Gln Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val 420
425 430Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu
Val Glu Arg Met Gly Tyr 435 440
445Thr Ile Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450
455 460Leu Gly Thr Lys Cys Ile Pro Val
Asp Ser Ser Gly Asp Gln Gln Leu465 470
475 480Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile
Leu Phe Gly Leu 485 490
495Thr Gln Glu Glu Phe Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser
500 505 510Thr Val Asp Thr Leu Cys
His Leu Asn Gly Trp Gly Arg Cys Ser Ile 515 520
525Pro Ile His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu
Asp Thr 530 535 540Val Asn Phe Phe Leu
Lys Ser Lys Glu Asn Leu Leu Ile His Pro Gln545 550
555 560Asn Leu Leu Tyr Leu Ile Ser Leu Ile Thr
Cys His Pro Ile Tyr Ile 565 570
575170559PRTHomo sapiens 170Met Ala Ala Glu Glu Gly Val Ala Ser Ala
Ala Ser Ala Gly Gly Ser1 5 10
15Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro
20 25 30Val Pro Ala Glu Ala Met
Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40
45Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser
Leu Gln 50 55 60Val Leu Ser Leu Thr
Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu65 70
75 80Glu Gly Pro Phe Trp His Phe Leu Trp Glu
Asp Ser Arg Asn Ser Ser 85 90
95Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu
100 105 110Leu Leu Ile Tyr Glu
Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115
120 125Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys
Leu Ile Asp Asp 130 135 140Gln Asp Ile
Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His145
150 155 160Asn Asn Thr Ser Leu Leu Phe
Ile Asn Lys Cys Val Ile Leu His Ile 165
170 175Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu
Asn Cys Phe Thr 180 185 190Leu
Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195
200 205Cys Arg Gly Ile Leu Phe Val Leu Ser
Ser Leu Gly Trp Ile Tyr Ile 210 215
220Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu225
230 235 240His Lys Glu Asp
Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile 245
250 255Ser Ser Phe Thr Ser Leu Lys Val Ser Gln
Asp Leu Asp Val Ala Val 260 265
270Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr
275 280 285Phe Arg Gln His Pro Gly His
Leu Leu Cys Glu Arg Ile Leu Glu Asp 290 295
300Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val
Asn305 310 315 320Ser Ala
Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg
325 330 335Ser Trp Lys Ala Gln Leu Ser
Ser Leu Asn Glu Thr Ile Lys Asn Ser 340 345
350Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile
Leu His 355 360 365Leu Glu Ser Pro
Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370
375 380Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr
Asn Val Leu Gln385 390 395
400Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met
405 410 415His Ile Ser Glu Gln
Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val 420
425 430Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu
Arg Met Gly Tyr 435 440 445Thr Ile
Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450
455 460Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser
Gly Asp Gln Gln Leu465 470 475
480Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu
485 490 495Thr Gln Glu Glu
Phe Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser 500
505 510Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp
Gly Arg Cys Ser Ile 515 520 525Pro
Ile His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530
535 540Val Asn Phe Phe Leu Lys Ser Lys Glu Asn
Leu Phe Asn Pro Ser545 550
555171576PRTHomo sapiens 171Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala
Ser Ala Gly Gly Ser1 5 10
15Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro
20 25 30Val Pro Ala Glu Ala Met Gly
Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40
45Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu
Gln 50 55 60Val Leu Ser Leu Thr Pro
Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu65 70
75 80Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp
Ser Arg Asn Ser Ser 85 90
95Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu
100 105 110Leu Leu Ile Tyr Glu Phe
Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115 120
125Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile
Asp Asp 130 135 140Gln Asp Ile Ser Ile
Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His145 150
155 160Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys
Cys Val Ile Leu His Ile 165 170
175Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr
180 185 190Leu Pro Leu Pro Ala
Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195
200 205Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly
Trp Ile Tyr Ile 210 215 220Phe Asp Val
Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu225
230 235 240His Lys Glu Asp Met Cys Asn
Glu Gln Gln Gln Glu Pro Ala Lys Ile 245
250 255Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu
Asp Val Ala Val 260 265 270Ile
Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275
280 285Phe Arg Gln His Pro Gly His Leu Leu
Cys Glu Arg Ile Leu Glu Asp 290 295
300Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn305
310 315 320Ser Ala Tyr Asn
Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg 325
330 335Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn
Glu Thr Ile Lys Asn Ser 340 345
350Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His
355 360 365Leu Glu Ser Pro Glu Ser Gly
Asn His Ser Thr Ser Val Gln Ser Trp 370 375
380Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu
Gln385 390 395 400Lys Asp
His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met
405 410 415His Ile Ser Glu Gln Glu Glu
Pro Ile Glu Leu Lys Cys Val Ser Val 420 425
430Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met
Gly Tyr 435 440 445Thr Ile Thr Leu
Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450
455 460Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly
Asp Gln Gln Leu465 470 475
480Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu
485 490 495Thr Gln Glu Glu Phe
Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser 500
505 510Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly
Arg Cys Ser Ile 515 520 525Pro Ile
His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530
535 540Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu
Phe Asn Pro Ser Ser545 550 555
560Lys Ser Ser Val Leu Ile Ser Leu Ile Thr Cys His Pro Ile Tyr Ile
565 570 5751722443PRTHomo
sapiens 172Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly
Ser1 5 10 15Trp Gly Thr
Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20
25 30Val Pro Ala Glu Ala Met Gly Gln Leu Gly
Ser Arg Ala Gln Leu Arg 35 40
45Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50
55 60Val Leu Ser Leu Thr Pro Gly Ser Arg
Gly Gly Gly Arg Cys Cys Leu65 70 75
80Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn
Ser Ser 85 90 95Thr Pro
Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100
105 110Leu Leu Ile Tyr Glu Phe Asn Leu Lys
Asp Gly Arg Cys Asp Ala Thr 115 120
125Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp
130 135 140Gln Asp Ile Ser Ile Ser Leu
Leu Ser Leu Arg Ile Leu Ser Phe His145 150
155 160Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val
Ile Leu His Ile 165 170
175Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr
180 185 190Leu Pro Leu Pro Ala Gln
Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200
205Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile
Tyr Ile 210 215 220Phe Asp Val Val Asp
Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu225 230
235 240His Lys Glu Asp Met Cys Asn Glu Gln Gln
Gln Glu Pro Ala Lys Ile 245 250
255Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val
260 265 270Ile Val Ser Ser Ser
Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275
280 285Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg
Ile Leu Glu Asp 290 295 300Leu Pro Ile
Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn305
310 315 320Ser Ala Tyr Asn Met Lys Leu
Ala Lys Phe Ser Phe Gln Ile Asp Arg 325
330 335Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr
Ile Lys Asn Ser 340 345 350Lys
Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355
360 365Leu Glu Ser Pro Glu Ser Gly Asn His
Ser Thr Ser Val Gln Ser Trp 370 375
380Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln385
390 395 400Lys Asp His Ala
Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met 405
410 415His Ile Ser Glu Gln Glu Glu Pro Ile Glu
Leu Lys Cys Val Ser Val 420 425
430Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met Gly Tyr
435 440 445Thr Ile Thr Leu Trp Asp Leu
Glu Thr Gln Gly Met Gln Cys Ser Ser 450 455
460Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly Asp Gln Gln
Leu465 470 475 480Cys Phe
Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu
485 490 495Thr Gln Glu Glu Phe Leu Asn
Arg Leu Met Ile His Gly Ser Ala Ser 500 505
510Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly Arg Cys
Ser Ile 515 520 525Pro Ile His Ala
Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530
535 540Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu Phe
Asn Pro Ser Ser545 550 555
560Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu Tyr
565 570 575Leu Arg Asn Val Glu
Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580
585 590Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln Ser Lys
His Phe Ser Glu 595 600 605Gln Leu
Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610
615 620Leu Phe Ile His Thr Glu Glu Leu Asp Glu His
Leu Gln Lys Gly Val625 630 635
640Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Arg Thr Phe Met Ile Lys
645 650 655Phe Pro Trp Lys
Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu 660
665 670Asn Val Pro Lys Val Lys Glu Ser Asn Ile Trp
Lys Lys Leu Ser Phe 675 680 685Glu
Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys Ile Pro Glu Ala 690
695 700Gln Thr Phe Phe Arg Ile Asp Ser His Ser
Ala Gln Lys Leu Glu Glu705 710 715
720Leu Ile Gly Ile Gly Leu Asn Leu Val Phe Asp Asn Leu Lys Lys
Asn 725 730 735Asn Ile Lys
Glu Ala Ser Glu Leu Leu Lys Asn Met Gly Phe Asp Val 740
745 750Lys Gly Gln Leu Leu Lys Ile Cys Phe Tyr
Thr Thr Asn Lys Asn Ile 755 760
765Arg Asp Phe Leu Val Glu Ile Leu Lys Glu Lys Asn Tyr Phe Ser Glu 770
775 780Lys Glu Lys Arg Thr Ile Asp Phe
Val His Gln Val Glu Lys Leu Tyr785 790
795 800Leu Gly His Phe Gln Glu Asn Met Gln Ile Gln Ser
Phe Pro Met Tyr 805 810
815Trp Ile Lys Glu Gln Asp Phe Phe Lys His Lys Ser Val Leu Asp Ser
820 825 830Phe Leu Lys Tyr Asp Cys
Lys Asp Glu Phe Asn Lys Gln Asp His Arg 835 840
845Ile Val Leu Asn Trp Ala Leu Trp Trp Asp Gln Leu Thr Gln
Glu Ser 850 855 860Ile Leu Leu Pro Arg
Ile Ser Pro Glu Glu Tyr Lys Ser Tyr Ser Pro865 870
875 880Glu Ala Leu Trp Arg Tyr Leu Thr Ala Arg
His Asp Trp Leu Asn Ile 885 890
895Ile Leu Trp Ile Gly Glu Phe Gln Thr Gln His Ser Tyr Ala Ser Leu
900 905 910Gln Gln Asn Lys Trp
Pro Leu Leu Thr Val Asp Val Ile Asn Gln Asn 915
920 925Thr Ser Cys Asn Asn Tyr Met Arg Asn Glu Ile Leu
Asp Lys Leu Ala 930 935 940Arg Asn Gly
Val Phe Leu Ala Ser Glu Leu Glu Asp Phe Glu Cys Phe945
950 955 960Leu Leu Arg Leu Ser Arg Ile
Gly Gly Val Ile Gln Asp Thr Leu Pro 965
970 975Val Gln Asn Tyr Lys Thr Lys Glu Gly Trp Asp Phe
His Ser Gln Phe 980 985 990Ile
Leu Tyr Cys Leu Glu His Ser Leu Gln His Leu Leu Tyr Val Tyr 995
1000 1005Leu Asp Cys Tyr Lys Leu Ser Pro
Glu Asn Cys Pro Phe Leu Glu 1010 1015
1020Lys Lys Glu Leu His Glu Ala His Pro Trp Phe Glu Phe Leu Val
1025 1030 1035Gln Cys Arg Gln Val Ala
Ser Asn Leu Thr Asp Pro Lys Leu Ile 1040 1045
1050Phe Gln Ala Ser Leu Ala Asn Ala Gln Ile Leu Ile Pro Thr
Asn 1055 1060 1065Gln Ala Ser Val Ser
Ser Met Leu Leu Glu Gly His Thr Leu Leu 1070 1075
1080Ala Leu Ala Thr Thr Met Tyr Ser Pro Gly Gly Val Ser
Gln Val 1085 1090 1095Val Gln Asn Glu
Glu Asn Glu Asn Cys Leu Lys Lys Val Asp Pro 1100
1105 1110Gln Leu Leu Lys Met Ala Leu Thr Pro Tyr Pro
Lys Leu Lys Thr 1115 1120 1125Ala Leu
Phe Pro Gln Cys Thr Pro Pro Ser Val Leu Pro Ser Asp 1130
1135 1140Ile Thr Ile Tyr His Leu Ile Gln Ser Leu
Ser Pro Phe Asp Pro 1145 1150 1155Ser
Arg Leu Phe Gly Trp Gln Ser Ala Asn Thr Leu Ala Ile Gly 1160
1165 1170Asp Ala Trp Ser His Leu Pro His Phe
Ser Ser Pro Asp Leu Val 1175 1180
1185Asn Lys Tyr Ala Ile Val Glu Arg Leu Asn Phe Ala Tyr Tyr Leu
1190 1195 1200His Asn Gly Arg Pro Ser
Phe Ala Phe Gly Thr Phe Leu Val Gln 1205 1210
1215Glu Leu Ile Lys Ser Lys Thr Pro Lys Gln Leu Ile Gln Gln
Val 1220 1225 1230Gly Asn Glu Ala Tyr
Val Ile Gly Leu Ser Ser Phe His Ile Pro 1235 1240
1245Ser Ile Gly Ala Ala Cys Val Cys Phe Leu Glu Leu Leu
Gly Leu 1250 1255 1260Asp Ser Leu Lys
Leu Arg Val Asp Met Lys Val Ala Asn Ile Ile 1265
1270 1275Leu Ser Tyr Lys Cys Arg Asn Glu Asp Ala Gln
Tyr Ser Phe Ile 1280 1285 1290Arg Glu
Ser Val Ala Glu Lys Leu Ser Lys Leu Ala Asp Gly Glu 1295
1300 1305Lys Thr Thr Thr Glu Glu Leu Leu Val Leu
Leu Glu Glu Gly Thr 1310 1315 1320Trp
Asn Ser Ile Gln Gln Gln Glu Ile Lys Arg Leu Ser Ser Glu 1325
1330 1335Ser Ser Ser Gln Trp Ala Leu Val Val
Gln Phe Cys Arg Leu His 1340 1345
1350Asn Met Lys Leu Ser Ile Ser Tyr Leu Arg Glu Cys Ala Lys Ala
1355 1360 1365Asn Asp Trp Leu Gln Phe
Ile Ile His Ser Gln Leu His Asn Tyr 1370 1375
1380His Pro Ala Glu Val Lys Ser Leu Ile Gln Tyr Phe Ser Pro
Val 1385 1390 1395Ile Gln Asp His Leu
Arg Leu Ala Phe Glu Asn Leu Pro Ser Val 1400 1405
1410Pro Thr Ser Lys Met Asp Ser Asp Gln Val Cys Asn Lys
Cys Pro 1415 1420 1425Gln Glu Leu Gln
Gly Ser Lys Gln Glu Met Thr Asp Leu Phe Glu 1430
1435 1440Ile Leu Leu Gln Cys Ser Glu Glu Pro Asp Ser
Trp His Trp Leu 1445 1450 1455Leu Val
Glu Ala Val Lys Gln Gln Ala Pro Ile Leu Ser Val Leu 1460
1465 1470Ala Ser Cys Leu Gln Gly Ala Ser Ala Ile
Ser Cys Leu Cys Val 1475 1480 1485Trp
Ile Ile Thr Ser Val Glu Asp Asn Val Ala Thr Glu Ala Met 1490
1495 1500Gly His Ile Gln Asp Ser Thr Glu Asp
His Thr Trp Asn Leu Glu 1505 1510
1515Asp Leu Ser Val Ile Trp Arg Thr Leu Leu Thr Arg Gln Lys Ser
1520 1525 1530Lys Thr Leu Ile Arg Gly
Phe Gln Leu Phe Phe Lys Asp Ser Pro 1535 1540
1545Leu Leu Leu Val Met Glu Met Tyr Glu Leu Cys Met Phe Phe
Arg 1550 1555 1560Asn Tyr Lys Glu Ala
Glu Ala Lys Leu Leu Glu Phe Gln Lys Ser 1565 1570
1575Leu Glu Thr Leu Asn Thr Ala Ala Thr Lys Val His Pro
Val Ile 1580 1585 1590Pro Ala Met Trp
Leu Glu Asp Gln Val Cys Phe Leu Leu Lys Leu 1595
1600 1605Met Leu Gln Gln Cys Lys Thr Gln Tyr Glu Leu
Gly Lys Leu Leu 1610 1615 1620Gln Leu
Phe Val Glu Arg Glu His Leu Phe Ser Asp Gly Pro Asp 1625
1630 1635Val Lys Lys Leu Cys Ile Leu Cys Gln Ile
Leu Lys Asp Thr Ser 1640 1645 1650Ile
Ala Ile Asn His Thr Ile Ile Thr Ser Tyr Ser Ile Glu Asn 1655
1660 1665Leu Gln His Glu Cys Arg Ser Ile Leu
Glu Arg Leu Gln Thr Asp 1670 1675
1680Gly Gln Phe Ala Leu Ala Arg Arg Val Ala Glu Leu Ala Glu Leu
1685 1690 1695Pro Val Asp Asn Leu Val
Ile Lys Glu Ile Thr Gln Glu Met Gln 1700 1705
1710Thr Leu Lys His Ile Glu Gln Trp Ser Leu Lys Gln Ala Arg
Ile 1715 1720 1725Asp Phe Trp Lys Lys
Cys His Glu Asn Phe Lys Lys Asn Ser Ile 1730 1735
1740Ser Ser Lys Ala Ala Ser Ser Phe Phe Ser Thr Gln Ala
His Val 1745 1750 1755Ala Cys Glu His
Pro Thr Gly Trp Ser Ser Met Glu Glu Arg His 1760
1765 1770Leu Leu Leu Thr Leu Ala Gly His Trp Leu Ala
Gln Glu Asp Val 1775 1780 1785Val Pro
Leu Asp Lys Leu Glu Glu Leu Glu Lys Gln Ile Trp Leu 1790
1795 1800Cys Arg Ile Thr Gln His Thr Leu Gly Arg
Asn Gln Glu Glu Thr 1805 1810 1815Glu
Pro Arg Phe Ser Arg Gln Ile Ser Thr Ser Gly Glu Leu Ser 1820
1825 1830Phe Asp Ser Leu Ala Ser Glu Phe Ser
Phe Ser Lys Leu Ala Ala 1835 1840
1845Leu Asn Thr Ser Lys Tyr Leu Glu Leu Asn Ser Leu Pro Ser Lys
1850 1855 1860Glu Thr Cys Glu Asn Arg
Leu Asp Trp Lys Glu Gln Glu Ser Leu 1865 1870
1875Asn Phe Leu Ile Gly Arg Leu Leu Asp Asp Gly Cys Val His
Glu 1880 1885 1890Ala Ser Arg Val Cys
Arg Tyr Phe His Phe Tyr Asn Pro Asp Val 1895 1900
1905Ala Leu Val Leu His Cys Arg Ala Leu Ala Ser Gly Glu
Ala Ser 1910 1915 1920Met Glu Asp Leu
His Pro Glu Ile His Ala Leu Leu Gln Ser Ala 1925
1930 1935Glu Leu Leu Glu Glu Glu Ala Pro Asp Ile Pro
Leu Arg Arg Val 1940 1945 1950His Ser
Thr Ser Ser Leu Asp Ser Gln Lys Phe Val Thr Val Pro 1955
1960 1965Ser Ser Asn Glu Val Val Thr Asn Leu Glu
Val Leu Thr Ser Lys 1970 1975 1980Cys
Leu His Gly Lys Asn Tyr Cys Arg Gln Val Leu Cys Leu Tyr 1985
1990 1995Asp Leu Ala Lys Glu Leu Gly Cys Ser
Tyr Thr Asp Val Ala Ala 2000 2005
2010Gln Asp Gly Glu Ala Met Leu Arg Lys Ile Leu Ala Ser Gln Gln
2015 2020 2025Pro Asp Arg Cys Lys Arg
Ala Gln Ala Phe Ile Ser Thr Gln Gly 2030 2035
2040Leu Lys Pro Asp Thr Val Ala Glu Leu Val Ala Glu Glu Val
Thr 2045 2050 2055Arg Glu Leu Leu Thr
Ser Ser Gln Gly Thr Gly His Lys Gln Met 2060 2065
2070Phe Asn Pro Thr Glu Glu Ser Gln Thr Phe Leu Gln Leu
Thr Thr 2075 2080 2085Leu Cys Gln Asp
Arg Thr Leu Val Gly Met Lys Leu Leu Asp Lys 2090
2095 2100Ile Ser Ser Val Pro His Gly Glu Leu Ser Cys
Thr Thr Glu Leu 2105 2110 2115Leu Ile
Leu Ala His His Cys Phe Thr Leu Thr Cys His Met Glu 2120
2125 2130Gly Ile Ile Arg Val Leu Gln Ala Ala His
Met Leu Thr Asp Asn 2135 2140 2145His
Leu Ala Pro Ser Glu Glu Tyr Gly Leu Val Val Arg Leu Leu 2150
2155 2160Thr Gly Ile Gly Arg Tyr Asn Glu Met
Thr Tyr Ile Phe Asp Leu 2165 2170
2175Leu His Lys Lys His Tyr Phe Glu Val Leu Met Arg Lys Lys Leu
2180 2185 2190Asp Pro Ser Gly Thr Leu
Lys Thr Ala Leu Leu Asp Tyr Ile Lys 2195 2200
2205Arg Cys Arg Pro Gly Asp Ser Glu Lys His Asn Met Ile Ala
Leu 2210 2215 2220Cys Phe Ser Met Cys
Arg Glu Ile Gly Glu Asn His Glu Ala Ala 2225 2230
2235Ala Arg Ile Gln Leu Lys Leu Ile Glu Ser Gln Pro Trp
Glu Asp 2240 2245 2250Ser Leu Lys Asp
Gly His Gln Leu Lys Gln Leu Leu Leu Lys Ala 2255
2260 2265Leu Thr Leu Met Leu Asp Ala Ala Glu Ser Tyr
Ala Lys Asp Ser 2270 2275 2280Cys Val
Arg Gln Ala Gln His Cys Gln Arg Leu Thr Lys Leu Ile 2285
2290 2295Thr Leu Gln Ile His Phe Leu Asn Thr Gly
Gln Asn Thr Met Leu 2300 2305 2310Ile
Asn Leu Gly Arg His Lys Leu Met Asp Cys Ile Leu Ala Leu 2315
2320 2325Pro Arg Phe Tyr Gln Ala Ser Ile Val
Ala Glu Ala Tyr Asp Phe 2330 2335
2340Val Pro Asp Trp Ala Glu Ile Leu Tyr Gln Gln Val Ile Leu Lys
2345 2350 2355Gly Asp Phe Asn Tyr Leu
Glu Glu Phe Lys Gln Gln Arg Leu Leu 2360 2365
2370Lys Ser Ser Ile Phe Glu Glu Ile Ser Lys Lys Tyr Lys Gln
His 2375 2380 2385Gln Pro Thr Asp Met
Val Met Glu Asn Leu Lys Lys Leu Leu Thr 2390 2395
2400Tyr Cys Glu Asp Val Tyr Leu Tyr Tyr Lys Leu Ala Tyr
Glu His 2405 2410 2415Lys Phe Tyr Glu
Ile Val Asn Val Leu Leu Lys Asp Pro Gln Thr 2420
2425 2430Gly Cys Cys Leu Lys Asp Met Leu Ala Gly
2435 2440173898PRTHomo sapiens 173Met Ala Ala Glu Glu Gly
Val Ala Ser Ala Ala Ser Ala Gly Gly Ser1 5
10 15Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met
Leu Leu Val Pro 20 25 30Val
Pro Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35
40 45Thr Gln Pro Glu Ala Leu Gly Ser Leu
Thr Ala Ala Gly Ser Leu Gln 50 55
60Val Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu65
70 75 80Glu Gly Pro Phe Trp
His Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser 85
90 95Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu
Gly Glu Asn Tyr Glu 100 105
110Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr
115 120 125Ile Leu Tyr Ser Cys Ser Arg
Glu Ala Leu Gln Lys Leu Ile Asp Asp 130 135
140Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe
His145 150 155 160Asn Asn
Thr Ser Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile
165 170 175Ile Phe Pro Glu Arg Asp Ala
Ala Ile Arg Val Leu Asn Cys Phe Thr 180 185
190Leu Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr
Gln Leu 195 200 205Cys Arg Gly Ile
Leu Phe Val Leu Ser Ser Leu Gly Trp Ile Tyr Ile 210
215 220Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val
Asp Leu Ala Leu225 230 235
240His Lys Glu Asp Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile
245 250 255Ser Ser Phe Thr Ser
Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val 260
265 270Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn
Leu Asn Leu Tyr 275 280 285Phe Arg
Gln His Pro Gly His Leu Leu Cys Glu Arg Ile Leu Glu Asp 290
295 300Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu
Asp Asp Pro Val Asn305 310 315
320Ser Ala Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg
325 330 335Ser Trp Lys Ala
Gln Leu Ser Ser Leu Asn Glu Thr Ile Lys Asn Ser 340
345 350Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe
Gln Asp Ile Leu His 355 360 365Leu
Glu Ser Pro Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370
375 380Ala Phe Ile Pro Gln Asp Ile Met His Gly
Gln Tyr Asn Val Leu Gln385 390 395
400Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile
Met 405 410 415His Ile Ser
Glu Gln Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val 420
425 430Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu
Val Glu Arg Met Gly Tyr 435 440
445Thr Ile Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450
455 460Leu Gly Thr Lys Cys Ile Pro Val
Asp Ser Ser Gly Asp Gln Gln Leu465 470
475 480Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile
Leu Phe Gly Leu 485 490
495Thr Gln Glu Glu Phe Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser
500 505 510Thr Val Asp Thr Leu Cys
His Leu Asn Gly Trp Gly Arg Cys Ser Ile 515 520
525Pro Ile His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu
Asp Thr 530 535 540Val Asn Phe Phe Leu
Lys Ser Lys Glu Asn Leu Phe Asn Pro Ser Ser545 550
555 560Lys Ser Ser Val Ser Asp Gln Phe Asp His
Leu Ser Ser His Leu Tyr 565 570
575Leu Arg Asn Val Glu Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser
580 585 590Ala Ile Arg Glu Ser
Tyr Ser Glu Pro Gln Ser Lys His Phe Ser Glu 595
600 605Gln Leu Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn
Gln Ile Lys Glu 610 615 620Leu Phe Ile
His Thr Glu Glu Leu Asp Glu His Leu Gln Lys Gly Val625
630 635 640Asn Ile Leu Thr Ser Tyr Ile
Asn Glu Leu Arg Thr Phe Met Ile Lys 645
650 655Phe Pro Trp Lys Leu Thr Asp Ala Ile Asp Glu Tyr
Asp Val His Glu 660 665 670Asn
Val Pro Lys Val Lys Glu Ser Asn Ile Trp Lys Lys Leu Ser Phe 675
680 685Glu Glu Val Ile Ala Ser Ala Ile Leu
Asn Asn Lys Ile Pro Glu Ala 690 695
700Gln Thr Phe Phe Arg Ile Asp Ser His Ser Ala Gln Lys Leu Glu Glu705
710 715 720Leu Ile Gly Ile
Gly Leu Asn Leu Val Phe Asp Asn Leu Lys Lys Asn 725
730 735Asn Ile Lys Glu Ala Ser Glu Leu Leu Lys
Asn Met Gly Phe Asp Val 740 745
750Lys Gly Gln Leu Leu Lys Ile Cys Phe Tyr Thr Thr Asn Lys Asn Ile
755 760 765Arg Asp Phe Leu Val Glu Ile
Leu Lys Glu Lys Asn Tyr Phe Ser Glu 770 775
780Lys Glu Lys Arg Thr Ile Asp Phe Val His Gln Val Glu Lys Leu
Tyr785 790 795 800Leu Gly
His Phe Gln Glu Asn Met Gln Ile Gln Ser Phe Pro Arg Tyr
805 810 815Trp Ile Lys Glu Gln Asp Phe
Phe Lys His Lys Ser Val Leu Asp Ser 820 825
830Phe Leu Lys Tyr Asp Cys Lys Asp Glu Phe Asn Lys Gln Asp
His Arg 835 840 845Ile Val Leu Asn
Trp Ala Leu Trp Trp Asp Gln Leu Thr Gln Glu Ser 850
855 860Ile Leu Leu Pro Arg Ile Ser Pro Glu Glu Tyr Lys
Ser Tyr Ser Pro865 870 875
880Glu Ala Leu Trp Arg Tyr Leu Thr Ala Arg His Asp Trp Leu Asn Ile
885 890 895Ile Leu174919PRTHomo
sapiens 174Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly
Ser1 5 10 15Trp Gly Thr
Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20
25 30Val Pro Ala Glu Ala Met Gly Gln Leu Gly
Ser Arg Ala Gln Leu Arg 35 40
45Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50
55 60Val Leu Ser Leu Thr Pro Gly Ser Arg
Gly Gly Gly Arg Cys Cys Leu65 70 75
80Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn
Ser Ser 85 90 95Thr Pro
Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100
105 110Leu Leu Ile Tyr Glu Phe Asn Leu Lys
Asp Gly Arg Cys Asp Ala Thr 115 120
125Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp
130 135 140Gln Asp Ile Ser Ile Ser Leu
Leu Ser Leu Arg Ile Leu Ser Phe His145 150
155 160Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val
Ile Leu His Ile 165 170
175Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr
180 185 190Leu Pro Leu Pro Ala Gln
Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200
205Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile
Tyr Ile 210 215 220Phe Asp Val Val Asp
Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu225 230
235 240His Lys Glu Asp Met Cys Asn Glu Gln Gln
Gln Glu Pro Ala Lys Ile 245 250
255Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val
260 265 270Ile Val Ser Ser Ser
Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275
280 285Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg
Ile Leu Glu Asp 290 295 300Leu Pro Ile
Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn305
310 315 320Ser Ala Tyr Asn Met Lys Leu
Ala Lys Phe Ser Phe Gln Ile Asp Arg 325
330 335Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr
Ile Lys Asn Ser 340 345 350Lys
Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355
360 365Leu Glu Ser Pro Glu Ser Gly Asn His
Ser Thr Ser Val Gln Ser Trp 370 375
380Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln385
390 395 400Lys Asp His Ala
Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met 405
410 415His Ile Ser Glu Gln Glu Glu Pro Ile Glu
Leu Lys Cys Val Ser Val 420 425
430Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met Gly Tyr
435 440 445Thr Ile Thr Leu Trp Asp Leu
Glu Thr Gln Gly Met Gln Cys Ser Ser 450 455
460Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly Asp Gln Gln
Leu465 470 475 480Cys Phe
Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu
485 490 495Thr Gln Glu Glu Phe Leu Asn
Arg Leu Met Ile His Gly Ser Ala Ser 500 505
510Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly Arg Cys
Ser Ile 515 520 525Pro Ile His Ala
Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530
535 540Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu Phe
Asn Pro Ser Ser545 550 555
560Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu Tyr
565 570 575Leu Arg Asn Val Glu
Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580
585 590Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln Ser Lys
His Phe Ser Glu 595 600 605Gln Leu
Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610
615 620Leu Phe Ile His Thr Glu Glu Leu Asp Glu His
Leu Gln Lys Gly Val625 630 635
640Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Arg Thr Phe Met Ile Lys
645 650 655Phe Pro Trp Lys
Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu 660
665 670Asn Val Pro Lys Val Lys Glu Ser Asn Ile Trp
Lys Lys Leu Ser Phe 675 680 685Glu
Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys Ile Pro Glu Ala 690
695 700Gln Thr Phe Phe Arg Ile Asp Ser His Ser
Ala Gln Lys Leu Glu Glu705 710 715
720Leu Ile Gly Ile Gly Leu Asn Leu Val Phe Asp Asn Leu Lys Lys
Asn 725 730 735Asn Ile Lys
Glu Ala Ser Glu Leu Leu Lys Asn Met Gly Phe Asp Val 740
745 750Lys Gly Gln Leu Leu Lys Ile Cys Phe Tyr
Thr Thr Asn Lys Asn Ile 755 760
765Arg Asp Phe Leu Val Glu Ile Leu Lys Glu Lys Asn Tyr Phe Ser Glu 770
775 780Lys Glu Lys Arg Thr Ile Asp Phe
Val His Gln Val Glu Lys Leu Tyr785 790
795 800Leu Gly His Phe Gln Glu Asn Met Gln Ile Gln Ser
Phe Pro Arg Tyr 805 810
815Trp Ile Lys Glu Gln Asp Phe Phe Lys His Lys Ser Val Leu Asp Ser
820 825 830Phe Leu Lys Tyr Asp Cys
Lys Asp Glu Phe Asn Lys Gln Asp His Arg 835 840
845Ile Val Leu Asn Trp Ala Leu Trp Trp Asp Gln Leu Thr Gln
Glu Ser 850 855 860Ile Leu Leu Pro Arg
Ile Ser Pro Glu Glu Tyr Lys Ser Tyr Ser Pro865 870
875 880Glu Ala Leu Trp Arg Tyr Leu Thr Ala Arg
His Asp Trp Leu Asn Ile 885 890
895Ile Leu Trp Ile Gly Glu Phe Gln Thr Ser Ile Val Met Leu His Phe
900 905 910Ser Arg Thr Asn Gly
Pro Phe 9151751028PRTHomo sapiens 175Met Ala Ala Glu Glu Gly Val
Ala Ser Ala Ala Ser Ala Gly Gly Ser1 5 10
15Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu
Leu Val Pro 20 25 30Val Pro
Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35
40 45Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr
Ala Ala Gly Ser Leu Gln 50 55 60Val
Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu65
70 75 80Glu Gly Pro Phe Trp His
Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser 85
90 95Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly
Glu Asn Tyr Glu 100 105 110Leu
Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115
120 125Ile Leu Tyr Ser Cys Ser Arg Glu Ala
Leu Gln Lys Leu Ile Asp Asp 130 135
140Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His145
150 155 160Asn Asn Thr Ser
Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile 165
170 175Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg
Val Leu Asn Cys Phe Thr 180 185
190Leu Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu
195 200 205Cys Arg Gly Ile Leu Phe Val
Leu Ser Ser Leu Gly Trp Ile Tyr Ile 210 215
220Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala
Leu225 230 235 240His Lys
Glu Asp Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile
245 250 255Ser Ser Phe Thr Ser Leu Lys
Val Ser Gln Asp Leu Asp Val Ala Val 260 265
270Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn
Leu Tyr 275 280 285Phe Arg Gln His
Pro Gly His Leu Leu Cys Glu Arg Ile Leu Glu Asp 290
295 300Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp
Asp Pro Val Asn305 310 315
320Ser Ala Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg
325 330 335Ser Trp Lys Ala Gln
Leu Ser Ser Leu Asn Glu Thr Ile Lys Asn Ser 340
345 350Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln
Asp Ile Leu His 355 360 365Leu Glu
Ser Pro Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370
375 380Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln
Tyr Asn Val Leu Gln385 390 395
400Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met
405 410 415His Ile Ser Glu
Gln Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val 420
425 430Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val
Glu Arg Met Gly Tyr 435 440 445Thr
Ile Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450
455 460Leu Gly Thr Lys Cys Ile Pro Val Asp Ser
Ser Gly Asp Gln Gln Leu465 470 475
480Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly
Leu 485 490 495Thr Gln Glu
Glu Phe Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser 500
505 510Thr Val Asp Thr Leu Cys His Leu Asn Gly
Trp Gly Arg Cys Ser Ile 515 520
525Pro Ile His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530
535 540Val Asn Phe Phe Leu Lys Ser Lys
Glu Asn Leu Phe Asn Pro Ser Ser545 550
555 560Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser
Ser His Leu Tyr 565 570
575Leu Arg Asn Val Glu Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser
580 585 590Ala Ile Arg Glu Ser Tyr
Ser Glu Pro Gln Ser Lys His Phe Ser Glu 595 600
605Gln Leu Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile
Lys Glu 610 615 620Leu Phe Ile His Thr
Glu Glu Leu Asp Glu His Leu Gln Lys Gly Val625 630
635 640Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu
Arg Thr Phe Met Ile Lys 645 650
655Phe Pro Trp Lys Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu
660 665 670Asn Val Pro Lys Val
Lys Glu Ser Asn Ile Trp Lys Lys Leu Ser Phe 675
680 685Glu Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys
Ile Pro Glu Ala 690 695 700Gln Thr Phe
Phe Arg Ile Asp Ser His Ser Ala Gln Lys Leu Glu Glu705
710 715 720Leu Ile Gly Ile Gly Leu Asn
Leu Val Phe Asp Asn Leu Lys Lys Asn 725
730 735Asn Ile Lys Glu Ala Ser Glu Leu Leu Lys Asn Met
Gly Phe Asp Val 740 745 750Lys
Gly Gln Leu Leu Lys Ile Cys Phe Tyr Thr Thr Asn Lys Asn Ile 755
760 765Arg Asp Phe Leu Val Glu Ile Leu Lys
Glu Lys Asn Tyr Phe Ser Glu 770 775
780Lys Glu Lys Arg Thr Ile Asp Phe Val His Gln Val Glu Lys Leu Tyr785
790 795 800Leu Gly His Phe
Gln Glu Asn Met Gln Ile Gln Ser Phe Pro Arg Tyr 805
810 815Trp Ile Lys Glu Gln Asp Phe Phe Lys His
Lys Ser Val Leu Asp Ser 820 825
830Phe Leu Lys Tyr Asp Cys Lys Asp Glu Phe Asn Lys Gln Asp His Arg
835 840 845Ile Val Leu Asn Trp Ala Leu
Trp Trp Asp Gln Leu Thr Gln Glu Ser 850 855
860Ile Leu Leu Pro Arg Ile Ser Pro Glu Glu Tyr Lys Ser Tyr Ser
Pro865 870 875 880Glu Ala
Leu Trp Arg Tyr Leu Thr Ala Arg His Asp Trp Leu Asn Ile
885 890 895Ile Leu Trp Ile Gly Glu Phe
Gln Thr Gln His Ser Tyr Ala Ser Leu 900 905
910Gln Gln Asn Lys Trp Pro Leu Leu Thr Val Asp Val Ile Asn
Gln Asn 915 920 925Thr Ser Cys Asn
Asn Tyr Met Arg Asn Glu Ile Leu Asp Lys Leu Ala 930
935 940Arg Asn Gly Val Phe Leu Ala Ser Glu Leu Glu Asp
Phe Glu Cys Phe945 950 955
960Leu Leu Arg Leu Ser Arg Ile Gly Gly Val Ile Gln Asp Thr Leu Pro
965 970 975Val Gln Asn Tyr Lys
Thr Lys Glu Gly Trp Asp Phe His Ser Gln Phe 980
985 990Ile Leu Tyr Cys Leu Glu His Ser Leu Gln His Leu
Leu Tyr Val Tyr 995 1000 1005Leu
Asp Cys Tyr Lys Leu Ser Pro Glu Asn Cys Pro Phe Leu Glu 1010
1015 1020Lys Lys Arg Val Thr
10251761263PRTHomo sapiens 176Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala
Ser Ala Gly Gly Ser1 5 10
15Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro
20 25 30Val Pro Ala Glu Ala Met Gly
Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40
45Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu
Gln 50 55 60Val Leu Ser Leu Thr Pro
Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu65 70
75 80Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp
Ser Arg Asn Ser Ser 85 90
95Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu
100 105 110Leu Leu Ile Tyr Glu Phe
Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115 120
125Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile
Asp Asp 130 135 140Gln Asp Ile Ser Ile
Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His145 150
155 160Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys
Cys Val Ile Leu His Ile 165 170
175Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr
180 185 190Leu Pro Leu Pro Ala
Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195
200 205Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly
Trp Ile Tyr Ile 210 215 220Phe Asp Val
Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu225
230 235 240His Lys Glu Asp Met Cys Asn
Glu Gln Gln Gln Glu Pro Ala Lys Ile 245
250 255Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu
Asp Val Ala Val 260 265 270Ile
Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275
280 285Phe Arg Gln His Pro Gly His Leu Leu
Cys Glu Arg Ile Leu Glu Asp 290 295
300Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn305
310 315 320Ser Ala Tyr Asn
Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg 325
330 335Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn
Glu Thr Ile Lys Asn Ser 340 345
350Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His
355 360 365Leu Glu Ser Pro Glu Ser Gly
Asn His Ser Thr Ser Val Gln Ser Trp 370 375
380Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu
Gln385 390 395 400Lys Asp
His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met
405 410 415His Ile Ser Glu Gln Glu Glu
Pro Ile Glu Leu Lys Cys Val Ser Val 420 425
430Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met
Gly Tyr 435 440 445Thr Ile Thr Leu
Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450
455 460Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly
Asp Gln Gln Leu465 470 475
480Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu
485 490 495Thr Gln Glu Glu Phe
Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser 500
505 510Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly
Arg Cys Ser Ile 515 520 525Pro Ile
His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530
535 540Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu
Phe Asn Pro Ser Ser545 550 555
560Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu Tyr
565 570 575Leu Arg Asn Val
Glu Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580
585 590Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln Ser
Lys His Phe Ser Glu 595 600 605Gln
Leu Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610
615 620Leu Phe Ile His Thr Glu Glu Leu Asp Glu
His Leu Gln Lys Gly Val625 630 635
640Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Arg Thr Phe Met Ile
Lys 645 650 655Phe Pro Trp
Lys Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu 660
665 670Asn Val Pro Lys Val Lys Glu Ser Asn Ile
Trp Lys Lys Leu Ser Phe 675 680
685Glu Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys Ile Pro Glu Ala 690
695 700Gln Thr Phe Phe Arg Ile Asp Ser
His Ser Ala Gln Lys Leu Glu Glu705 710
715 720Leu Ile Gly Ile Gly Leu Asn Leu Val Phe Asp Asn
Leu Lys Lys Asn 725 730
735Asn Ile Lys Glu Ala Ser Glu Leu Leu Lys Asn Met Gly Phe Asp Val
740 745 750Lys Gly Gln Leu Leu Lys
Ile Cys Phe Tyr Thr Thr Asn Lys Asn Ile 755 760
765Arg Asp Phe Leu Val Glu Ile Leu Lys Glu Lys Asn Tyr Phe
Ser Glu 770 775 780Lys Glu Lys Arg Thr
Ile Asp Phe Val His Gln Val Glu Lys Leu Tyr785 790
795 800Leu Gly His Phe Gln Glu Asn Met Gln Ile
Gln Ser Phe Pro Arg Tyr 805 810
815Trp Ile Lys Glu Gln Asp Phe Phe Lys His Lys Ser Val Leu Asp Ser
820 825 830Phe Leu Lys Tyr Asp
Cys Lys Asp Glu Phe Asn Lys Gln Asp His Arg 835
840 845Ile Val Leu Asn Trp Ala Leu Trp Trp Asp Gln Leu
Thr Gln Glu Ser 850 855 860Ile Leu Leu
Pro Arg Ile Ser Pro Glu Glu Tyr Lys Ser Tyr Ser Pro865
870 875 880Glu Ala Leu Trp Arg Tyr Leu
Thr Ala Arg His Asp Trp Leu Asn Ile 885
890 895Ile Leu Trp Ile Gly Glu Phe Gln Thr Gln His Ser
Tyr Ala Ser Leu 900 905 910Gln
Gln Asn Lys Trp Pro Leu Leu Thr Val Asp Val Ile Asn Gln Asn 915
920 925Thr Ser Cys Asn Asn Tyr Met Arg Asn
Glu Ile Leu Asp Lys Leu Ala 930 935
940Arg Asn Gly Val Phe Leu Ala Ser Glu Leu Glu Asp Phe Glu Cys Phe945
950 955 960Leu Leu Arg Leu
Ser Arg Ile Gly Gly Val Ile Gln Asp Thr Leu Pro 965
970 975Val Gln Asn Tyr Lys Thr Lys Glu Gly Trp
Asp Phe His Ser Gln Phe 980 985
990Ile Leu Tyr Cys Leu Glu His Ser Leu Gln His Leu Leu Tyr Val Tyr
995 1000 1005Leu Asp Cys Tyr Lys Leu
Ser Pro Glu Asn Cys Pro Phe Leu Glu 1010 1015
1020Lys Lys Glu Leu His Glu Ala His Pro Trp Phe Glu Phe Leu
Val 1025 1030 1035Gln Cys Arg Gln Val
Ala Ser Asn Leu Thr Asp Pro Lys Leu Ile 1040 1045
1050Phe Gln Ala Ser Leu Ala Asn Ala Gln Ile Leu Ile Pro
Thr Asn 1055 1060 1065Gln Ala Ser Val
Ser Ser Met Leu Leu Glu Gly His Thr Leu Leu 1070
1075 1080Ala Leu Ala Thr Thr Met Tyr Ser Pro Gly Gly
Val Ser Gln Val 1085 1090 1095Val Gln
Asn Glu Glu Asn Glu Asn Cys Leu Lys Lys Val Asp Pro 1100
1105 1110Gln Leu Leu Lys Met Ala Leu Thr Pro Tyr
Pro Lys Leu Lys Thr 1115 1120 1125Ala
Leu Phe Pro Gln Cys Thr Pro Pro Ser Val Leu Pro Ser Asp 1130
1135 1140Ile Thr Ile Tyr His Leu Ile Gln Ser
Leu Ser Pro Phe Asp Pro 1145 1150
1155Ser Arg Leu Phe Gly Trp Gln Ser Ala Asn Thr Leu Ala Ile Gly
1160 1165 1170Asp Ala Trp Ser His Leu
Pro His Phe Ser Ser Pro Asp Leu Val 1175 1180
1185Asn Lys Tyr Ala Ile Val Glu Arg Leu Asn Phe Ala Tyr Tyr
Leu 1190 1195 1200His Asn Gly Arg Pro
Ser Phe Ala Phe Gly Thr Phe Leu Val Gln 1205 1210
1215Glu Leu Ile Lys Ser Lys Thr Pro Lys Gln Leu Ile Gln
Gln Val 1220 1225 1230Gly Asn Glu Ala
Tyr Val Ile Gly Leu Ser Ser Phe His Ile Thr 1235
1240 1245Phe Asn Arg Ser Cys Met Cys Leu Phe Leu Arg
Ile Ala Trp Pro 1250 1255
12601771441PRTHomo sapiens 177Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala
Ser Ala Gly Gly Ser1 5 10
15Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro
20 25 30Val Pro Ala Glu Ala Met Gly
Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40
45Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu
Gln 50 55 60Val Leu Ser Leu Thr Pro
Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu65 70
75 80Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp
Ser Arg Asn Ser Ser 85 90
95Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu
100 105 110Leu Leu Ile Tyr Glu Phe
Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115 120
125Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile
Asp Asp 130 135 140Gln Asp Ile Ser Ile
Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His145 150
155 160Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys
Cys Val Ile Leu His Ile 165 170
175Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr
180 185 190Leu Pro Leu Pro Ala
Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195
200 205Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly
Trp Ile Tyr Ile 210 215 220Phe Asp Val
Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu225
230 235 240His Lys Glu Asp Met Cys Asn
Glu Gln Gln Gln Glu Pro Ala Lys Ile 245
250 255Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu
Asp Val Ala Val 260 265 270Ile
Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275
280 285Phe Arg Gln His Pro Gly His Leu Leu
Cys Glu Arg Ile Leu Glu Asp 290 295
300Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn305
310 315 320Ser Ala Tyr Asn
Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg 325
330 335Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn
Glu Thr Ile Lys Asn Ser 340 345
350Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His
355 360 365Leu Glu Ser Pro Glu Ser Gly
Asn His Ser Thr Ser Val Gln Ser Trp 370 375
380Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu
Gln385 390 395 400Lys Asp
His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met
405 410 415His Ile Ser Glu Gln Glu Glu
Pro Ile Glu Leu Lys Cys Val Ser Val 420 425
430Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met
Gly Tyr 435 440 445Thr Ile Thr Leu
Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450
455 460Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly
Asp Gln Gln Leu465 470 475
480Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu
485 490 495Thr Gln Glu Glu Phe
Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser 500
505 510Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly
Arg Cys Ser Ile 515 520 525Pro Ile
His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530
535 540Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu
Phe Asn Pro Ser Ser545 550 555
560Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu Tyr
565 570 575Leu Arg Asn Val
Glu Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580
585 590Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln Ser
Lys His Phe Ser Glu 595 600 605Gln
Leu Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610
615 620Leu Phe Ile His Thr Glu Glu Leu Asp Glu
His Leu Gln Lys Gly Val625 630 635
640Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Arg Thr Phe Met Ile
Lys 645 650 655Phe Pro Trp
Lys Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu 660
665 670Asn Val Pro Lys Val Lys Glu Ser Asn Ile
Trp Lys Lys Leu Ser Phe 675 680
685Glu Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys Ile Pro Glu Ala 690
695 700Gln Thr Phe Phe Arg Ile Asp Ser
His Ser Ala Gln Lys Leu Glu Glu705 710
715 720Leu Ile Gly Ile Gly Leu Asn Leu Val Phe Asp Asn
Leu Lys Lys Asn 725 730
735Asn Ile Lys Glu Ala Ser Glu Leu Leu Lys Asn Met Gly Phe Asp Val
740 745 750Lys Gly Gln Leu Leu Lys
Ile Cys Phe Tyr Thr Thr Asn Lys Asn Ile 755 760
765Arg Asp Phe Leu Val Glu Ile Leu Lys Glu Lys Asn Tyr Phe
Ser Glu 770 775 780Lys Glu Lys Arg Thr
Ile Asp Phe Val His Gln Val Glu Lys Leu Tyr785 790
795 800Leu Gly His Phe Gln Glu Asn Met Gln Ile
Gln Ser Phe Pro Arg Tyr 805 810
815Trp Ile Lys Glu Gln Asp Phe Phe Lys His Lys Ser Val Leu Asp Ser
820 825 830Phe Leu Lys Tyr Asp
Cys Lys Asp Glu Phe Asn Lys Gln Asp His Arg 835
840 845Ile Val Leu Asn Trp Ala Leu Trp Trp Asp Gln Leu
Thr Gln Glu Ser 850 855 860Ile Leu Leu
Pro Arg Ile Ser Pro Glu Glu Tyr Lys Ser Tyr Ser Pro865
870 875 880Glu Ala Leu Trp Arg Tyr Leu
Thr Ala Arg His Asp Trp Leu Asn Ile 885
890 895Ile Leu Trp Ile Gly Glu Phe Gln Thr Gln His Ser
Tyr Ala Ser Leu 900 905 910Gln
Gln Asn Lys Trp Pro Leu Leu Thr Val Asp Val Ile Asn Gln Asn 915
920 925Thr Ser Cys Asn Asn Tyr Met Arg Asn
Glu Ile Leu Asp Lys Leu Ala 930 935
940Arg Asn Gly Val Phe Leu Ala Ser Glu Leu Glu Asp Phe Glu Cys Phe945
950 955 960Leu Leu Arg Leu
Ser Arg Ile Gly Gly Val Ile Gln Asp Thr Leu Pro 965
970 975Val Gln Asn Tyr Lys Thr Lys Glu Gly Trp
Asp Phe His Ser Gln Phe 980 985
990Ile Leu Tyr Cys Leu Glu His Ser Leu Gln His Leu Leu Tyr Val Tyr
995 1000 1005Leu Asp Cys Tyr Lys Leu
Ser Pro Glu Asn Cys Pro Phe Leu Glu 1010 1015
1020Lys Lys Glu Leu His Glu Ala His Pro Trp Phe Glu Phe Leu
Val 1025 1030 1035Gln Cys Arg Gln Val
Ala Ser Asn Leu Thr Asp Pro Lys Leu Ile 1040 1045
1050Phe Gln Ala Ser Leu Ala Asn Ala Gln Ile Leu Ile Pro
Thr Asn 1055 1060 1065Gln Ala Ser Val
Ser Ser Met Leu Leu Glu Gly His Thr Leu Leu 1070
1075 1080Ala Leu Ala Thr Thr Met Tyr Ser Pro Gly Gly
Val Ser Gln Val 1085 1090 1095Val Gln
Asn Glu Glu Asn Glu Asn Cys Leu Lys Lys Val Asp Pro 1100
1105 1110Gln Leu Leu Lys Met Ala Leu Thr Pro Tyr
Pro Lys Leu Lys Thr 1115 1120 1125Ala
Leu Phe Pro Gln Cys Thr Pro Pro Ser Val Leu Pro Ser Asp 1130
1135 1140Ile Thr Ile Tyr His Leu Ile Gln Ser
Leu Ser Pro Phe Asp Pro 1145 1150
1155Ser Arg Leu Phe Gly Trp Gln Ser Ala Asn Thr Leu Ala Ile Gly
1160 1165 1170Asp Ala Trp Ser His Leu
Pro His Phe Ser Ser Pro Asp Leu Val 1175 1180
1185Asn Lys Tyr Ala Ile Val Glu Arg Leu Asn Phe Ala Tyr Tyr
Leu 1190 1195 1200His Asn Gly Arg Pro
Ser Phe Ala Phe Gly Thr Phe Leu Val Gln 1205 1210
1215Glu Leu Ile Lys Ser Lys Thr Pro Lys Gln Leu Ile Gln
Gln Val 1220 1225 1230Gly Asn Glu Ala
Tyr Val Ile Gly Leu Ser Ser Phe His Ile Pro 1235
1240 1245Ser Ile Gly Ala Ala Cys Val Cys Phe Leu Glu
Leu Leu Gly Leu 1250 1255 1260Asp Ser
Leu Lys Leu Arg Val Asp Met Lys Val Ala Asn Ile Ile 1265
1270 1275Leu Ser Tyr Lys Cys Arg Asn Glu Asp Ala
Gln Tyr Ser Phe Ile 1280 1285 1290Arg
Glu Ser Val Ala Glu Lys Leu Ser Lys Leu Ala Asp Gly Glu 1295
1300 1305Lys Thr Thr Thr Glu Glu Leu Leu Val
Leu Leu Glu Glu Gly Thr 1310 1315
1320Trp Asn Ser Ile Gln Gln Gln Glu Ile Lys Arg Leu Ser Ser Glu
1325 1330 1335Ser Ser Ser Gln Trp Ala
Leu Val Val Gln Phe Cys Arg Leu His 1340 1345
1350Asn Met Lys Leu Ser Ile Ser Tyr Leu Arg Glu Cys Ala Lys
Ala 1355 1360 1365Asn Asp Trp Leu Gln
Phe Ile Ile His Ser Gln Leu His Asn Tyr 1370 1375
1380His Pro Ala Glu Val Lys Ser Leu Ile Gln Tyr Phe Ser
Pro Val 1385 1390 1395Ile Gln Asp His
Leu Arg Leu Ala Phe Glu Asn Leu Pro Ser Val 1400
1405 1410Pro Thr Ser Lys Met Asp Ser Asp Gln Val Cys
Asn Lys Cys Pro 1415 1420 1425Gln Glu
Leu Gln Gly Ser Lys Arg Asp Asp Arg Phe Ile 1430
1435 14401781823PRTHomo sapiens 178Met Ala Ala Glu Glu
Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser1 5
10 15Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro
Met Leu Leu Val Pro 20 25
30Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg
35 40 45Thr Gln Pro Glu Ala Leu Gly Ser
Leu Thr Ala Ala Gly Ser Leu Gln 50 55
60Val Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu65
70 75 80Glu Gly Pro Phe Trp
His Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser 85
90 95Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu
Gly Glu Asn Tyr Glu 100 105
110Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr
115 120 125Ile Leu Tyr Ser Cys Ser Arg
Glu Ala Leu Gln Lys Leu Ile Asp Asp 130 135
140Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe
His145 150 155 160Asn Asn
Thr Ser Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile
165 170 175Ile Phe Pro Glu Arg Asp Ala
Ala Ile Arg Val Leu Asn Cys Phe Thr 180 185
190Leu Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr
Gln Leu 195 200 205Cys Arg Gly Ile
Leu Phe Val Leu Ser Ser Leu Gly Trp Ile Tyr Ile 210
215 220Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val
Asp Leu Ala Leu225 230 235
240His Lys Glu Asp Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile
245 250 255Ser Ser Phe Thr Ser
Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val 260
265 270Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn
Leu Asn Leu Tyr 275 280 285Phe Arg
Gln His Pro Gly His Leu Leu Cys Glu Arg Ile Leu Glu Asp 290
295 300Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu
Asp Asp Pro Val Asn305 310 315
320Ser Ala Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg
325 330 335Ser Trp Lys Ala
Gln Leu Ser Ser Leu Asn Glu Thr Ile Lys Asn Ser 340
345 350Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe
Gln Asp Ile Leu His 355 360 365Leu
Glu Ser Pro Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370
375 380Ala Phe Ile Pro Gln Asp Ile Met His Gly
Gln Tyr Asn Val Leu Gln385 390 395
400Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile
Met 405 410 415His Ile Ser
Glu Gln Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val 420
425 430Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu
Val Glu Arg Met Gly Tyr 435 440
445Thr Ile Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450
455 460Leu Gly Thr Lys Cys Ile Pro Val
Asp Ser Ser Gly Asp Gln Gln Leu465 470
475 480Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile
Leu Phe Gly Leu 485 490
495Thr Gln Glu Glu Phe Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser
500 505 510Thr Val Asp Thr Leu Cys
His Leu Asn Gly Trp Gly Arg Cys Ser Ile 515 520
525Pro Ile His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu
Asp Thr 530 535 540Val Asn Phe Phe Leu
Lys Ser Lys Glu Asn Leu Phe Asn Pro Ser Ser545 550
555 560Lys Ser Ser Val Ser Asp Gln Phe Asp His
Leu Ser Ser His Leu Tyr 565 570
575Leu Arg Asn Val Glu Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser
580 585 590Ala Ile Arg Glu Ser
Tyr Ser Glu Pro Gln Ser Lys His Phe Ser Glu 595
600 605Gln Leu Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn
Gln Ile Lys Glu 610 615 620Leu Phe Ile
His Thr Glu Glu Leu Asp Glu His Leu Gln Lys Gly Val625
630 635 640Asn Ile Leu Thr Ser Tyr Ile
Asn Glu Leu Arg Thr Phe Met Ile Lys 645
650 655Phe Pro Trp Lys Leu Thr Asp Ala Ile Asp Glu Tyr
Asp Val His Glu 660 665 670Asn
Val Pro Lys Val Lys Glu Ser Asn Ile Trp Lys Lys Leu Ser Phe 675
680 685Glu Glu Val Ile Ala Ser Ala Ile Leu
Asn Asn Lys Ile Pro Glu Ala 690 695
700Gln Thr Phe Phe Arg Ile Asp Ser His Ser Ala Gln Lys Leu Glu Glu705
710 715 720Leu Ile Gly Ile
Gly Leu Asn Leu Val Phe Asp Asn Leu Lys Lys Asn 725
730 735Asn Ile Lys Glu Ala Ser Glu Leu Leu Lys
Asn Met Gly Phe Asp Val 740 745
750Lys Gly Gln Leu Leu Lys Ile Cys Phe Tyr Thr Thr Asn Lys Asn Ile
755 760 765Arg Asp Phe Leu Val Glu Ile
Leu Lys Glu Lys Asn Tyr Phe Ser Glu 770 775
780Lys Glu Lys Arg Thr Ile Asp Phe Val His Gln Val Glu Lys Leu
Tyr785 790 795 800Leu Gly
His Phe Gln Glu Asn Met Gln Ile Gln Ser Phe Pro Arg Tyr
805 810 815Trp Ile Lys Glu Gln Asp Phe
Phe Lys His Lys Ser Val Leu Asp Ser 820 825
830Phe Leu Lys Tyr Asp Cys Lys Asp Glu Phe Asn Lys Gln Asp
His Arg 835 840 845Ile Val Leu Asn
Trp Ala Leu Trp Trp Asp Gln Leu Thr Gln Glu Ser 850
855 860Ile Leu Leu Pro Arg Ile Ser Pro Glu Glu Tyr Lys
Ser Tyr Ser Pro865 870 875
880Glu Ala Leu Trp Arg Tyr Leu Thr Ala Arg His Asp Trp Leu Asn Ile
885 890 895Ile Leu Trp Ile Gly
Glu Phe Gln Thr Gln His Ser Tyr Ala Ser Leu 900
905 910Gln Gln Asn Lys Trp Pro Leu Leu Thr Val Asp Val
Ile Asn Gln Asn 915 920 925Thr Ser
Cys Asn Asn Tyr Met Arg Asn Glu Ile Leu Asp Lys Leu Ala 930
935 940Arg Asn Gly Val Phe Leu Ala Ser Glu Leu Glu
Asp Phe Glu Cys Phe945 950 955
960Leu Leu Arg Leu Ser Arg Ile Gly Gly Val Ile Gln Asp Thr Leu Pro
965 970 975Val Gln Asn Tyr
Lys Thr Lys Glu Gly Trp Asp Phe His Ser Gln Phe 980
985 990Ile Leu Tyr Cys Leu Glu His Ser Leu Gln His
Leu Leu Tyr Val Tyr 995 1000
1005Leu Asp Cys Tyr Lys Leu Ser Pro Glu Asn Cys Pro Phe Leu Glu
1010 1015 1020Lys Lys Glu Leu His Glu
Ala His Pro Trp Phe Glu Phe Leu Val 1025 1030
1035Gln Cys Arg Gln Val Ala Ser Asn Leu Thr Asp Pro Lys Leu
Ile 1040 1045 1050Phe Gln Ala Ser Leu
Ala Asn Ala Gln Ile Leu Ile Pro Thr Asn 1055 1060
1065Gln Ala Ser Val Ser Ser Met Leu Leu Glu Gly His Thr
Leu Leu 1070 1075 1080Ala Leu Ala Thr
Thr Met Tyr Ser Pro Gly Gly Val Ser Gln Val 1085
1090 1095Val Gln Asn Glu Glu Asn Glu Asn Cys Leu Lys
Lys Val Asp Pro 1100 1105 1110Gln Leu
Leu Lys Met Ala Leu Thr Pro Tyr Pro Lys Leu Lys Thr 1115
1120 1125Ala Leu Phe Pro Gln Cys Thr Pro Pro Ser
Val Leu Pro Ser Asp 1130 1135 1140Ile
Thr Ile Tyr His Leu Ile Gln Ser Leu Ser Pro Phe Asp Pro 1145
1150 1155Ser Arg Leu Phe Gly Trp Gln Ser Ala
Asn Thr Leu Ala Ile Gly 1160 1165
1170Asp Ala Trp Ser His Leu Pro His Phe Ser Ser Pro Asp Leu Val
1175 1180 1185Asn Lys Tyr Ala Ile Val
Glu Arg Leu Asn Phe Ala Tyr Tyr Leu 1190 1195
1200His Asn Gly Arg Pro Ser Phe Ala Phe Gly Thr Phe Leu Val
Gln 1205 1210 1215Glu Leu Ile Lys Ser
Lys Thr Pro Lys Gln Leu Ile Gln Gln Val 1220 1225
1230Gly Asn Glu Ala Tyr Val Ile Gly Leu Ser Ser Phe His
Ile Pro 1235 1240 1245Ser Ile Gly Ala
Ala Cys Val Cys Phe Leu Glu Leu Leu Gly Leu 1250
1255 1260Asp Ser Leu Lys Leu Arg Val Asp Met Lys Val
Ala Asn Ile Ile 1265 1270 1275Leu Ser
Tyr Lys Cys Arg Asn Glu Asp Ala Gln Tyr Ser Phe Ile 1280
1285 1290Arg Glu Ser Val Ala Glu Lys Leu Ser Lys
Leu Ala Asp Gly Glu 1295 1300 1305Lys
Thr Thr Thr Glu Glu Leu Leu Val Leu Leu Glu Glu Gly Thr 1310
1315 1320Trp Asn Ser Ile Gln Gln Gln Glu Ile
Lys Arg Leu Ser Ser Glu 1325 1330
1335Ser Ser Ser Gln Trp Ala Leu Val Val Gln Phe Cys Arg Leu His
1340 1345 1350Asn Met Lys Leu Ser Ile
Ser Tyr Leu Arg Glu Cys Ala Lys Ala 1355 1360
1365Asn Asp Trp Leu Gln Phe Ile Ile His Ser Gln Leu His Asn
Tyr 1370 1375 1380His Pro Ala Glu Val
Lys Ser Leu Ile Gln Tyr Phe Ser Pro Val 1385 1390
1395Ile Gln Asp His Leu Arg Leu Ala Phe Glu Asn Leu Pro
Ser Val 1400 1405 1410Pro Thr Ser Lys
Met Asp Ser Asp Gln Val Cys Asn Lys Cys Pro 1415
1420 1425Gln Glu Leu Gln Gly Ser Lys Gln Glu Met Thr
Asp Leu Phe Glu 1430 1435 1440Ile Leu
Leu Gln Cys Ser Glu Glu Pro Asp Ser Trp His Trp Leu 1445
1450 1455Leu Val Glu Ala Val Lys Gln Gln Ala Pro
Ile Leu Ser Val Leu 1460 1465 1470Ala
Ser Cys Leu Gln Gly Ala Ser Ala Ile Ser Cys Leu Cys Val 1475
1480 1485Trp Ile Ile Thr Ser Val Glu Asp Asn
Val Ala Thr Glu Ala Met 1490 1495
1500Gly His Ile Gln Asp Ser Thr Glu Asp His Thr Trp Asn Leu Glu
1505 1510 1515Asp Leu Ser Val Ile Trp
Arg Thr Leu Leu Thr Arg Gln Lys Ser 1520 1525
1530Lys Thr Leu Ile Arg Gly Phe Gln Leu Phe Phe Lys Asp Ser
Pro 1535 1540 1545Leu Leu Leu Val Met
Glu Met Tyr Glu Leu Cys Met Phe Phe Arg 1550 1555
1560Asn Tyr Lys Glu Ala Glu Ala Lys Leu Leu Glu Phe Gln
Lys Ser 1565 1570 1575Leu Glu Thr Leu
Asn Thr Ala Ala Thr Lys Val His Pro Val Ile 1580
1585 1590Pro Ala Met Trp Leu Glu Asp Gln Val Cys Phe
Leu Leu Lys Leu 1595 1600 1605Met Leu
Gln Gln Cys Lys Thr Gln Tyr Glu Leu Gly Lys Leu Leu 1610
1615 1620Gln Leu Phe Val Glu Arg Glu His Leu Phe
Ser Asp Gly Pro Asp 1625 1630 1635Val
Lys Lys Leu Cys Ile Leu Cys Gln Ile Leu Lys Asp Thr Ser 1640
1645 1650Ile Ala Ile Asn His Thr Ile Ile Thr
Ser Tyr Ser Ile Glu Asn 1655 1660
1665Leu Gln His Glu Cys Arg Ser Ile Leu Glu Arg Leu Gln Thr Asp
1670 1675 1680Gly Gln Phe Ala Leu Ala
Arg Arg Val Ala Glu Leu Ala Glu Leu 1685 1690
1695Pro Val Asp Asn Leu Val Ile Lys Glu Ile Thr Gln Glu Met
Gln 1700 1705 1710Thr Leu Lys His Ile
Glu Gln Trp Ser Leu Lys Gln Ala Arg Ile 1715 1720
1725Asp Phe Trp Lys Lys Cys His Glu Asn Phe Lys Lys Asn
Ser Ile 1730 1735 1740Ser Ser Lys Ala
Ala Ser Ser Phe Phe Ser Thr Gln Ala His Val 1745
1750 1755Ala Cys Glu His Pro Thr Gly Trp Ser Ser Met
Glu Glu Arg His 1760 1765 1770Leu Leu
Leu Thr Leu Ala Gly His Trp Leu Ala Gln Glu Asp Val 1775
1780 1785Val Pro Leu Asp Lys Leu Glu Glu Leu Glu
Lys Gln Ile Trp Leu 1790 1795 1800Cys
Arg Ile Thr Gln His Thr Leu Gly Arg Asn Gln Glu Glu Thr 1805
1810 1815Glu Pro Arg Phe Ser
18201791856PRTHomo sapiens 179Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala
Ser Ala Gly Gly Ser1 5 10
15Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro
20 25 30Val Pro Ala Glu Ala Met Gly
Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40
45Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu
Gln 50 55 60Val Leu Ser Leu Thr Pro
Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu65 70
75 80Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp
Ser Arg Asn Ser Ser 85 90
95Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu
100 105 110Leu Leu Ile Tyr Glu Phe
Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115 120
125Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile
Asp Asp 130 135 140Gln Asp Ile Ser Ile
Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His145 150
155 160Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys
Cys Val Ile Leu His Ile 165 170
175Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr
180 185 190Leu Pro Leu Pro Ala
Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195
200 205Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly
Trp Ile Tyr Ile 210 215 220Phe Asp Val
Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu225
230 235 240His Lys Glu Asp Met Cys Asn
Glu Gln Gln Gln Glu Pro Ala Lys Ile 245
250 255Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu
Asp Val Ala Val 260 265 270Ile
Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275
280 285Phe Arg Gln His Pro Gly His Leu Leu
Cys Glu Arg Ile Leu Glu Asp 290 295
300Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn305
310 315 320Ser Ala Tyr Asn
Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg 325
330 335Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn
Glu Thr Ile Lys Asn Ser 340 345
350Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His
355 360 365Leu Glu Ser Pro Glu Ser Gly
Asn His Ser Thr Ser Val Gln Ser Trp 370 375
380Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu
Gln385 390 395 400Lys Asp
His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met
405 410 415His Ile Ser Glu Gln Glu Glu
Pro Ile Glu Leu Lys Cys Val Ser Val 420 425
430Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met
Gly Tyr 435 440 445Thr Ile Thr Leu
Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450
455 460Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly
Asp Gln Gln Leu465 470 475
480Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu
485 490 495Thr Gln Glu Glu Phe
Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser 500
505 510Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly
Arg Cys Ser Ile 515 520 525Pro Ile
His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530
535 540Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu
Phe Asn Pro Ser Ser545 550 555
560Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu Tyr
565 570 575Leu Arg Asn Val
Glu Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580
585 590Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln Ser
Lys His Phe Ser Glu 595 600 605Gln
Leu Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610
615 620Leu Phe Ile His Thr Glu Glu Leu Asp Glu
His Leu Gln Lys Gly Val625 630 635
640Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Arg Thr Phe Met Ile
Lys 645 650 655Phe Pro Trp
Lys Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu 660
665 670Asn Val Pro Lys Val Lys Glu Ser Asn Ile
Trp Lys Lys Leu Ser Phe 675 680
685Glu Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys Ile Pro Glu Ala 690
695 700Gln Thr Phe Phe Arg Ile Asp Ser
His Ser Ala Gln Lys Leu Glu Glu705 710
715 720Leu Ile Gly Ile Gly Leu Asn Leu Val Phe Asp Asn
Leu Lys Lys Asn 725 730
735Asn Ile Lys Glu Ala Ser Glu Leu Leu Lys Asn Met Gly Phe Asp Val
740 745 750Lys Gly Gln Leu Leu Lys
Ile Cys Phe Tyr Thr Thr Asn Lys Asn Ile 755 760
765Arg Asp Phe Leu Val Glu Ile Leu Lys Glu Lys Asn Tyr Phe
Ser Glu 770 775 780Lys Glu Lys Arg Thr
Ile Asp Phe Val His Gln Val Glu Lys Leu Tyr785 790
795 800Leu Gly His Phe Gln Glu Asn Met Gln Ile
Gln Ser Phe Pro Arg Tyr 805 810
815Trp Ile Lys Glu Gln Asp Phe Phe Lys His Lys Ser Val Leu Asp Ser
820 825 830Phe Leu Lys Tyr Asp
Cys Lys Asp Glu Phe Asn Lys Gln Asp His Arg 835
840 845Ile Val Leu Asn Trp Ala Leu Trp Trp Asp Gln Leu
Thr Gln Glu Ser 850 855 860Ile Leu Leu
Pro Arg Ile Ser Pro Glu Glu Tyr Lys Ser Tyr Ser Pro865
870 875 880Glu Ala Leu Trp Arg Tyr Leu
Thr Ala Arg His Asp Trp Leu Asn Ile 885
890 895Ile Leu Trp Ile Gly Glu Phe Gln Thr Gln His Ser
Tyr Ala Ser Leu 900 905 910Gln
Gln Asn Lys Trp Pro Leu Leu Thr Val Asp Val Ile Asn Gln Asn 915
920 925Thr Ser Cys Asn Asn Tyr Met Arg Asn
Glu Ile Leu Asp Lys Leu Ala 930 935
940Arg Asn Gly Val Phe Leu Ala Ser Glu Leu Glu Asp Phe Glu Cys Phe945
950 955 960Leu Leu Arg Leu
Ser Arg Ile Gly Gly Val Ile Gln Asp Thr Leu Pro 965
970 975Val Gln Asn Tyr Lys Thr Lys Glu Gly Trp
Asp Phe His Ser Gln Phe 980 985
990Ile Leu Tyr Cys Leu Glu His Ser Leu Gln His Leu Leu Tyr Val Tyr
995 1000 1005Leu Asp Cys Tyr Lys Leu
Ser Pro Glu Asn Cys Pro Phe Leu Glu 1010 1015
1020Lys Lys Glu Leu His Glu Ala His Pro Trp Phe Glu Phe Leu
Val1025 1030 1035Gln Cys Arg Gln Val Ala
Ser Asn Leu Thr Asp Pro Lys Leu Ile 1040
1045 1050Phe Gln Ala Ser Leu Ala Asn Ala Gln Ile Leu
Ile Pro Thr Asn 1055 1060
1065Gln Ala Ser Val Ser Ser Met Leu Leu Glu Gly His Thr Leu Leu
1070 1075 1080Ala Leu Ala Thr Thr Met
Tyr Ser Pro Gly Gly Val Ser Gln Val 1085 1090
1095Val Gln Asn Glu Glu Asn Glu Asn Cys Leu Lys Lys Val Asp
Pro 1100 1105 1110Gln Leu Leu Lys Met
Ala Leu Thr Pro Tyr Pro Lys Leu Lys Thr 1115 1120
1125Ala Leu Phe Pro Gln Cys Thr Pro Pro Ser Val Leu Pro
Ser Asp 1130 1135 1140Ile Thr Ile Tyr
His Leu Ile Gln Ser Leu Ser Pro Phe Asp Pro 1145
1150 1155Ser Arg Leu Phe Gly Trp Gln Ser Ala Asn Thr
Leu Ala Ile Gly 1160 1165 1170Asp Ala
Trp Ser His Leu Pro His Phe Ser Ser Pro Asp Leu Val 1175
1180 1185Asn Lys Tyr Ala Ile Val Glu Arg Leu Asn
Phe Ala Tyr Tyr Leu 1190 1195 1200His
Asn Gly Arg Pro Ser Phe Ala Phe Gly Thr Phe Leu Val Gln 1205
1210 1215Glu Leu Ile Lys Ser Lys Thr Pro Lys
Gln Leu Ile Gln Gln Val 1220 1225
1230Gly Asn Glu Ala Tyr Val Ile Gly Leu Ser Ser Phe His Ile Pro
1235 1240 1245Ser Ile Gly Ala Ala Cys
Val Cys Phe Leu Glu Leu Leu Gly Leu 1250 1255
1260Asp Ser Leu Lys Leu Arg Val Asp Met Lys Val Ala Asn Ile
Ile 1265 1270 1275Leu Ser Tyr Lys Cys
Arg Asn Glu Asp Ala Gln Tyr Ser Phe Ile 1280 1285
1290Arg Glu Ser Val Ala Glu Lys Leu Ser Lys Leu Ala Asp
Gly Glu 1295 1300 1305Lys Thr Thr Thr
Glu Glu Leu Leu Val Leu Leu Glu Glu Gly Thr 1310
1315 1320Trp Asn Ser Ile Gln Gln Gln Glu Ile Lys Arg
Leu Ser Ser Glu 1325 1330 1335Ser Ser
Ser Gln Trp Ala Leu Val Val Gln Phe Cys Arg Leu His 1340
1345 1350Asn Met Lys Leu Ser Ile Ser Tyr Leu Arg
Glu Cys Ala Lys Ala 1355 1360 1365Asn
Asp Trp Leu Gln Phe Ile Ile His Ser Gln Leu His Asn Tyr 1370
1375 1380His Pro Ala Glu Val Lys Ser Leu Ile
Gln Tyr Phe Ser Pro Val 1385 1390
1395Ile Gln Asp His Leu Arg Leu Ala Phe Glu Asn Leu Pro Ser Val
1400 1405 1410Pro Thr Ser Lys Met Asp
Ser Asp Gln Val Cys Asn Lys Cys Pro 1415 1420
1425Gln Glu Leu Gln Gly Ser Lys Gln Glu Met Thr Asp Leu Phe
Glu 1430 1435 1440Ile Leu Leu Gln Cys
Ser Glu Glu Pro Asp Ser Trp His Trp Leu 1445 1450
1455Leu Val Glu Ala Val Lys Gln Gln Ala Pro Ile Leu Ser
Val Leu 1460 1465 1470Ala Ser Cys Leu
Gln Gly Ala Ser Ala Ile Ser Cys Leu Cys Val 1475
1480 1485Trp Ile Ile Thr Ser Val Glu Asp Asn Val Ala
Thr Glu Ala Met 1490 1495 1500Gly His
Ile Gln Asp Ser Thr Glu Asp His Thr Trp Asn Leu Glu 1505
1510 1515Asp Leu Ser Val Ile Trp Arg Thr Leu Leu
Thr Arg Gln Lys Ser 1520 1525 1530Lys
Thr Leu Ile Arg Gly Phe Gln Leu Phe Phe Lys Asp Ser Pro 1535
1540 1545Leu Leu Leu Val Met Glu Met Tyr Glu
Leu Cys Met Phe Phe Arg 1550 1555
1560Asn Tyr Lys Glu Ala Glu Ala Lys Leu Leu Glu Phe Gln Lys Ser
1565 1570 1575Leu Glu Thr Leu Asn Thr
Ala Ala Thr Lys Val His Pro Val Ile 1580 1585
1590Pro Ala Met Trp Leu Glu Asp Gln Val Cys Phe Leu Leu Lys
Leu 1595 1600 1605Met Leu Gln Gln Cys
Lys Thr Gln Tyr Glu Leu Gly Lys Leu Leu 1610 1615
1620Gln Leu Phe Val Glu Arg Glu His Leu Phe Ser Asp Gly
Pro Asp 1625 1630 1635Val Lys Lys Leu
Cys Ile Leu Cys Gln Ile Leu Lys Asp Thr Ser 1640
1645 1650Ile Ala Ile Asn His Thr Ile Ile Thr Ser Tyr
Ser Ile Glu Asn 1655 1660 1665Leu Gln
His Glu Cys Arg Ser Ile Leu Glu Arg Leu Gln Thr Asp 1670
1675 1680Gly Gln Phe Ala Leu Ala Arg Arg Val Ala
Glu Leu Ala Glu Leu 1685 1690 1695Pro
Val Asp Asn Leu Val Ile Lys Glu Ile Thr Gln Glu Met Gln 1700
1705 1710Thr Leu Lys His Ile Glu Gln Trp Ser
Leu Lys Gln Ala Arg Ile 1715 1720
1725Asp Phe Trp Lys Lys Cys His Glu Asn Phe Lys Lys Asn Ser Ile
1730 1735 1740Ser Ser Lys Ala Ala Ser
Ser Phe Phe Ser Thr Gln Ala His Val 1745 1750
1755Ala Cys Glu His Pro Thr Gly Trp Ser Ser Met Glu Glu Arg
His 1760 1765 1770Leu Leu Leu Thr Leu
Ala Gly His Trp Leu Ala Gln Glu Asp Val 1775 1780
1785Val Pro Leu Asp Lys Leu Glu Glu Leu Glu Lys Gln Ile
Trp Leu 1790 1795 1800Cys Arg Ile Thr
Gln His Thr Leu Gly Arg Asn Gln Glu Glu Thr 1805
1810 1815Glu Pro Arg Phe Ser Arg Gln Ile Ser Thr Ser
Gly Glu Leu Ser 1820 1825 1830Phe Asp
Ser Leu Ala Ser Glu Phe Ser Phe Ser Val Gly Cys Ser 1835
1840 1845Glu His Ile Lys Ile Leu Arg Thr 1850
18551801949PRTHomo sapiens 180Met Ala Ala Glu Glu Gly Val
Ala Ser Ala Ala Ser Ala Gly Gly Ser1 5 10
15Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu
Leu Val Pro 20 25 30Val Pro
Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35
40 45Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr
Ala Ala Gly Ser Leu Gln 50 55 60Val
Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu65
70 75 80Glu Gly Pro Phe Trp His
Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser 85
90 95Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly
Glu Asn Tyr Glu 100 105 110Leu
Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115
120 125Ile Leu Tyr Ser Cys Ser Arg Glu Ala
Leu Gln Lys Leu Ile Asp Asp 130 135
140Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His145
150 155 160Asn Asn Thr Ser
Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile 165
170 175Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg
Val Leu Asn Cys Phe Thr 180 185
190Leu Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu
195 200 205Cys Arg Gly Ile Leu Phe Val
Leu Ser Ser Leu Gly Trp Ile Tyr Ile 210 215
220Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala
Leu225 230 235 240His Lys
Glu Asp Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile
245 250 255Ser Ser Phe Thr Ser Leu Lys
Val Ser Gln Asp Leu Asp Val Ala Val 260 265
270Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn
Leu Tyr 275 280 285Phe Arg Gln His
Pro Gly His Leu Leu Cys Glu Arg Ile Leu Glu Asp 290
295 300Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp
Asp Pro Val Asn305 310 315
320Ser Ala Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg
325 330 335Ser Trp Lys Ala Gln
Leu Ser Ser Leu Asn Glu Thr Ile Lys Asn Ser 340
345 350Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln
Asp Ile Leu His 355 360 365Leu Glu
Ser Pro Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370
375 380Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln
Tyr Asn Val Leu Gln385 390 395
400Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met
405 410 415His Ile Ser Glu
Gln Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val 420
425 430Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val
Glu Arg Met Gly Tyr 435 440 445Thr
Ile Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450
455 460Leu Gly Thr Lys Cys Ile Pro Val Asp Ser
Ser Gly Asp Gln Gln Leu465 470 475
480Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly
Leu 485 490 495Thr Gln Glu
Glu Phe Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser 500
505 510Thr Val Asp Thr Leu Cys His Leu Asn Gly
Trp Gly Arg Cys Ser Ile 515 520
525Pro Ile His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530
535 540Val Asn Phe Phe Leu Lys Ser Lys
Glu Asn Leu Phe Asn Pro Ser Ser545 550
555 560Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser
Ser His Leu Tyr 565 570
575Leu Arg Asn Val Glu Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser
580 585 590Ala Ile Arg Glu Ser Tyr
Ser Glu Pro Gln Ser Lys His Phe Ser Glu 595 600
605Gln Leu Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile
Lys Glu 610 615 620Leu Phe Ile His Thr
Glu Glu Leu Asp Glu His Leu Gln Lys Gly Val625 630
635 640Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu
Arg Thr Phe Met Ile Lys 645 650
655Phe Pro Trp Lys Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu
660 665 670Asn Val Pro Lys Val
Lys Glu Ser Asn Ile Trp Lys Lys Leu Ser Phe 675
680 685Glu Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys
Ile Pro Glu Ala 690 695 700Gln Thr Phe
Phe Arg Ile Asp Ser His Ser Ala Gln Lys Leu Glu Glu705
710 715 720Leu Ile Gly Ile Gly Leu Asn
Leu Val Phe Asp Asn Leu Lys Lys Asn 725
730 735Asn Ile Lys Glu Ala Ser Glu Leu Leu Lys Asn Met
Gly Phe Asp Val 740 745 750Lys
Gly Gln Leu Leu Lys Ile Cys Phe Tyr Thr Thr Asn Lys Asn Ile 755
760 765Arg Asp Phe Leu Val Glu Ile Leu Lys
Glu Lys Asn Tyr Phe Ser Glu 770 775
780Lys Glu Lys Arg Thr Ile Asp Phe Val His Gln Val Glu Lys Leu Tyr785
790 795 800Leu Gly His Phe
Gln Glu Asn Met Gln Ile Gln Ser Phe Pro Arg Tyr 805
810 815Trp Ile Lys Glu Gln Asp Phe Phe Lys His
Lys Ser Val Leu Asp Ser 820 825
830Phe Leu Lys Tyr Asp Cys Lys Asp Glu Phe Asn Lys Gln Asp His Arg
835 840 845Ile Val Leu Asn Trp Ala Leu
Trp Trp Asp Gln Leu Thr Gln Glu Ser 850 855
860Ile Leu Leu Pro Arg Ile Ser Pro Glu Glu Tyr Lys Ser Tyr Ser
Pro865 870 875 880Glu Ala
Leu Trp Arg Tyr Leu Thr Ala Arg His Asp Trp Leu Asn Ile
885 890 895Ile Leu Trp Ile Gly Glu Phe
Gln Thr Gln His Ser Tyr Ala Ser Leu 900 905
910Gln Gln Asn Lys Trp Pro Leu Leu Thr Val Asp Val Ile Asn
Gln Asn 915 920 925Thr Ser Cys Asn
Asn Tyr Met Arg Asn Glu Ile Leu Asp Lys Leu Ala 930
935 940Arg Asn Gly Val Phe Leu Ala Ser Glu Leu Glu Asp
Phe Glu Cys Phe945 950 955
960Leu Leu Arg Leu Ser Arg Ile Gly Gly Val Ile Gln Asp Thr Leu Pro
965 970 975Val Gln Asn Tyr Lys
Thr Lys Glu Gly Trp Asp Phe His Ser Gln Phe 980
985 990Ile Leu Tyr Cys Leu Glu His Ser Leu Gln His Leu
Leu Tyr Val Tyr 995 1000 1005Leu
Asp Cys Tyr Lys Leu Ser Pro Glu Asn Cys Pro Phe Leu Glu 1010
1015 1020Lys Lys Glu Leu His Glu Ala His Pro
Trp Phe Glu Phe Leu Val 1025 1030
1035Gln Cys Arg Gln Val Ala Ser Asn Leu Thr Asp Pro Lys Leu Ile
1040 1045 1050Phe Gln Ala Ser Leu Ala
Asn Ala Gln Ile Leu Ile Pro Thr Asn 1055 1060
1065Gln Ala Ser Val Ser Ser Met Leu Leu Glu Gly His Thr Leu
Leu 1070 1075 1080Ala Leu Ala Thr Thr
Met Tyr Ser Pro Gly Gly Val Ser Gln Val 1085 1090
1095Val Gln Asn Glu Glu Asn Glu Asn Cys Leu Lys Lys Val
Asp Pro 1100 1105 1110Gln Leu Leu Lys
Met Ala Leu Thr Pro Tyr Pro Lys Leu Lys Thr 1115
1120 1125Ala Leu Phe Pro Gln Cys Thr Pro Pro Ser Val
Leu Pro Ser Asp 1130 1135 1140Ile Thr
Ile Tyr His Leu Ile Gln Ser Leu Ser Pro Phe Asp Pro 1145
1150 1155Ser Arg Leu Phe Gly Trp Gln Ser Ala Asn
Thr Leu Ala Ile Gly 1160 1165 1170Asp
Ala Trp Ser His Leu Pro His Phe Ser Ser Pro Asp Leu Val 1175
1180 1185Asn Lys Tyr Ala Ile Val Glu Arg Leu
Asn Phe Ala Tyr Tyr Leu 1190 1195
1200His Asn Gly Arg Pro Ser Phe Ala Phe Gly Thr Phe Leu Val Gln
1205 1210 1215Glu Leu Ile Lys Ser Lys
Thr Pro Lys Gln Leu Ile Gln Gln Val 1220 1225
1230Gly Asn Glu Ala Tyr Val Ile Gly Leu Ser Ser Phe His Ile
Pro 1235 1240 1245Ser Ile Gly Ala Ala
Cys Val Cys Phe Leu Glu Leu Leu Gly Leu 1250 1255
1260Asp Ser Leu Lys Leu Arg Val Asp Met Lys Val Ala Asn
Ile Ile 1265 1270 1275Leu Ser Tyr Lys
Cys Arg Asn Glu Asp Ala Gln Tyr Ser Phe Ile 1280
1285 1290Arg Glu Ser Val Ala Glu Lys Leu Ser Lys Leu
Ala Asp Gly Glu 1295 1300 1305Lys Thr
Thr Thr Glu Glu Leu Leu Val Leu Leu Glu Glu Gly Thr 1310
1315 1320Trp Asn Ser Ile Gln Gln Gln Glu Ile Lys
Arg Leu Ser Ser Glu 1325 1330 1335Ser
Ser Ser Gln Trp Ala Leu Val Val Gln Phe Cys Arg Leu His 1340
1345 1350Asn Met Lys Leu Ser Ile Ser Tyr Leu
Arg Glu Cys Ala Lys Ala 1355 1360
1365Asn Asp Trp Leu Gln Phe Ile Ile His Ser Gln Leu His Asn Tyr
1370 1375 1380His Pro Ala Glu Val Lys
Ser Leu Ile Gln Tyr Phe Ser Pro Val 1385 1390
1395Ile Gln Asp His Leu Arg Leu Ala Phe Glu Asn Leu Pro Ser
Val 1400 1405 1410Pro Thr Ser Lys Met
Asp Ser Asp Gln Val Cys Asn Lys Cys Pro 1415 1420
1425Gln Glu Leu Gln Gly Ser Lys Gln Glu Met Thr Asp Leu
Phe Glu 1430 1435 1440Ile Leu Leu Gln
Cys Ser Glu Glu Pro Asp Ser Trp His Trp Leu 1445
1450 1455Leu Val Glu Ala Val Lys Gln Gln Ala Pro Ile
Leu Ser Val Leu 1460 1465 1470Ala Ser
Cys Leu Gln Gly Ala Ser Ala Ile Ser Cys Leu Cys Val 1475
1480 1485Trp Ile Ile Thr Ser Val Glu Asp Asn Val
Ala Thr Glu Ala Met 1490 1495 1500Gly
His Ile Gln Asp Ser Thr Glu Asp His Thr Trp Asn Leu Glu 1505
1510 1515Asp Leu Ser Val Ile Trp Arg Thr Leu
Leu Thr Arg Gln Lys Ser 1520 1525
1530Lys Thr Leu Ile Arg Gly Phe Gln Leu Phe Phe Lys Asp Ser Pro
1535 1540 1545Leu Leu Leu Val Met Glu
Met Tyr Glu Leu Cys Met Phe Phe Arg 1550 1555
1560Asn Tyr Lys Glu Ala Glu Ala Lys Leu Leu Glu Phe Gln Lys
Ser 1565 1570 1575Leu Glu Thr Leu Asn
Thr Ala Ala Thr Lys Val His Pro Val Ile 1580 1585
1590Pro Ala Met Trp Leu Glu Asp Gln Val Cys Phe Leu Leu
Lys Leu 1595 1600 1605Met Leu Gln Gln
Cys Lys Thr Gln Tyr Glu Leu Gly Lys Leu Leu 1610
1615 1620Gln Leu Phe Val Glu Arg Glu His Leu Phe Ser
Asp Gly Pro Asp 1625 1630 1635Val Lys
Lys Leu Cys Ile Leu Cys Gln Ile Leu Lys Asp Thr Ser 1640
1645 1650Ile Ala Ile Asn His Thr Ile Ile Thr Ser
Tyr Ser Ile Glu Asn 1655 1660 1665Leu
Gln His Glu Cys Arg Ser Ile Leu Glu Arg Leu Gln Thr Asp 1670
1675 1680Gly Gln Phe Ala Leu Ala Arg Arg Val
Ala Glu Leu Ala Glu Leu 1685 1690
1695Pro Val Asp Asn Leu Val Ile Lys Glu Ile Thr Gln Glu Met Gln
1700 1705 1710Thr Leu Lys His Ile Glu
Gln Trp Ser Leu Lys Gln Ala Arg Ile 1715 1720
1725Asp Phe Trp Lys Lys Cys His Glu Asn Phe Lys Lys Asn Ser
Ile 1730 1735 1740Ser Ser Lys Ala Ala
Ser Ser Phe Phe Ser Thr Gln Ala His Val 1745 1750
1755Ala Cys Glu His Pro Thr Gly Trp Ser Ser Met Glu Glu
Arg His 1760 1765 1770Leu Leu Leu Thr
Leu Ala Gly His Trp Leu Ala Gln Glu Asp Val 1775
1780 1785Val Pro Leu Asp Lys Leu Glu Glu Leu Glu Lys
Gln Ile Trp Leu 1790 1795 1800Cys Arg
Ile Thr Gln His Thr Leu Gly Arg Asn Gln Glu Glu Thr 1805
1810 1815Glu Pro Arg Phe Ser Arg Gln Ile Ser Thr
Ser Gly Glu Leu Ser 1820 1825 1830Phe
Asp Ser Leu Ala Ser Glu Phe Ser Phe Ser Lys Leu Ala Ala 1835
1840 1845Leu Asn Thr Ser Lys Tyr Leu Glu Leu
Asn Ser Leu Pro Ser Lys 1850 1855
1860Glu Thr Cys Glu Asn Arg Leu Asp Trp Lys Glu Gln Glu Ser Leu
1865 1870 1875Asn Phe Leu Ile Gly Arg
Leu Leu Asp Asp Gly Cys Val His Glu 1880 1885
1890Ala Ser Arg Val Cys Arg Tyr Phe His Phe Tyr Asn Pro Asp
Val 1895 1900 1905Ala Leu Val Leu His
Cys Arg Ala Leu Ala Ser Gly Glu Ala Arg 1910 1915
1920Trp Arg Ile Cys Thr Gln Arg Ser Met Leu Ser Tyr Lys
Val Leu 1925 1930 1935Ser Cys Leu Arg
Lys Lys His Pro Thr Phe Pro 1940 19451811956PRTHomo
sapiens 181Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly
Ser1 5 10 15Trp Gly Thr
Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20
25 30Val Pro Ala Glu Ala Met Gly Gln Leu Gly
Ser Arg Ala Gln Leu Arg 35 40
45Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50
55 60Val Leu Ser Leu Thr Pro Gly Ser Arg
Gly Gly Gly Arg Cys Cys Leu65 70 75
80Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn
Ser Ser 85 90 95Thr Pro
Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100
105 110Leu Leu Ile Tyr Glu Phe Asn Leu Lys
Asp Gly Arg Cys Asp Ala Thr 115 120
125Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp
130 135 140Gln Asp Ile Ser Ile Ser Leu
Leu Ser Leu Arg Ile Leu Ser Phe His145 150
155 160Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val
Ile Leu His Ile 165 170
175Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr
180 185 190Leu Pro Leu Pro Ala Gln
Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200
205Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile
Tyr Ile 210 215 220Phe Asp Val Val Asp
Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu225 230
235 240His Lys Glu Asp Met Cys Asn Glu Gln Gln
Gln Glu Pro Ala Lys Ile 245 250
255Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val
260 265 270Ile Val Ser Ser Ser
Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275
280 285Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg
Ile Leu Glu Asp 290 295 300Leu Pro Ile
Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn305
310 315 320Ser Ala Tyr Asn Met Lys Leu
Ala Lys Phe Ser Phe Gln Ile Asp Arg 325
330 335Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr
Ile Lys Asn Ser 340 345 350Lys
Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355
360 365Leu Glu Ser Pro Glu Ser Gly Asn His
Ser Thr Ser Val Gln Ser Trp 370 375
380Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln385
390 395 400Lys Asp His Ala
Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met 405
410 415His Ile Ser Glu Gln Glu Glu Pro Ile Glu
Leu Lys Cys Val Ser Val 420 425
430Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met Gly Tyr
435 440 445Thr Ile Thr Leu Trp Asp Leu
Glu Thr Gln Gly Met Gln Cys Ser Ser 450 455
460Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly Asp Gln Gln
Leu465 470 475 480Cys Phe
Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu
485 490 495Thr Gln Glu Glu Phe Leu Asn
Arg Leu Met Ile His Gly Ser Ala Ser 500 505
510Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly Arg Cys
Ser Ile 515 520 525Pro Ile His Ala
Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530
535 540Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu Phe
Asn Pro Ser Ser545 550 555
560Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu Tyr
565 570 575Leu Arg Asn Val Glu
Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580
585 590Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln Ser Lys
His Phe Ser Glu 595 600 605Gln Leu
Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610
615 620Leu Phe Ile His Thr Glu Glu Leu Asp Glu His
Leu Gln Lys Gly Val625 630 635
640Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Arg Thr Phe Met Ile Lys
645 650 655Phe Pro Trp Lys
Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu 660
665 670Asn Val Pro Lys Val Lys Glu Ser Asn Ile Trp
Lys Lys Leu Ser Phe 675 680 685Glu
Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys Ile Pro Glu Ala 690
695 700Gln Thr Phe Phe Arg Ile Asp Ser His Ser
Ala Gln Lys Leu Glu Glu705 710 715
720Leu Ile Gly Ile Gly Leu Asn Leu Val Phe Asp Asn Leu Lys Lys
Asn 725 730 735Asn Ile Lys
Glu Ala Ser Glu Leu Leu Lys Asn Met Gly Phe Asp Val 740
745 750Lys Gly Gln Leu Leu Lys Ile Cys Phe Tyr
Thr Thr Asn Lys Asn Ile 755 760
765Arg Asp Phe Leu Val Glu Ile Leu Lys Glu Lys Asn Tyr Phe Ser Glu 770
775 780Lys Glu Lys Arg Thr Ile Asp Phe
Val His Gln Val Glu Lys Leu Tyr785 790
795 800Leu Gly His Phe Gln Glu Asn Met Gln Ile Gln Ser
Phe Pro Arg Tyr 805 810
815Trp Ile Lys Glu Gln Asp Phe Phe Lys His Lys Ser Val Leu Asp Ser
820 825 830Phe Leu Lys Tyr Asp Cys
Lys Asp Glu Phe Asn Lys Gln Asp His Arg 835 840
845Ile Val Leu Asn Trp Ala Leu Trp Trp Asp Gln Leu Thr Gln
Glu Ser 850 855 860Ile Leu Leu Pro Arg
Ile Ser Pro Glu Glu Tyr Lys Ser Tyr Ser Pro865 870
875 880Glu Ala Leu Trp Arg Tyr Leu Thr Ala Arg
His Asp Trp Leu Asn Ile 885 890
895Ile Leu Trp Ile Gly Glu Phe Gln Thr Gln His Ser Tyr Ala Ser Leu
900 905 910Gln Gln Asn Lys Trp
Pro Leu Leu Thr Val Asp Val Ile Asn Gln Asn 915
920 925Thr Ser Cys Asn Asn Tyr Met Arg Asn Glu Ile Leu
Asp Lys Leu Ala 930 935 940Arg Asn Gly
Val Phe Leu Ala Ser Glu Leu Glu Asp Phe Glu Cys Phe945
950 955 960Leu Leu Arg Leu Ser Arg Ile
Gly Gly Val Ile Gln Asp Thr Leu Pro 965
970 975Val Gln Asn Tyr Lys Thr Lys Glu Gly Trp Asp Phe
His Ser Gln Phe 980 985 990Ile
Leu Tyr Cys Leu Glu His Ser Leu Gln His Leu Leu Tyr Val Tyr 995
1000 1005Leu Asp Cys Tyr Lys Leu Ser Pro
Glu Asn Cys Pro Phe Leu Glu 1010 1015
1020Lys Lys Glu Leu His Glu Ala His Pro Trp Phe Glu Phe Leu Val
1025 1030 1035Gln Cys Arg Gln Val Ala
Ser Asn Leu Thr Asp Pro Lys Leu Ile 1040 1045
1050Phe Gln Ala Ser Leu Ala Asn Ala Gln Ile Leu Ile Pro Thr
Asn 1055 1060 1065Gln Ala Ser Val Ser
Ser Met Leu Leu Glu Gly His Thr Leu Leu 1070 1075
1080Ala Leu Ala Thr Thr Met Tyr Ser Pro Gly Gly Val Ser
Gln Val 1085 1090 1095Val Gln Asn Glu
Glu Asn Glu Asn Cys Leu Lys Lys Val Asp Pro 1100
1105 1110Gln Leu Leu Lys Met Ala Leu Thr Pro Tyr Pro
Lys Leu Lys Thr 1115 1120 1125Ala Leu
Phe Pro Gln Cys Thr Pro Pro Ser Val Leu Pro Ser Asp 1130
1135 1140Ile Thr Ile Tyr His Leu Ile Gln Ser Leu
Ser Pro Phe Asp Pro 1145 1150 1155Ser
Arg Leu Phe Gly Trp Gln Ser Ala Asn Thr Leu Ala Ile Gly 1160
1165 1170Asp Ala Trp Ser His Leu Pro His Phe
Ser Ser Pro Asp Leu Val 1175 1180
1185Asn Lys Tyr Ala Ile Val Glu Arg Leu Asn Phe Ala Tyr Tyr Leu
1190 1195 1200His Asn Gly Arg Pro Ser
Phe Ala Phe Gly Thr Phe Leu Val Gln 1205 1210
1215Glu Leu Ile Lys Ser Lys Thr Pro Lys Gln Leu Ile Gln Gln
Val 1220 1225 1230Gly Asn Glu Ala Tyr
Val Ile Gly Leu Ser Ser Phe His Ile Pro 1235 1240
1245Ser Ile Gly Ala Ala Cys Val Cys Phe Leu Glu Leu Leu
Gly Leu 1250 1255 1260Asp Ser Leu Lys
Leu Arg Val Asp Met Lys Val Ala Asn Ile Ile 1265
1270 1275Leu Ser Tyr Lys Cys Arg Asn Glu Asp Ala Gln
Tyr Ser Phe Ile 1280 1285 1290Arg Glu
Ser Val Ala Glu Lys Leu Ser Lys Leu Ala Asp Gly Glu 1295
1300 1305Lys Thr Thr Thr Glu Glu Leu Leu Val Leu
Leu Glu Glu Gly Thr 1310 1315 1320Trp
Asn Ser Ile Gln Gln Gln Glu Ile Lys Arg Leu Ser Ser Glu 1325
1330 1335Ser Ser Ser Gln Trp Ala Leu Val Val
Gln Phe Cys Arg Leu His 1340 1345
1350Asn Met Lys Leu Ser Ile Ser Tyr Leu Arg Glu Cys Ala Lys Ala
1355 1360 1365Asn Asp Trp Leu Gln Phe
Ile Ile His Ser Gln Leu His Asn Tyr 1370 1375
1380His Pro Ala Glu Val Lys Ser Leu Ile Gln Tyr Phe Ser Pro
Val 1385 1390 1395Ile Gln Asp His Leu
Arg Leu Ala Phe Glu Asn Leu Pro Ser Val 1400 1405
1410Pro Thr Ser Lys Met Asp Ser Asp Gln Val Cys Asn Lys
Cys Pro 1415 1420 1425Gln Glu Leu Gln
Gly Ser Lys Gln Glu Met Thr Asp Leu Phe Glu 1430
1435 1440Ile Leu Leu Gln Cys Ser Glu Glu Pro Asp Ser
Trp His Trp Leu 1445 1450 1455Leu Val
Glu Ala Val Lys Gln Gln Ala Pro Ile Leu Ser Val Leu 1460
1465 1470Ala Ser Cys Leu Gln Gly Ala Ser Ala Ile
Ser Cys Leu Cys Val 1475 1480 1485Trp
Ile Ile Thr Ser Val Glu Asp Asn Val Ala Thr Glu Ala Met 1490
1495 1500Gly His Ile Gln Asp Ser Thr Glu Asp
His Thr Trp Asn Leu Glu 1505 1510
1515Asp Leu Ser Val Ile Trp Arg Thr Leu Leu Thr Arg Gln Lys Ser
1520 1525 1530Lys Thr Leu Ile Arg Gly
Phe Gln Leu Phe Phe Lys Asp Ser Pro 1535 1540
1545Leu Leu Leu Val Met Glu Met Tyr Glu Leu Cys Met Phe Phe
Arg 1550 1555 1560Asn Tyr Lys Glu Ala
Glu Ala Lys Leu Leu Glu Phe Gln Lys Ser 1565 1570
1575Leu Glu Thr Leu Asn Thr Ala Ala Thr Lys Val His Pro
Val Ile 1580 1585 1590Pro Ala Met Trp
Leu Glu Asp Gln Val Cys Phe Leu Leu Lys Leu 1595
1600 1605Met Leu Gln Gln Cys Lys Thr Gln Tyr Glu Leu
Gly Lys Leu Leu 1610 1615 1620Gln Leu
Phe Val Glu Arg Glu His Leu Phe Ser Asp Gly Pro Asp 1625
1630 1635Val Lys Lys Leu Cys Ile Leu Cys Gln Ile
Leu Lys Asp Thr Ser 1640 1645 1650Ile
Ala Ile Asn His Thr Ile Ile Thr Ser Tyr Ser Ile Glu Asn 1655
1660 1665Leu Gln His Glu Cys Arg Ser Ile Leu
Glu Arg Leu Gln Thr Asp 1670 1675
1680Gly Gln Phe Ala Leu Ala Arg Arg Val Ala Glu Leu Ala Glu Leu
1685 1690 1695Pro Val Asp Asn Leu Val
Ile Lys Glu Ile Thr Gln Glu Met Gln 1700 1705
1710Thr Leu Lys His Ile Glu Gln Trp Ser Leu Lys Gln Ala Arg
Ile 1715 1720 1725Asp Phe Trp Lys Lys
Cys His Glu Asn Phe Lys Lys Asn Ser Ile 1730 1735
1740Ser Ser Lys Ala Ala Ser Ser Phe Phe Ser Thr Gln Ala
His Val 1745 1750 1755Ala Cys Glu His
Pro Thr Gly Trp Ser Ser Met Glu Glu Arg His 1760
1765 1770Leu Leu Leu Thr Leu Ala Gly His Trp Leu Ala
Gln Glu Asp Val 1775 1780 1785Val Pro
Leu Asp Lys Leu Glu Glu Leu Glu Lys Gln Ile Trp Leu 1790
1795 1800Cys Arg Ile Thr Gln His Thr Leu Gly Arg
Asn Gln Glu Glu Thr 1805 1810 1815Glu
Pro Arg Phe Ser Arg Gln Ile Ser Thr Ser Gly Glu Leu Ser 1820
1825 1830Phe Asp Ser Leu Ala Ser Glu Phe Ser
Phe Ser Lys Leu Ala Ala 1835 1840
1845Leu Asn Thr Ser Lys Tyr Leu Glu Leu Asn Ser Leu Pro Ser Lys
1850 1855 1860Glu Thr Cys Glu Asn Arg
Leu Asp Trp Lys Glu Gln Glu Ser Leu 1865 1870
1875Asn Phe Leu Ile Gly Arg Leu Leu Asp Asp Gly Cys Val His
Glu 1880 1885 1890Ala Ser Arg Val Cys
Arg Tyr Phe His Phe Tyr Asn Pro Asp Val 1895 1900
1905Ala Leu Val Leu His Cys Arg Ala Leu Ala Ser Gly Glu
Ala Ser 1910 1915 1920Met Glu Asp Leu
His Pro Glu Ile His Ala Leu Leu Gln Ser Ala 1925
1930 1935Glu Leu Leu Glu Glu Glu Ala Pro Asp Ile Pro
Leu Arg Arg Val 1940 1945 1950His Ser
Thr 19551821999PRTHomo sapiens 182Met Ala Ala Glu Glu Gly Val Ala Ser
Ala Ala Ser Ala Gly Gly Ser1 5 10
15Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val
Pro 20 25 30Val Pro Ala Glu
Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35
40 45Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala
Gly Ser Leu Gln 50 55 60Val Leu Ser
Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu65 70
75 80Glu Gly Pro Phe Trp His Phe Leu
Trp Glu Asp Ser Arg Asn Ser Ser 85 90
95Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn
Tyr Glu 100 105 110Leu Leu Ile
Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115
120 125Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln
Lys Leu Ile Asp Asp 130 135 140Gln Asp
Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His145
150 155 160Asn Asn Thr Ser Leu Leu Phe
Ile Asn Lys Cys Val Ile Leu His Ile 165
170 175Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu
Asn Cys Phe Thr 180 185 190Leu
Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195
200 205Cys Arg Gly Ile Leu Phe Val Leu Ser
Ser Leu Gly Trp Ile Tyr Ile 210 215
220Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu225
230 235 240His Lys Glu Asp
Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile 245
250 255Ser Ser Phe Thr Ser Leu Lys Val Ser Gln
Asp Leu Asp Val Ala Val 260 265
270Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr
275 280 285Phe Arg Gln His Pro Gly His
Leu Leu Cys Glu Arg Ile Leu Glu Asp 290 295
300Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val
Asn305 310 315 320Ser Ala
Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg
325 330 335Ser Trp Lys Ala Gln Leu Ser
Ser Leu Asn Glu Thr Ile Lys Asn Ser 340 345
350Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile
Leu His 355 360 365Leu Glu Ser Pro
Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370
375 380Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr
Asn Val Leu Gln385 390 395
400Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met
405 410 415His Ile Ser Glu Gln
Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val 420
425 430Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu
Arg Met Gly Tyr 435 440 445Thr Ile
Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450
455 460Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser
Gly Asp Gln Gln Leu465 470 475
480Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu
485 490 495Thr Gln Glu Glu
Phe Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser 500
505 510Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp
Gly Arg Cys Ser Ile 515 520 525Pro
Ile His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530
535 540Val Asn Phe Phe Leu Lys Ser Lys Glu Asn
Leu Phe Asn Pro Ser Ser545 550 555
560Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu
Tyr 565 570 575Leu Arg Asn
Val Glu Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580
585 590Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln
Ser Lys His Phe Ser Glu 595 600
605Gln Leu Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610
615 620Leu Phe Ile His Thr Glu Glu Leu
Asp Glu His Leu Gln Lys Gly Val625 630
635 640Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Arg Thr
Phe Met Ile Lys 645 650
655Phe Pro Trp Lys Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu
660 665 670Asn Val Pro Lys Val Lys
Glu Ser Asn Ile Trp Lys Lys Leu Ser Phe 675 680
685Glu Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys Ile Pro
Glu Ala 690 695 700Gln Thr Phe Phe Arg
Ile Asp Ser His Ser Ala Gln Lys Leu Glu Glu705 710
715 720Leu Ile Gly Ile Gly Leu Asn Leu Val Phe
Asp Asn Leu Lys Lys Asn 725 730
735Asn Ile Lys Glu Ala Ser Glu Leu Leu Lys Asn Met Gly Phe Asp Val
740 745 750Lys Gly Gln Leu Leu
Lys Ile Cys Phe Tyr Thr Thr Asn Lys Asn Ile 755
760 765Arg Asp Phe Leu Val Glu Ile Leu Lys Glu Lys Asn
Tyr Phe Ser Glu 770 775 780Lys Glu Lys
Arg Thr Ile Asp Phe Val His Gln Val Glu Lys Leu Tyr785
790 795 800Leu Gly His Phe Gln Glu Asn
Met Gln Ile Gln Ser Phe Pro Arg Tyr 805
810 815Trp Ile Lys Glu Gln Asp Phe Phe Lys His Lys Ser
Val Leu Asp Ser 820 825 830Phe
Leu Lys Tyr Asp Cys Lys Asp Glu Phe Asn Lys Gln Asp His Arg 835
840 845Ile Val Leu Asn Trp Ala Leu Trp Trp
Asp Gln Leu Thr Gln Glu Ser 850 855
860Ile Leu Leu Pro Arg Ile Ser Pro Glu Glu Tyr Lys Ser Tyr Ser Pro865
870 875 880Glu Ala Leu Trp
Arg Tyr Leu Thr Ala Arg His Asp Trp Leu Asn Ile 885
890 895Ile Leu Trp Ile Gly Glu Phe Gln Thr Gln
His Ser Tyr Ala Ser Leu 900 905
910Gln Gln Asn Lys Trp Pro Leu Leu Thr Val Asp Val Ile Asn Gln Asn
915 920 925Thr Ser Cys Asn Asn Tyr Met
Arg Asn Glu Ile Leu Asp Lys Leu Ala 930 935
940Arg Asn Gly Val Phe Leu Ala Ser Glu Leu Glu Asp Phe Glu Cys
Phe945 950 955 960Leu Leu
Arg Leu Ser Arg Ile Gly Gly Val Ile Gln Asp Thr Leu Pro
965 970 975Val Gln Asn Tyr Lys Thr Lys
Glu Gly Trp Asp Phe His Ser Gln Phe 980 985
990Ile Leu Tyr Cys Leu Glu His Ser Leu Gln His Leu Leu Tyr
Val Tyr 995 1000 1005Leu Asp Cys
Tyr Lys Leu Ser Pro Glu Asn Cys Pro Phe Leu Glu 1010
1015 1020Lys Lys Glu Leu His Glu Ala His Pro Trp Phe
Glu Phe Leu Val 1025 1030 1035Gln Cys
Arg Gln Val Ala Ser Asn Leu Thr Asp Pro Lys Leu Ile 1040
1045 1050Phe Gln Ala Ser Leu Ala Asn Ala Gln Ile
Leu Ile Pro Thr Asn 1055 1060 1065Gln
Ala Ser Val Ser Ser Met Leu Leu Glu Gly His Thr Leu Leu 1070
1075 1080Ala Leu Ala Thr Thr Met Tyr Ser Pro
Gly Gly Val Ser Gln Val 1085 1090
1095Val Gln Asn Glu Glu Asn Glu Asn Cys Leu Lys Lys Val Asp Pro
1100 1105 1110Gln Leu Leu Lys Met Ala
Leu Thr Pro Tyr Pro Lys Leu Lys Thr 1115 1120
1125Ala Leu Phe Pro Gln Cys Thr Pro Pro Ser Val Leu Pro Ser
Asp 1130 1135 1140Ile Thr Ile Tyr His
Leu Ile Gln Ser Leu Ser Pro Phe Asp Pro 1145 1150
1155Ser Arg Leu Phe Gly Trp Gln Ser Ala Asn Thr Leu Ala
Ile Gly 1160 1165 1170Asp Ala Trp Ser
His Leu Pro His Phe Ser Ser Pro Asp Leu Val 1175
1180 1185Asn Lys Tyr Ala Ile Val Glu Arg Leu Asn Phe
Ala Tyr Tyr Leu 1190 1195 1200His Asn
Gly Arg Pro Ser Phe Ala Phe Gly Thr Phe Leu Val Gln 1205
1210 1215Glu Leu Ile Lys Ser Lys Thr Pro Lys Gln
Leu Ile Gln Gln Val 1220 1225 1230Gly
Asn Glu Ala Tyr Val Ile Gly Leu Ser Ser Phe His Ile Pro 1235
1240 1245Ser Ile Gly Ala Ala Cys Val Cys Phe
Leu Glu Leu Leu Gly Leu 1250 1255
1260Asp Ser Leu Lys Leu Arg Val Asp Met Lys Val Ala Asn Ile Ile
1265 1270 1275Leu Ser Tyr Lys Cys Arg
Asn Glu Asp Ala Gln Tyr Ser Phe Ile 1280 1285
1290Arg Glu Ser Val Ala Glu Lys Leu Ser Lys Leu Ala Asp Gly
Glu 1295 1300 1305Lys Thr Thr Thr Glu
Glu Leu Leu Val Leu Leu Glu Glu Gly Thr 1310 1315
1320Trp Asn Ser Ile Gln Gln Gln Glu Ile Lys Arg Leu Ser
Ser Glu 1325 1330 1335Ser Ser Ser Gln
Trp Ala Leu Val Val Gln Phe Cys Arg Leu His 1340
1345 1350Asn Met Lys Leu Ser Ile Ser Tyr Leu Arg Glu
Cys Ala Lys Ala 1355 1360 1365Asn Asp
Trp Leu Gln Phe Ile Ile His Ser Gln Leu His Asn Tyr 1370
1375 1380His Pro Ala Glu Val Lys Ser Leu Ile Gln
Tyr Phe Ser Pro Val 1385 1390 1395Ile
Gln Asp His Leu Arg Leu Ala Phe Glu Asn Leu Pro Ser Val 1400
1405 1410Pro Thr Ser Lys Met Asp Ser Asp Gln
Val Cys Asn Lys Cys Pro 1415 1420
1425Gln Glu Leu Gln Gly Ser Lys Gln Glu Met Thr Asp Leu Phe Glu
1430 1435 1440Ile Leu Leu Gln Cys Ser
Glu Glu Pro Asp Ser Trp His Trp Leu 1445 1450
1455Leu Val Glu Ala Val Lys Gln Gln Ala Pro Ile Leu Ser Val
Leu 1460 1465 1470Ala Ser Cys Leu Gln
Gly Ala Ser Ala Ile Ser Cys Leu Cys Val 1475 1480
1485Trp Ile Ile Thr Ser Val Glu Asp Asn Val Ala Thr Glu
Ala Met 1490 1495 1500Gly His Ile Gln
Asp Ser Thr Glu Asp His Thr Trp Asn Leu Glu 1505
1510 1515Asp Leu Ser Val Ile Trp Arg Thr Leu Leu Thr
Arg Gln Lys Ser 1520 1525 1530Lys Thr
Leu Ile Arg Gly Phe Gln Leu Phe Phe Lys Asp Ser Pro 1535
1540 1545Leu Leu Leu Val Met Glu Met Tyr Glu Leu
Cys Met Phe Phe Arg 1550 1555 1560Asn
Tyr Lys Glu Ala Glu Ala Lys Leu Leu Glu Phe Gln Lys Ser 1565
1570 1575Leu Glu Thr Leu Asn Thr Ala Ala Thr
Lys Val His Pro Val Ile 1580 1585
1590Pro Ala Met Trp Leu Glu Asp Gln Val Cys Phe Leu Leu Lys Leu
1595 1600 1605Met Leu Gln Gln Cys Lys
Thr Gln Tyr Glu Leu Gly Lys Leu Leu 1610 1615
1620Gln Leu Phe Val Glu Arg Glu His Leu Phe Ser Asp Gly Pro
Asp 1625 1630 1635Val Lys Lys Leu Cys
Ile Leu Cys Gln Ile Leu Lys Asp Thr Ser 1640 1645
1650Ile Ala Ile Asn His Thr Ile Ile Thr Ser Tyr Ser Ile
Glu Asn 1655 1660 1665Leu Gln His Glu
Cys Arg Ser Ile Leu Glu Arg Leu Gln Thr Asp 1670
1675 1680Gly Gln Phe Ala Leu Ala Arg Arg Val Ala Glu
Leu Ala Glu Leu 1685 1690 1695Pro Val
Asp Asn Leu Val Ile Lys Glu Ile Thr Gln Glu Met Gln 1700
1705 1710Thr Leu Lys His Ile Glu Gln Trp Ser Leu
Lys Gln Ala Arg Ile 1715 1720 1725Asp
Phe Trp Lys Lys Cys His Glu Asn Phe Lys Lys Asn Ser Ile 1730
1735 1740Ser Ser Lys Ala Ala Ser Ser Phe Phe
Ser Thr Gln Ala His Val 1745 1750
1755Ala Cys Glu His Pro Thr Gly Trp Ser Ser Met Glu Glu Arg His
1760 1765 1770Leu Leu Leu Thr Leu Ala
Gly His Trp Leu Ala Gln Glu Asp Val 1775 1780
1785Val Pro Leu Asp Lys Leu Glu Glu Leu Glu Lys Gln Ile Trp
Leu 1790 1795 1800Cys Arg Ile Thr Gln
His Thr Leu Gly Arg Asn Gln Glu Glu Thr 1805 1810
1815Glu Pro Arg Phe Ser Arg Gln Ile Ser Thr Ser Gly Glu
Leu Ser 1820 1825 1830Phe Asp Ser Leu
Ala Ser Glu Phe Ser Phe Ser Lys Leu Ala Ala 1835
1840 1845Leu Asn Thr Ser Lys Tyr Leu Glu Leu Asn Ser
Leu Pro Ser Lys 1850 1855 1860Glu Thr
Cys Glu Asn Arg Leu Asp Trp Lys Glu Gln Glu Ser Leu 1865
1870 1875Asn Phe Leu Ile Gly Arg Leu Leu Asp Asp
Gly Cys Val His Glu 1880 1885 1890Ala
Ser Arg Val Cys Arg Tyr Phe His Phe Tyr Asn Pro Asp Val 1895
1900 1905Ala Leu Val Leu His Cys Arg Ala Leu
Ala Ser Gly Glu Ala Ser 1910 1915
1920Met Glu Asp Leu His Pro Glu Ile His Ala Leu Leu Gln Ser Ala
1925 1930 1935Glu Leu Leu Glu Glu Glu
Ala Pro Asp Ile Pro Leu Arg Arg Val 1940 1945
1950His Ser Thr Ser Ser Leu Asp Ser Gln Lys Phe Val Thr Val
Pro 1955 1960 1965Ser Ser Asn Glu Val
Val Thr Asn Leu Glu Val Leu Thr Ser Lys 1970 1975
1980Cys Leu His Gly Lys Asn Tyr Cys Arg Gln Val Leu Ser
Leu Ser 1985 1990
1995Val1831998PRTHomo sapiens 183Met Ala Ala Glu Glu Gly Val Ala Ser Ala
Ala Ser Ala Gly Gly Ser1 5 10
15Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro
20 25 30Val Pro Ala Glu Ala Met
Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40
45Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser
Leu Gln 50 55 60Val Leu Ser Leu Thr
Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu65 70
75 80Glu Gly Pro Phe Trp His Phe Leu Trp Glu
Asp Ser Arg Asn Ser Ser 85 90
95Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu
100 105 110Leu Leu Ile Tyr Glu
Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115
120 125Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys
Leu Ile Asp Asp 130 135 140Gln Asp Ile
Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His145
150 155 160Asn Asn Thr Ser Leu Leu Phe
Ile Asn Lys Cys Val Ile Leu His Ile 165
170 175Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu
Asn Cys Phe Thr 180 185 190Leu
Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195
200 205Cys Arg Gly Ile Leu Phe Val Leu Ser
Ser Leu Gly Trp Ile Tyr Ile 210 215
220Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu225
230 235 240His Lys Glu Asp
Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile 245
250 255Ser Ser Phe Thr Ser Leu Lys Val Ser Gln
Asp Leu Asp Val Ala Val 260 265
270Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr
275 280 285Phe Arg Gln His Pro Gly His
Leu Leu Cys Glu Arg Ile Leu Glu Asp 290 295
300Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val
Asn305 310 315 320Ser Ala
Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg
325 330 335Ser Trp Lys Ala Gln Leu Ser
Ser Leu Asn Glu Thr Ile Lys Asn Ser 340 345
350Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile
Leu His 355 360 365Leu Glu Ser Pro
Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370
375 380Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr
Asn Val Leu Gln385 390 395
400Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met
405 410 415His Ile Ser Glu Gln
Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val 420
425 430Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu
Arg Met Gly Tyr 435 440 445Thr Ile
Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450
455 460Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser
Gly Asp Gln Gln Leu465 470 475
480Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu
485 490 495Thr Gln Glu Glu
Phe Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser 500
505 510Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp
Gly Arg Cys Ser Ile 515 520 525Pro
Ile His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530
535 540Val Asn Phe Phe Leu Lys Ser Lys Glu Asn
Leu Phe Asn Pro Ser Ser545 550 555
560Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu
Tyr 565 570 575Leu Arg Asn
Val Glu Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580
585 590Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln
Ser Lys His Phe Ser Glu 595 600
605Gln Leu Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610
615 620Leu Phe Ile His Thr Glu Glu Leu
Asp Glu His Leu Gln Lys Gly Val625 630
635 640Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Arg Thr
Phe Met Ile Lys 645 650
655Phe Pro Trp Lys Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu
660 665 670Asn Val Pro Lys Val Lys
Glu Ser Asn Ile Trp Lys Lys Leu Ser Phe 675 680
685Glu Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys Ile Pro
Glu Ala 690 695 700Gln Thr Phe Phe Arg
Ile Asp Ser His Ser Ala Gln Lys Leu Glu Glu705 710
715 720Leu Ile Gly Ile Gly Leu Asn Leu Val Phe
Asp Asn Leu Lys Lys Asn 725 730
735Asn Ile Lys Glu Ala Ser Glu Leu Leu Lys Asn Met Gly Phe Asp Val
740 745 750Lys Gly Gln Leu Leu
Lys Ile Cys Phe Tyr Thr Thr Asn Lys Asn Ile 755
760 765Arg Asp Phe Leu Val Glu Ile Leu Lys Glu Lys Asn
Tyr Phe Ser Glu 770 775 780Lys Glu Lys
Arg Thr Ile Asp Phe Val His Gln Val Glu Lys Leu Tyr785
790 795 800Leu Gly His Phe Gln Glu Asn
Met Gln Ile Gln Ser Phe Pro Arg Tyr 805
810 815Trp Ile Lys Glu Gln Asp Phe Phe Lys His Lys Ser
Val Leu Asp Ser 820 825 830Phe
Leu Lys Tyr Asp Cys Lys Asp Glu Phe Asn Lys Gln Asp His Arg 835
840 845Ile Val Leu Asn Trp Ala Leu Trp Trp
Asp Gln Leu Thr Gln Glu Ser 850 855
860Ile Leu Leu Pro Arg Ile Ser Pro Glu Glu Tyr Lys Ser Tyr Ser Pro865
870 875 880Glu Ala Leu Trp
Arg Tyr Leu Thr Ala Arg His Asp Trp Leu Asn Ile 885
890 895Ile Leu Trp Ile Gly Glu Phe Gln Thr Gln
His Ser Tyr Ala Ser Leu 900 905
910Gln Gln Asn Lys Trp Pro Leu Leu Thr Val Asp Val Ile Asn Gln Asn
915 920 925Thr Ser Cys Asn Asn Tyr Met
Arg Asn Glu Ile Leu Asp Lys Leu Ala 930 935
940Arg Asn Gly Val Phe Leu Ala Ser Glu Leu Glu Asp Phe Glu Cys
Phe945 950 955 960Leu Leu
Arg Leu Ser Arg Ile Gly Gly Val Ile Gln Asp Thr Leu Pro
965 970 975Val Gln Asn Tyr Lys Thr Lys
Glu Gly Trp Asp Phe His Ser Gln Phe 980 985
990Ile Leu Tyr Cys Leu Glu His Ser Leu Gln His Leu Leu Tyr
Val Tyr 995 1000 1005Leu Asp Cys
Tyr Lys Leu Ser Pro Glu Asn Cys Pro Phe Leu Glu 1010
1015 1020Lys Lys Glu Leu His Glu Ala His Pro Trp Phe
Glu Phe Leu Val 1025 1030 1035Gln Cys
Arg Gln Val Ala Ser Asn Leu Thr Asp Pro Lys Leu Ile 1040
1045 1050Phe Gln Ala Ser Leu Ala Asn Ala Gln Ile
Leu Ile Pro Thr Asn 1055 1060 1065Gln
Ala Ser Val Ser Ser Met Leu Leu Glu Gly His Thr Leu Leu 1070
1075 1080Ala Leu Ala Thr Thr Met Tyr Ser Pro
Gly Gly Val Ser Gln Val 1085 1090
1095Val Gln Asn Glu Glu Asn Glu Asn Cys Leu Lys Lys Val Asp Pro
1100 1105 1110Gln Leu Leu Lys Met Ala
Leu Thr Pro Tyr Pro Lys Leu Lys Thr 1115 1120
1125Ala Leu Phe Pro Gln Cys Thr Pro Pro Ser Val Leu Pro Ser
Asp 1130 1135 1140Ile Thr Ile Tyr His
Leu Ile Gln Ser Leu Ser Pro Phe Asp Pro 1145 1150
1155Ser Arg Leu Phe Gly Trp Gln Ser Ala Asn Thr Leu Ala
Ile Gly 1160 1165 1170Asp Ala Trp Ser
His Leu Pro His Phe Ser Ser Pro Asp Leu Val 1175
1180 1185Asn Lys Tyr Ala Ile Val Glu Arg Leu Asn Phe
Ala Tyr Tyr Leu 1190 1195 1200His Asn
Gly Arg Pro Ser Phe Ala Phe Gly Thr Phe Leu Val Gln 1205
1210 1215Glu Leu Ile Lys Ser Lys Thr Pro Lys Gln
Leu Ile Gln Gln Val 1220 1225 1230Gly
Asn Glu Ala Tyr Val Ile Gly Leu Ser Ser Phe His Ile Pro 1235
1240 1245Ser Ile Gly Ala Ala Cys Val Cys Phe
Leu Glu Leu Leu Gly Leu 1250 1255
1260Asp Ser Leu Lys Leu Arg Val Asp Met Lys Val Ala Asn Ile Ile
1265 1270 1275Leu Ser Tyr Lys Cys Arg
Asn Glu Asp Ala Gln Tyr Ser Phe Ile 1280 1285
1290Arg Glu Ser Val Ala Glu Lys Leu Ser Lys Leu Ala Asp Gly
Glu 1295 1300 1305Lys Thr Thr Thr Glu
Glu Leu Leu Val Leu Leu Glu Glu Gly Thr 1310 1315
1320Trp Asn Ser Ile Gln Gln Gln Glu Ile Lys Arg Leu Ser
Ser Glu 1325 1330 1335Ser Ser Ser Gln
Trp Ala Leu Val Val Gln Phe Cys Arg Leu His 1340
1345 1350Asn Met Lys Leu Ser Ile Ser Tyr Leu Arg Glu
Cys Ala Lys Ala 1355 1360 1365Asn Asp
Trp Leu Gln Phe Ile Ile His Ser Gln Leu His Asn Tyr 1370
1375 1380His Pro Ala Glu Val Lys Ser Leu Ile Gln
Tyr Phe Ser Pro Val 1385 1390 1395Ile
Gln Asp His Leu Arg Leu Ala Phe Glu Asn Leu Pro Ser Val 1400
1405 1410Pro Thr Ser Lys Met Asp Ser Asp Gln
Val Cys Asn Lys Cys Pro 1415 1420
1425Gln Glu Leu Gln Gly Ser Lys Gln Glu Met Thr Asp Leu Phe Glu
1430 1435 1440Ile Leu Leu Gln Cys Ser
Glu Glu Pro Asp Ser Trp His Trp Leu 1445 1450
1455Leu Val Glu Ala Val Lys Gln Gln Ala Pro Ile Leu Ser Val
Leu 1460 1465 1470Ala Ser Cys Leu Gln
Gly Ala Ser Ala Ile Ser Cys Leu Cys Val 1475 1480
1485Trp Ile Ile Thr Ser Val Glu Asp Asn Val Ala Thr Glu
Ala Met 1490 1495 1500Gly His Ile Gln
Asp Ser Thr Glu Asp His Thr Trp Asn Leu Glu 1505
1510 1515Asp Leu Ser Val Ile Trp Arg Thr Leu Leu Thr
Arg Gln Lys Ser 1520 1525 1530Lys Thr
Leu Ile Arg Gly Phe Gln Leu Phe Phe Lys Asp Ser Pro 1535
1540 1545Leu Leu Leu Val Met Glu Met Tyr Glu Leu
Cys Met Phe Phe Arg 1550 1555 1560Asn
Tyr Lys Glu Ala Glu Ala Lys Leu Leu Glu Phe Gln Lys Ser 1565
1570 1575Leu Glu Thr Leu Asn Thr Ala Ala Thr
Lys Val His Pro Val Ile 1580 1585
1590Pro Ala Met Trp Leu Glu Asp Gln Val Cys Phe Leu Leu Lys Leu
1595 1600 1605Met Leu Gln Gln Cys Lys
Thr Gln Tyr Glu Leu Gly Lys Leu Leu 1610 1615
1620Gln Leu Phe Val Glu Arg Glu His Leu Phe Ser Asp Gly Pro
Asp 1625 1630 1635Val Lys Lys Leu Cys
Ile Leu Cys Gln Ile Leu Lys Asp Thr Ser 1640 1645
1650Ile Ala Ile Asn His Thr Ile Ile Thr Ser Tyr Ser Ile
Glu Asn 1655 1660 1665Leu Gln His Glu
Cys Arg Ser Ile Leu Glu Arg Leu Gln Thr Asp 1670
1675 1680Gly Gln Phe Ala Leu Ala Arg Arg Val Ala Glu
Leu Ala Glu Leu 1685 1690 1695Pro Val
Asp Asn Leu Val Ile Lys Glu Ile Thr Gln Glu Met Gln 1700
1705 1710Thr Leu Lys His Ile Glu Gln Trp Ser Leu
Lys Gln Ala Arg Ile 1715 1720 1725Asp
Phe Trp Lys Lys Cys His Glu Asn Phe Lys Lys Asn Ser Ile 1730
1735 1740Ser Ser Lys Ala Ala Ser Ser Phe Phe
Ser Thr Gln Ala His Val 1745 1750
1755Ala Cys Glu His Pro Thr Gly Trp Ser Ser Met Glu Glu Arg His
1760 1765 1770Leu Leu Leu Thr Leu Ala
Gly His Trp Leu Ala Gln Glu Asp Val 1775 1780
1785Val Pro Leu Asp Lys Leu Glu Glu Leu Glu Lys Gln Ile Trp
Leu 1790 1795 1800Cys Arg Ile Thr Gln
His Thr Leu Gly Arg Asn Gln Glu Glu Thr 1805 1810
1815Glu Pro Arg Phe Ser Arg Gln Ile Ser Thr Ser Gly Glu
Leu Ser 1820 1825 1830Phe Asp Ser Leu
Ala Ser Glu Phe Ser Phe Ser Lys Leu Ala Ala 1835
1840 1845Leu Asn Thr Ser Lys Tyr Leu Glu Leu Asn Ser
Leu Pro Ser Lys 1850 1855 1860Glu Thr
Cys Glu Asn Arg Leu Asp Trp Lys Glu Gln Glu Ser Leu 1865
1870 1875Asn Phe Leu Ile Gly Arg Leu Leu Asp Asp
Gly Cys Val His Glu 1880 1885 1890Ala
Ser Arg Val Cys Arg Tyr Phe His Phe Tyr Asn Pro Asp Val 1895
1900 1905Ala Leu Val Leu His Cys Arg Ala Leu
Ala Ser Gly Glu Ala Ser 1910 1915
1920Met Glu Asp Leu His Pro Glu Ile His Ala Leu Leu Gln Ser Ala
1925 1930 1935Glu Leu Leu Glu Glu Glu
Ala Pro Asp Ile Pro Leu Arg Arg Val 1940 1945
1950His Ser Thr Ser Ser Leu Asp Ser Gln Lys Phe Val Thr Val
Pro 1955 1960 1965Ser Ser Asn Glu Val
Val Thr Asn Leu Glu Val Leu Thr Ser Lys 1970 1975
1980Cys Leu His Gly Lys Asn Tyr Cys Arg Gln Val Leu Leu
Ser Val 1985 1990 19951842055PRTHomo
sapiens 184Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly
Ser1 5 10 15Trp Gly Thr
Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20
25 30Val Pro Ala Glu Ala Met Gly Gln Leu Gly
Ser Arg Ala Gln Leu Arg 35 40
45Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50
55 60Val Leu Ser Leu Thr Pro Gly Ser Arg
Gly Gly Gly Arg Cys Cys Leu65 70 75
80Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn
Ser Ser 85 90 95Thr Pro
Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100
105 110Leu Leu Ile Tyr Glu Phe Asn Leu Lys
Asp Gly Arg Cys Asp Ala Thr 115 120
125Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp
130 135 140Gln Asp Ile Ser Ile Ser Leu
Leu Ser Leu Arg Ile Leu Ser Phe His145 150
155 160Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val
Ile Leu His Ile 165 170
175Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr
180 185 190Leu Pro Leu Pro Ala Gln
Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200
205Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile
Tyr Ile 210 215 220Phe Asp Val Val Asp
Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu225 230
235 240His Lys Glu Asp Met Cys Asn Glu Gln Gln
Gln Glu Pro Ala Lys Ile 245 250
255Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val
260 265 270Ile Val Ser Ser Ser
Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275
280 285Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg
Ile Leu Glu Asp 290 295 300Leu Pro Ile
Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn305
310 315 320Ser Ala Tyr Asn Met Lys Leu
Ala Lys Phe Ser Phe Gln Ile Asp Arg 325
330 335Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr
Ile Lys Asn Ser 340 345 350Lys
Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355
360 365Leu Glu Ser Pro Glu Ser Gly Asn His
Ser Thr Ser Val Gln Ser Trp 370 375
380Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln385
390 395 400Lys Asp His Ala
Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met 405
410 415His Ile Ser Glu Gln Glu Glu Pro Ile Glu
Leu Lys Cys Val Ser Val 420 425
430Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met Gly Tyr
435 440 445Thr Ile Thr Leu Trp Asp Leu
Glu Thr Gln Gly Met Gln Cys Ser Ser 450 455
460Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly Asp Gln Gln
Leu465 470 475 480Cys Phe
Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu
485 490 495Thr Gln Glu Glu Phe Leu Asn
Arg Leu Met Ile His Gly Ser Ala Ser 500 505
510Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly Arg Cys
Ser Ile 515 520 525Pro Ile His Ala
Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530
535 540Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu Phe
Asn Pro Ser Ser545 550 555
560Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu Tyr
565 570 575Leu Arg Asn Val Glu
Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580
585 590Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln Ser Lys
His Phe Ser Glu 595 600 605Gln Leu
Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610
615 620Leu Phe Ile His Thr Glu Glu Leu Asp Glu His
Leu Gln Lys Gly Val625 630 635
640Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Arg Thr Phe Met Ile Lys
645 650 655Phe Pro Trp Lys
Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu 660
665 670Asn Val Pro Lys Val Lys Glu Ser Asn Ile Trp
Lys Lys Leu Ser Phe 675 680 685Glu
Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys Ile Pro Glu Ala 690
695 700Gln Thr Phe Phe Arg Ile Asp Ser His Ser
Ala Gln Lys Leu Glu Glu705 710 715
720Leu Ile Gly Ile Gly Leu Asn Leu Val Phe Asp Asn Leu Lys Lys
Asn 725 730 735Asn Ile Lys
Glu Ala Ser Glu Leu Leu Lys Asn Met Gly Phe Asp Val 740
745 750Lys Gly Gln Leu Leu Lys Ile Cys Phe Tyr
Thr Thr Asn Lys Asn Ile 755 760
765Arg Asp Phe Leu Val Glu Ile Leu Lys Glu Lys Asn Tyr Phe Ser Glu 770
775 780Lys Glu Lys Arg Thr Ile Asp Phe
Val His Gln Val Glu Lys Leu Tyr785 790
795 800Leu Gly His Phe Gln Glu Asn Met Gln Ile Gln Ser
Phe Pro Arg Tyr 805 810
815Trp Ile Lys Glu Gln Asp Phe Phe Lys His Lys Ser Val Leu Asp Ser
820 825 830Phe Leu Lys Tyr Asp Cys
Lys Asp Glu Phe Asn Lys Gln Asp His Arg 835 840
845Ile Val Leu Asn Trp Ala Leu Trp Trp Asp Gln Leu Thr Gln
Glu Ser 850 855 860Ile Leu Leu Pro Arg
Ile Ser Pro Glu Glu Tyr Lys Ser Tyr Ser Pro865 870
875 880Glu Ala Leu Trp Arg Tyr Leu Thr Ala Arg
His Asp Trp Leu Asn Ile 885 890
895Ile Leu Trp Ile Gly Glu Phe Gln Thr Gln His Ser Tyr Ala Ser Leu
900 905 910Gln Gln Asn Lys Trp
Pro Leu Leu Thr Val Asp Val Ile Asn Gln Asn 915
920 925Thr Ser Cys Asn Asn Tyr Met Arg Asn Glu Ile Leu
Asp Lys Leu Ala 930 935 940Arg Asn Gly
Val Phe Leu Ala Ser Glu Leu Glu Asp Phe Glu Cys Phe945
950 955 960Leu Leu Arg Leu Ser Arg Ile
Gly Gly Val Ile Gln Asp Thr Leu Pro 965
970 975Val Gln Asn Tyr Lys Thr Lys Glu Gly Trp Asp Phe
His Ser Gln Phe 980 985 990Ile
Leu Tyr Cys Leu Glu His Ser Leu Gln His Leu Leu Tyr Val Tyr 995
1000 1005Leu Asp Cys Tyr Lys Leu Ser Pro
Glu Asn Cys Pro Phe Leu Glu 1010 1015
1020Lys Lys Glu Leu His Glu Ala His Pro Trp Phe Glu Phe Leu Val
1025 1030 1035Gln Cys Arg Gln Val Ala
Ser Asn Leu Thr Asp Pro Lys Leu Ile 1040 1045
1050Phe Gln Ala Ser Leu Ala Asn Ala Gln Ile Leu Ile Pro Thr
Asn 1055 1060 1065Gln Ala Ser Val Ser
Ser Met Leu Leu Glu Gly His Thr Leu Leu 1070 1075
1080Ala Leu Ala Thr Thr Met Tyr Ser Pro Gly Gly Val Ser
Gln Val 1085 1090 1095Val Gln Asn Glu
Glu Asn Glu Asn Cys Leu Lys Lys Val Asp Pro 1100
1105 1110Gln Leu Leu Lys Met Ala Leu Thr Pro Tyr Pro
Lys Leu Lys Thr 1115 1120 1125Ala Leu
Phe Pro Gln Cys Thr Pro Pro Ser Val Leu Pro Ser Asp 1130
1135 1140Ile Thr Ile Tyr His Leu Ile Gln Ser Leu
Ser Pro Phe Asp Pro 1145 1150 1155Ser
Arg Leu Phe Gly Trp Gln Ser Ala Asn Thr Leu Ala Ile Gly 1160
1165 1170Asp Ala Trp Ser His Leu Pro His Phe
Ser Ser Pro Asp Leu Val 1175 1180
1185Asn Lys Tyr Ala Ile Val Glu Arg Leu Asn Phe Ala Tyr Tyr Leu
1190 1195 1200His Asn Gly Arg Pro Ser
Phe Ala Phe Gly Thr Phe Leu Val Gln 1205 1210
1215Glu Leu Ile Lys Ser Lys Thr Pro Lys Gln Leu Ile Gln Gln
Val 1220 1225 1230Gly Asn Glu Ala Tyr
Val Ile Gly Leu Ser Ser Phe His Ile Pro 1235 1240
1245Ser Ile Gly Ala Ala Cys Val Cys Phe Leu Glu Leu Leu
Gly Leu 1250 1255 1260Asp Ser Leu Lys
Leu Arg Val Asp Met Lys Val Ala Asn Ile Ile 1265
1270 1275Leu Ser Tyr Lys Cys Arg Asn Glu Asp Ala Gln
Tyr Ser Phe Ile 1280 1285 1290Arg Glu
Ser Val Ala Glu Lys Leu Ser Lys Leu Ala Asp Gly Glu 1295
1300 1305Lys Thr Thr Thr Glu Glu Leu Leu Val Leu
Leu Glu Glu Gly Thr 1310 1315 1320Trp
Asn Ser Ile Gln Gln Gln Glu Ile Lys Arg Leu Ser Ser Glu 1325
1330 1335Ser Ser Ser Gln Trp Ala Leu Val Val
Gln Phe Cys Arg Leu His 1340 1345
1350Asn Met Lys Leu Ser Ile Ser Tyr Leu Arg Glu Cys Ala Lys Ala
1355 1360 1365Asn Asp Trp Leu Gln Phe
Ile Ile His Ser Gln Leu His Asn Tyr 1370 1375
1380His Pro Ala Glu Val Lys Ser Leu Ile Gln Tyr Phe Ser Pro
Val 1385 1390 1395Ile Gln Asp His Leu
Arg Leu Ala Phe Glu Asn Leu Pro Ser Val 1400 1405
1410Pro Thr Ser Lys Met Asp Ser Asp Gln Val Cys Asn Lys
Cys Pro 1415 1420 1425Gln Glu Leu Gln
Gly Ser Lys Gln Glu Met Thr Asp Leu Phe Glu 1430
1435 1440Ile Leu Leu Gln Cys Ser Glu Glu Pro Asp Ser
Trp His Trp Leu 1445 1450 1455Leu Val
Glu Ala Val Lys Gln Gln Ala Pro Ile Leu Ser Val Leu 1460
1465 1470Ala Ser Cys Leu Gln Gly Ala Ser Ala Ile
Ser Cys Leu Cys Val 1475 1480 1485Trp
Ile Ile Thr Ser Val Glu Asp Asn Val Ala Thr Glu Ala Met 1490
1495 1500Gly His Ile Gln Asp Ser Thr Glu Asp
His Thr Trp Asn Leu Glu 1505 1510
1515Asp Leu Ser Val Ile Trp Arg Thr Leu Leu Thr Arg Gln Lys Ser
1520 1525 1530Lys Thr Leu Ile Arg Gly
Phe Gln Leu Phe Phe Lys Asp Ser Pro 1535 1540
1545Leu Leu Leu Val Met Glu Met Tyr Glu Leu Cys Met Phe Phe
Arg 1550 1555 1560Asn Tyr Lys Glu Ala
Glu Ala Lys Leu Leu Glu Phe Gln Lys Ser 1565 1570
1575Leu Glu Thr Leu Asn Thr Ala Ala Thr Lys Val His Pro
Val Ile 1580 1585 1590Pro Ala Met Trp
Leu Glu Asp Gln Val Cys Phe Leu Leu Lys Leu 1595
1600 1605Met Leu Gln Gln Cys Lys Thr Gln Tyr Glu Leu
Gly Lys Leu Leu 1610 1615 1620Gln Leu
Phe Val Glu Arg Glu His Leu Phe Ser Asp Gly Pro Asp 1625
1630 1635Val Lys Lys Leu Cys Ile Leu Cys Gln Ile
Leu Lys Asp Thr Ser 1640 1645 1650Ile
Ala Ile Asn His Thr Ile Ile Thr Ser Tyr Ser Ile Glu Asn 1655
1660 1665Leu Gln His Glu Cys Arg Ser Ile Leu
Glu Arg Leu Gln Thr Asp 1670 1675
1680Gly Gln Phe Ala Leu Ala Arg Arg Val Ala Glu Leu Ala Glu Leu
1685 1690 1695Pro Val Asp Asn Leu Val
Ile Lys Glu Ile Thr Gln Glu Met Gln 1700 1705
1710Thr Leu Lys His Ile Glu Gln Trp Ser Leu Lys Gln Ala Arg
Ile 1715 1720 1725Asp Phe Trp Lys Lys
Cys His Glu Asn Phe Lys Lys Asn Ser Ile 1730 1735
1740Ser Ser Lys Ala Ala Ser Ser Phe Phe Ser Thr Gln Ala
His Val 1745 1750 1755Ala Cys Glu His
Pro Thr Gly Trp Ser Ser Met Glu Glu Arg His 1760
1765 1770Leu Leu Leu Thr Leu Ala Gly His Trp Leu Ala
Gln Glu Asp Val 1775 1780 1785Val Pro
Leu Asp Lys Leu Glu Glu Leu Glu Lys Gln Ile Trp Leu 1790
1795 1800Cys Arg Ile Thr Gln His Thr Leu Gly Arg
Asn Gln Glu Glu Thr 1805 1810 1815Glu
Pro Arg Phe Ser Arg Gln Ile Ser Thr Ser Gly Glu Leu Ser 1820
1825 1830Phe Asp Ser Leu Ala Ser Glu Phe Ser
Phe Ser Lys Leu Ala Ala 1835 1840
1845Leu Asn Thr Ser Lys Tyr Leu Glu Leu Asn Ser Leu Pro Ser Lys
1850 1855 1860Glu Thr Cys Glu Asn Arg
Leu Asp Trp Lys Glu Gln Glu Ser Leu 1865 1870
1875Asn Phe Leu Ile Gly Arg Leu Leu Asp Asp Gly Cys Val His
Glu 1880 1885 1890Ala Ser Arg Val Cys
Arg Tyr Phe His Phe Tyr Asn Pro Asp Val 1895 1900
1905Ala Leu Val Leu His Cys Arg Ala Leu Ala Ser Gly Glu
Ala Ser 1910 1915 1920Met Glu Asp Leu
His Pro Glu Ile His Ala Leu Leu Gln Ser Ala 1925
1930 1935Glu Leu Leu Glu Glu Glu Ala Pro Asp Ile Pro
Leu Arg Arg Val 1940 1945 1950His Ser
Thr Ser Ser Leu Asp Ser Gln Lys Phe Val Thr Val Pro 1955
1960 1965Ser Ser Asn Glu Val Val Thr Asn Leu Glu
Val Leu Thr Ser Lys 1970 1975 1980Cys
Leu His Gly Lys Asn Tyr Cys Arg Gln Val Leu Cys Met Ile 1985
1990 1995Leu Pro Arg Ser Trp Ala Val Pro Thr
Gln Met Leu Leu Leu Arg 2000 2005
2010Met Val Lys Pro Cys Ser Gly Lys Ser Trp Pro Leu Ser Ser Leu
2015 2020 2025Thr Asp Ala Asn Glu Pro
Arg Pro Ser Ser Ala His Arg Ala Leu 2030 2035
2040Ser Gln Ile Leu Trp Leu Asn Ser Trp Gln Lys Arg 2045
2050 20551852030PRTHomo sapiens 185Met Ala
Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser1 5
10 15Trp Gly Thr Ala Ala Met Gly Arg
Val Leu Pro Met Leu Leu Val Pro 20 25
30Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu
Arg 35 40 45Thr Gln Pro Glu Ala
Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50 55
60Val Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys
Cys Leu65 70 75 80Glu
Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser
85 90 95Thr Pro Thr Glu Lys Pro Lys
Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100 105
110Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp
Ala Thr 115 120 125Ile Leu Tyr Ser
Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp 130
135 140Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile
Leu Ser Phe His145 150 155
160Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile
165 170 175Ile Phe Pro Glu Arg
Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr 180
185 190Leu Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile
Asp Thr Gln Leu 195 200 205Cys Arg
Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile Tyr Ile 210
215 220Phe Asp Val Val Asp Gly Thr Tyr Val Ala His
Val Asp Leu Ala Leu225 230 235
240His Lys Glu Asp Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile
245 250 255Ser Ser Phe Thr
Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val 260
265 270Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu
Asn Leu Asn Leu Tyr 275 280 285Phe
Arg Gln His Pro Gly His Leu Leu Cys Glu Arg Ile Leu Glu Asp 290
295 300Leu Pro Ile Gln Gly Pro Lys Gly Val Asp
Glu Asp Asp Pro Val Asn305 310 315
320Ser Ala Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp
Arg 325 330 335Ser Trp Lys
Ala Gln Leu Ser Ser Leu Asn Glu Thr Ile Lys Asn Ser 340
345 350Lys Leu Glu Val Ser Cys Cys Ala Pro Trp
Phe Gln Asp Ile Leu His 355 360
365Leu Glu Ser Pro Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370
375 380Ala Phe Ile Pro Gln Asp Ile Met
His Gly Gln Tyr Asn Val Leu Gln385 390
395 400Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser
Trp Lys Ile Met 405 410
415His Ile Ser Glu Gln Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val
420 425 430Thr Gly Phe Thr Ala Leu
Phe Thr Trp Glu Val Glu Arg Met Gly Tyr 435 440
445Thr Ile Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys
Ser Ser 450 455 460Leu Gly Thr Lys Cys
Ile Pro Val Asp Ser Ser Gly Asp Gln Gln Leu465 470
475 480Cys Phe Val Leu Thr Glu Asn Gly Leu Ser
Leu Ile Leu Phe Gly Leu 485 490
495Thr Gln Glu Glu Phe Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser
500 505 510Thr Val Asp Thr Leu
Cys His Leu Asn Gly Trp Gly Arg Cys Ser Ile 515
520 525Pro Ile His Ala Leu Glu Ala Gly Ile Glu Asn Arg
Gln Leu Asp Thr 530 535 540Val Asn Phe
Phe Leu Lys Ser Lys Glu Asn Leu Phe Asn Pro Ser Ser545
550 555 560Lys Ser Ser Val Ser Asp Gln
Phe Asp His Leu Ser Ser His Leu Tyr 565
570 575Leu Arg Asn Val Glu Glu Leu Ile Pro Ala Leu Asp
Leu Leu Cys Ser 580 585 590Ala
Ile Arg Glu Ser Tyr Ser Glu Pro Gln Ser Lys His Phe Ser Glu 595
600 605Gln Leu Leu Asn Leu Thr Leu Ser Phe
Leu Asn Asn Gln Ile Lys Glu 610 615
620Leu Phe Ile His Thr Glu Glu Leu Asp Glu His Leu Gln Lys Gly Val625
630 635 640Asn Ile Leu Thr
Ser Tyr Ile Asn Glu Leu Arg Thr Phe Met Ile Lys 645
650 655Phe Pro Trp Lys Leu Thr Asp Ala Ile Asp
Glu Tyr Asp Val His Glu 660 665
670Asn Val Pro Lys Val Lys Glu Ser Asn Ile Trp Lys Lys Leu Ser Phe
675 680 685Glu Glu Val Ile Ala Ser Ala
Ile Leu Asn Asn Lys Ile Pro Glu Ala 690 695
700Gln Thr Phe Phe Arg Ile Asp Ser His Ser Ala Gln Lys Leu Glu
Glu705 710 715 720Leu Ile
Gly Ile Gly Leu Asn Leu Val Phe Asp Asn Leu Lys Lys Asn
725 730 735Asn Ile Lys Glu Ala Ser Glu
Leu Leu Lys Asn Met Gly Phe Asp Val 740 745
750Lys Gly Gln Leu Leu Lys Ile Cys Phe Tyr Thr Thr Asn Lys
Asn Ile 755 760 765Arg Asp Phe Leu
Val Glu Ile Leu Lys Glu Lys Asn Tyr Phe Ser Glu 770
775 780Lys Glu Lys Arg Thr Ile Asp Phe Val His Gln Val
Glu Lys Leu Tyr785 790 795
800Leu Gly His Phe Gln Glu Asn Met Gln Ile Gln Ser Phe Pro Arg Tyr
805 810 815Trp Ile Lys Glu Gln
Asp Phe Phe Lys His Lys Ser Val Leu Asp Ser 820
825 830Phe Leu Lys Tyr Asp Cys Lys Asp Glu Phe Asn Lys
Gln Asp His Arg 835 840 845Ile Val
Leu Asn Trp Ala Leu Trp Trp Asp Gln Leu Thr Gln Glu Ser 850
855 860Ile Leu Leu Pro Arg Ile Ser Pro Glu Glu Tyr
Lys Ser Tyr Ser Pro865 870 875
880Glu Ala Leu Trp Arg Tyr Leu Thr Ala Arg His Asp Trp Leu Asn Ile
885 890 895Ile Leu Trp Ile
Gly Glu Phe Gln Thr Gln His Ser Tyr Ala Ser Leu 900
905 910Gln Gln Asn Lys Trp Pro Leu Leu Thr Val Asp
Val Ile Asn Gln Asn 915 920 925Thr
Ser Cys Asn Asn Tyr Met Arg Asn Glu Ile Leu Asp Lys Leu Ala 930
935 940Arg Asn Gly Val Phe Leu Ala Ser Glu Leu
Glu Asp Phe Glu Cys Phe945 950 955
960Leu Leu Arg Leu Ser Arg Ile Gly Gly Val Ile Gln Asp Thr Leu
Pro 965 970 975Val Gln Asn
Tyr Lys Thr Lys Glu Gly Trp Asp Phe His Ser Gln Phe 980
985 990Ile Leu Tyr Cys Leu Glu His Ser Leu Gln
His Leu Leu Tyr Val Tyr 995 1000
1005Leu Asp Cys Tyr Lys Leu Ser Pro Glu Asn Cys Pro Phe Leu Glu
1010 1015 1020Lys Lys Glu Leu His Glu
Ala His Pro Trp Phe Glu Phe Leu Val 1025 1030
1035Gln Cys Arg Gln Val Ala Ser Asn Leu Thr Asp Pro Lys Leu
Ile 1040 1045 1050Phe Gln Ala Ser Leu
Ala Asn Ala Gln Ile Leu Ile Pro Thr Asn 1055 1060
1065Gln Ala Ser Val Ser Ser Met Leu Leu Glu Gly His Thr
Leu Leu 1070 1075 1080Ala Leu Ala Thr
Thr Met Tyr Ser Pro Gly Gly Val Ser Gln Val 1085
1090 1095Val Gln Asn Glu Glu Asn Glu Asn Cys Leu Lys
Lys Val Asp Pro 1100 1105 1110Gln Leu
Leu Lys Met Ala Leu Thr Pro Tyr Pro Lys Leu Lys Thr 1115
1120 1125Ala Leu Phe Pro Gln Cys Thr Pro Pro Ser
Val Leu Pro Ser Asp 1130 1135 1140Ile
Thr Ile Tyr His Leu Ile Gln Ser Leu Ser Pro Phe Asp Pro 1145
1150 1155Ser Arg Leu Phe Gly Trp Gln Ser Ala
Asn Thr Leu Ala Ile Gly 1160 1165
1170Asp Ala Trp Ser His Leu Pro His Phe Ser Ser Pro Asp Leu Val
1175 1180 1185Asn Lys Tyr Ala Ile Val
Glu Arg Leu Asn Phe Ala Tyr Tyr Leu 1190 1195
1200His Asn Gly Arg Pro Ser Phe Ala Phe Gly Thr Phe Leu Val
Gln 1205 1210 1215Glu Leu Ile Lys Ser
Lys Thr Pro Lys Gln Leu Ile Gln Gln Val 1220 1225
1230Gly Asn Glu Ala Tyr Val Ile Gly Leu Ser Ser Phe His
Ile Pro 1235 1240 1245Ser Ile Gly Ala
Ala Cys Val Cys Phe Leu Glu Leu Leu Gly Leu 1250
1255 1260Asp Ser Leu Lys Leu Arg Val Asp Met Lys Val
Ala Asn Ile Ile 1265 1270 1275Leu Ser
Tyr Lys Cys Arg Asn Glu Asp Ala Gln Tyr Ser Phe Ile 1280
1285 1290Arg Glu Ser Val Ala Glu Lys Leu Ser Lys
Leu Ala Asp Gly Glu 1295 1300 1305Lys
Thr Thr Thr Glu Glu Leu Leu Val Leu Leu Glu Glu Gly Thr 1310
1315 1320Trp Asn Ser Ile Gln Gln Gln Glu Ile
Lys Arg Leu Ser Ser Glu 1325 1330
1335Ser Ser Ser Gln Trp Ala Leu Val Val Gln Phe Cys Arg Leu His
1340 1345 1350Asn Met Lys Leu Ser Ile
Ser Tyr Leu Arg Glu Cys Ala Lys Ala 1355 1360
1365Asn Asp Trp Leu Gln Phe Ile Ile His Ser Gln Leu His Asn
Tyr 1370 1375 1380His Pro Ala Glu Val
Lys Ser Leu Ile Gln Tyr Phe Ser Pro Val 1385 1390
1395Ile Gln Asp His Leu Arg Leu Ala Phe Glu Asn Leu Pro
Ser Val 1400 1405 1410Pro Thr Ser Lys
Met Asp Ser Asp Gln Val Cys Asn Lys Cys Pro 1415
1420 1425Gln Glu Leu Gln Gly Ser Lys Gln Glu Met Thr
Asp Leu Phe Glu 1430 1435 1440Ile Leu
Leu Gln Cys Ser Glu Glu Pro Asp Ser Trp His Trp Leu 1445
1450 1455Leu Val Glu Ala Val Lys Gln Gln Ala Pro
Ile Leu Ser Val Leu 1460 1465 1470Ala
Ser Cys Leu Gln Gly Ala Ser Ala Ile Ser Cys Leu Cys Val 1475
1480 1485Trp Ile Ile Thr Ser Val Glu Asp Asn
Val Ala Thr Glu Ala Met 1490 1495
1500Gly His Ile Gln Asp Ser Thr Glu Asp His Thr Trp Asn Leu Glu
1505 1510 1515Asp Leu Ser Val Ile Trp
Arg Thr Leu Leu Thr Arg Gln Lys Ser 1520 1525
1530Lys Thr Leu Ile Arg Gly Phe Gln Leu Phe Phe Lys Asp Ser
Pro 1535 1540 1545Leu Leu Leu Val Met
Glu Met Tyr Glu Leu Cys Met Phe Phe Arg 1550 1555
1560Asn Tyr Lys Glu Ala Glu Ala Lys Leu Leu Glu Phe Gln
Lys Ser 1565 1570 1575Leu Glu Thr Leu
Asn Thr Ala Ala Thr Lys Val His Pro Val Ile 1580
1585 1590Pro Ala Met Trp Leu Glu Asp Gln Val Cys Phe
Leu Leu Lys Leu 1595 1600 1605Met Leu
Gln Gln Cys Lys Thr Gln Tyr Glu Leu Gly Lys Leu Leu 1610
1615 1620Gln Leu Phe Val Glu Arg Glu His Leu Phe
Ser Asp Gly Pro Asp 1625 1630 1635Val
Lys Lys Leu Cys Ile Leu Cys Gln Ile Leu Lys Asp Thr Ser 1640
1645 1650Ile Ala Ile Asn His Thr Ile Ile Thr
Ser Tyr Ser Ile Glu Asn 1655 1660
1665Leu Gln His Glu Cys Arg Ser Ile Leu Glu Arg Leu Gln Thr Asp
1670 1675 1680Gly Gln Phe Ala Leu Ala
Arg Arg Val Ala Glu Leu Ala Glu Leu 1685 1690
1695Pro Val Asp Asn Leu Val Ile Lys Glu Ile Thr Gln Glu Met
Gln 1700 1705 1710Thr Leu Lys His Ile
Glu Gln Trp Ser Leu Lys Gln Ala Arg Ile 1715 1720
1725Asp Phe Trp Lys Lys Cys His Glu Asn Phe Lys Lys Asn
Ser Ile 1730 1735 1740Ser Ser Lys Ala
Ala Ser Ser Phe Phe Ser Thr Gln Ala His Val 1745
1750 1755Ala Cys Glu His Pro Thr Gly Trp Ser Ser Met
Glu Glu Arg His 1760 1765 1770Leu Leu
Leu Thr Leu Ala Gly His Trp Leu Ala Gln Glu Asp Val 1775
1780 1785Val Pro Leu Asp Lys Leu Glu Glu Leu Glu
Lys Gln Ile Trp Leu 1790 1795 1800Cys
Arg Ile Thr Gln His Thr Leu Gly Arg Asn Gln Glu Glu Thr 1805
1810 1815Glu Pro Arg Phe Ser Arg Gln Ile Ser
Thr Ser Gly Glu Leu Ser 1820 1825
1830Phe Asp Ser Leu Ala Ser Glu Phe Ser Phe Ser Lys Leu Ala Ala
1835 1840 1845Leu Asn Thr Ser Lys Tyr
Leu Glu Leu Asn Ser Leu Pro Ser Lys 1850 1855
1860Glu Thr Cys Glu Asn Arg Leu Asp Trp Lys Glu Gln Glu Ser
Leu 1865 1870 1875Asn Phe Leu Ile Gly
Arg Leu Leu Asp Asp Gly Cys Val His Glu 1880 1885
1890Ala Ser Arg Val Cys Arg Tyr Phe His Phe Tyr Asn Pro
Asp Val 1895 1900 1905Ala Leu Val Leu
His Cys Arg Ala Leu Ala Ser Gly Glu Ala Ser 1910
1915 1920Met Glu Asp Leu His Pro Glu Ile His Ala Leu
Leu Gln Ser Ala 1925 1930 1935Glu Leu
Leu Glu Glu Glu Ala Pro Asp Ile Pro Leu Arg Arg Val 1940
1945 1950His Ser Thr Ser Ser Leu Asp Ser Gln Lys
Phe Val Thr Val Pro 1955 1960 1965Ser
Ser Asn Glu Val Val Thr Asn Leu Glu Val Leu Thr Ser Lys 1970
1975 1980Cys Leu His Gly Lys Asn Tyr Cys Arg
Gln Val Leu Cys Leu Tyr 1985 1990
1995Asp Leu Ala Lys Glu Leu Gly Cys Ser Tyr Thr Asp Val Ala Ala
2000 2005 2010Gln Asp Gly Glu Ala Met
Leu Arg Lys Ile Leu Ala Ser Gln Gln 2015 2020
2025Pro Asp 20301862259PRTHomo sapiens 186Met Ala Ala Glu Glu
Gly Val Ala Ser Ala Ala Ser Ala Gly Gly Ser1 5
10 15Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro
Met Leu Leu Val Pro 20 25
30Val Pro Ala Glu Ala Met Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg
35 40 45Thr Gln Pro Glu Ala Leu Gly Ser
Leu Thr Ala Ala Gly Ser Leu Gln 50 55
60Val Leu Ser Leu Thr Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu65
70 75 80Glu Gly Pro Phe Trp
His Phe Leu Trp Glu Asp Ser Arg Asn Ser Ser 85
90 95Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu
Gly Glu Asn Tyr Glu 100 105
110Leu Leu Ile Tyr Glu Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr
115 120 125Ile Leu Tyr Ser Cys Ser Arg
Glu Ala Leu Gln Lys Leu Ile Asp Asp 130 135
140Gln Asp Ile Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe
His145 150 155 160Asn Asn
Thr Ser Leu Leu Phe Ile Asn Lys Cys Val Ile Leu His Ile
165 170 175Ile Phe Pro Glu Arg Asp Ala
Ala Ile Arg Val Leu Asn Cys Phe Thr 180 185
190Leu Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr
Gln Leu 195 200 205Cys Arg Gly Ile
Leu Phe Val Leu Ser Ser Leu Gly Trp Ile Tyr Ile 210
215 220Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val
Asp Leu Ala Leu225 230 235
240His Lys Glu Asp Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile
245 250 255Ser Ser Phe Thr Ser
Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val 260
265 270Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn
Leu Asn Leu Tyr 275 280 285Phe Arg
Gln His Pro Gly His Leu Leu Cys Glu Arg Ile Leu Glu Asp 290
295 300Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu
Asp Asp Pro Val Asn305 310 315
320Ser Ala Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg
325 330 335Ser Trp Lys Ala
Gln Leu Ser Ser Leu Asn Glu Thr Ile Lys Asn Ser 340
345 350Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe
Gln Asp Ile Leu His 355 360 365Leu
Glu Ser Pro Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370
375 380Ala Phe Ile Pro Gln Asp Ile Met His Gly
Gln Tyr Asn Val Leu Gln385 390 395
400Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile
Met 405 410 415His Ile Ser
Glu Gln Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val 420
425 430Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu
Val Glu Arg Met Gly Tyr 435 440
445Thr Ile Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450
455 460Leu Gly Thr Lys Cys Ile Pro Val
Asp Ser Ser Gly Asp Gln Gln Leu465 470
475 480Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile
Leu Phe Gly Leu 485 490
495Thr Gln Glu Glu Phe Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser
500 505 510Thr Val Asp Thr Leu Cys
His Leu Asn Gly Trp Gly Arg Cys Ser Ile 515 520
525Pro Ile His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu
Asp Thr 530 535 540Val Asn Phe Phe Leu
Lys Ser Lys Glu Asn Leu Phe Asn Pro Ser Ser545 550
555 560Lys Ser Ser Val Ser Asp Gln Phe Asp His
Leu Ser Ser His Leu Tyr 565 570
575Leu Arg Asn Val Glu Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser
580 585 590Ala Ile Arg Glu Ser
Tyr Ser Glu Pro Gln Ser Lys His Phe Ser Glu 595
600 605Gln Leu Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn
Gln Ile Lys Glu 610 615 620Leu Phe Ile
His Thr Glu Glu Leu Asp Glu His Leu Gln Lys Gly Val625
630 635 640Asn Ile Leu Thr Ser Tyr Ile
Asn Glu Leu Arg Thr Phe Met Ile Lys 645
650 655Phe Pro Trp Lys Leu Thr Asp Ala Ile Asp Glu Tyr
Asp Val His Glu 660 665 670Asn
Val Pro Lys Val Lys Glu Ser Asn Ile Trp Lys Lys Leu Ser Phe 675
680 685Glu Glu Val Ile Ala Ser Ala Ile Leu
Asn Asn Lys Ile Pro Glu Ala 690 695
700Gln Thr Phe Phe Arg Ile Asp Ser His Ser Ala Gln Lys Leu Glu Glu705
710 715 720Leu Ile Gly Ile
Gly Leu Asn Leu Val Phe Asp Asn Leu Lys Lys Asn 725
730 735Asn Ile Lys Glu Ala Ser Glu Leu Leu Lys
Asn Met Gly Phe Asp Val 740 745
750Lys Gly Gln Leu Leu Lys Ile Cys Phe Tyr Thr Thr Asn Lys Asn Ile
755 760 765Arg Asp Phe Leu Val Glu Ile
Leu Lys Glu Lys Asn Tyr Phe Ser Glu 770 775
780Lys Glu Lys Arg Thr Ile Asp Phe Val His Gln Val Glu Lys Leu
Tyr785 790 795 800Leu Gly
His Phe Gln Glu Asn Met Gln Ile Gln Ser Phe Pro Arg Tyr
805 810 815Trp Ile Lys Glu Gln Asp Phe
Phe Lys His Lys Ser Val Leu Asp Ser 820 825
830Phe Leu Lys Tyr Asp Cys Lys Asp Glu Phe Asn Lys Gln Asp
His Arg 835 840 845Ile Val Leu Asn
Trp Ala Leu Trp Trp Asp Gln Leu Thr Gln Glu Ser 850
855 860Ile Leu Leu Pro Arg Ile Ser Pro Glu Glu Tyr Lys
Ser Tyr Ser Pro865 870 875
880Glu Ala Leu Trp Arg Tyr Leu Thr Ala Arg His Asp Trp Leu Asn Ile
885 890 895Ile Leu Trp Ile Gly
Glu Phe Gln Thr Gln His Ser Tyr Ala Ser Leu 900
905 910Gln Gln Asn Lys Trp Pro Leu Leu Thr Val Asp Val
Ile Asn Gln Asn 915 920 925Thr Ser
Cys Asn Asn Tyr Met Arg Asn Glu Ile Leu Asp Lys Leu Ala 930
935 940Arg Asn Gly Val Phe Leu Ala Ser Glu Leu Glu
Asp Phe Glu Cys Phe945 950 955
960Leu Leu Arg Leu Ser Arg Ile Gly Gly Val Ile Gln Asp Thr Leu Pro
965 970 975Val Gln Asn Tyr
Lys Thr Lys Glu Gly Trp Asp Phe His Ser Gln Phe 980
985 990Ile Leu Tyr Cys Leu Glu His Ser Leu Gln His
Leu Leu Tyr Val Tyr 995 1000
1005Leu Asp Cys Tyr Lys Leu Ser Pro Glu Asn Cys Pro Phe Leu Glu
1010 1015 1020Lys Lys Glu Leu His Glu
Ala His Pro Trp Phe Glu Phe Leu Val 1025 1030
1035Gln Cys Arg Gln Val Ala Ser Asn Leu Thr Asp Pro Lys Leu
Ile 1040 1045 1050Phe Gln Ala Ser Leu
Ala Asn Ala Gln Ile Leu Ile Pro Thr Asn 1055 1060
1065Gln Ala Ser Val Ser Ser Met Leu Leu Glu Gly His Thr
Leu Leu 1070 1075 1080Ala Leu Ala Thr
Thr Met Tyr Ser Pro Gly Gly Val Ser Gln Val 1085
1090 1095Val Gln Asn Glu Glu Asn Glu Asn Cys Leu Lys
Lys Val Asp Pro 1100 1105 1110Gln Leu
Leu Lys Met Ala Leu Thr Pro Tyr Pro Lys Leu Lys Thr 1115
1120 1125Ala Leu Phe Pro Gln Cys Thr Pro Pro Ser
Val Leu Pro Ser Asp 1130 1135 1140Ile
Thr Ile Tyr His Leu Ile Gln Ser Leu Ser Pro Phe Asp Pro 1145
1150 1155Ser Arg Leu Phe Gly Trp Gln Ser Ala
Asn Thr Leu Ala Ile Gly 1160 1165
1170Asp Ala Trp Ser His Leu Pro His Phe Ser Ser Pro Asp Leu Val
1175 1180 1185Asn Lys Tyr Ala Ile Val
Glu Arg Leu Asn Phe Ala Tyr Tyr Leu 1190 1195
1200His Asn Gly Arg Pro Ser Phe Ala Phe Gly Thr Phe Leu Val
Gln 1205 1210 1215Glu Leu Ile Lys Ser
Lys Thr Pro Lys Gln Leu Ile Gln Gln Val 1220 1225
1230Gly Asn Glu Ala Tyr Val Ile Gly Leu Ser Ser Phe His
Ile Pro 1235 1240 1245Ser Ile Gly Ala
Ala Cys Val Cys Phe Leu Glu Leu Leu Gly Leu 1250
1255 1260Asp Ser Leu Lys Leu Arg Val Asp Met Lys Val
Ala Asn Ile Ile 1265 1270 1275Leu Ser
Tyr Lys Cys Arg Asn Glu Asp Ala Gln Tyr Ser Phe Ile 1280
1285 1290Arg Glu Ser Val Ala Glu Lys Leu Ser Lys
Leu Ala Asp Gly Glu 1295 1300 1305Lys
Thr Thr Thr Glu Glu Leu Leu Val Leu Leu Glu Glu Gly Thr 1310
1315 1320Trp Asn Ser Ile Gln Gln Gln Glu Ile
Lys Arg Leu Ser Ser Glu 1325 1330
1335Ser Ser Ser Gln Trp Ala Leu Val Val Gln Phe Cys Arg Leu His
1340 1345 1350Asn Met Lys Leu Ser Ile
Ser Tyr Leu Arg Glu Cys Ala Lys Ala 1355 1360
1365Asn Asp Trp Leu Gln Phe Ile Ile His Ser Gln Leu His Asn
Tyr 1370 1375 1380His Pro Ala Glu Val
Lys Ser Leu Ile Gln Tyr Phe Ser Pro Val 1385 1390
1395Ile Gln Asp His Leu Arg Leu Ala Phe Glu Asn Leu Pro
Ser Val 1400 1405 1410Pro Thr Ser Lys
Met Asp Ser Asp Gln Val Cys Asn Lys Cys Pro 1415
1420 1425Gln Glu Leu Gln Gly Ser Lys Gln Glu Met Thr
Asp Leu Phe Glu 1430 1435 1440Ile Leu
Leu Gln Cys Ser Glu Glu Pro Asp Ser Trp His Trp Leu 1445
1450 1455Leu Val Glu Ala Val Lys Gln Gln Ala Pro
Ile Leu Ser Val Leu 1460 1465 1470Ala
Ser Cys Leu Gln Gly Ala Ser Ala Ile Ser Cys Leu Cys Val 1475
1480 1485Trp Ile Ile Thr Ser Val Glu Asp Asn
Val Ala Thr Glu Ala Met 1490 1495
1500Gly His Ile Gln Asp Ser Thr Glu Asp His Thr Trp Asn Leu Glu
1505 1510 1515Asp Leu Ser Val Ile Trp
Arg Thr Leu Leu Thr Arg Gln Lys Ser 1520 1525
1530Lys Thr Leu Ile Arg Gly Phe Gln Leu Phe Phe Lys Asp Ser
Pro 1535 1540 1545Leu Leu Leu Val Met
Glu Met Tyr Glu Leu Cys Met Phe Phe Arg 1550 1555
1560Asn Tyr Lys Glu Ala Glu Ala Lys Leu Leu Glu Phe Gln
Lys Ser 1565 1570 1575Leu Glu Thr Leu
Asn Thr Ala Ala Thr Lys Val His Pro Val Ile 1580
1585 1590Pro Ala Met Trp Leu Glu Asp Gln Val Cys Phe
Leu Leu Lys Leu 1595 1600 1605Met Leu
Gln Gln Cys Lys Thr Gln Tyr Glu Leu Gly Lys Leu Leu 1610
1615 1620Gln Leu Phe Val Glu Arg Glu His Leu Phe
Ser Asp Gly Pro Asp 1625 1630 1635Val
Lys Lys Leu Cys Ile Leu Cys Gln Ile Leu Lys Asp Thr Ser 1640
1645 1650Ile Ala Ile Asn His Thr Ile Ile Thr
Ser Tyr Ser Ile Glu Asn 1655 1660
1665Leu Gln His Glu Cys Arg Ser Ile Leu Glu Arg Leu Gln Thr Asp
1670 1675 1680Gly Gln Phe Ala Leu Ala
Arg Arg Val Ala Glu Leu Ala Glu Leu 1685 1690
1695Pro Val Asp Asn Leu Val Ile Lys Glu Ile Thr Gln Glu Met
Gln 1700 1705 1710Thr Leu Lys His Ile
Glu Gln Trp Ser Leu Lys Gln Ala Arg Ile 1715 1720
1725Asp Phe Trp Lys Lys Cys His Glu Asn Phe Lys Lys Asn
Ser Ile 1730 1735 1740Ser Ser Lys Ala
Ala Ser Ser Phe Phe Ser Thr Gln Ala His Val 1745
1750 1755Ala Cys Glu His Pro Thr Gly Trp Ser Ser Met
Glu Glu Arg His 1760 1765 1770Leu Leu
Leu Thr Leu Ala Gly His Trp Leu Ala Gln Glu Asp Val 1775
1780 1785Val Pro Leu Asp Lys Leu Glu Glu Leu Glu
Lys Gln Ile Trp Leu 1790 1795 1800Cys
Arg Ile Thr Gln His Thr Leu Gly Arg Asn Gln Glu Glu Thr 1805
1810 1815Glu Pro Arg Phe Ser Arg Gln Ile Ser
Thr Ser Gly Glu Leu Ser 1820 1825
1830Phe Asp Ser Leu Ala Ser Glu Phe Ser Phe Ser Lys Leu Ala Ala
1835 1840 1845Leu Asn Thr Ser Lys Tyr
Leu Glu Leu Asn Ser Leu Pro Ser Lys 1850 1855
1860Glu Thr Cys Glu Asn Arg Leu Asp Trp Lys Glu Gln Glu Ser
Leu 1865 1870 1875Asn Phe Leu Ile Gly
Arg Leu Leu Asp Asp Gly Cys Val His Glu 1880 1885
1890Ala Ser Arg Val Cys Arg Tyr Phe His Phe Tyr Asn Pro
Asp Val 1895 1900 1905Ala Leu Val Leu
His Cys Arg Ala Leu Ala Ser Gly Glu Ala Ser 1910
1915 1920Met Glu Asp Leu His Pro Glu Ile His Ala Leu
Leu Gln Ser Ala 1925 1930 1935Glu Leu
Leu Glu Glu Glu Ala Pro Asp Ile Pro Leu Arg Arg Val 1940
1945 1950His Ser Thr Ser Ser Leu Asp Ser Gln Lys
Phe Val Thr Val Pro 1955 1960 1965Ser
Ser Asn Glu Val Val Thr Asn Leu Glu Val Leu Thr Ser Lys 1970
1975 1980Cys Leu His Gly Lys Asn Tyr Cys Arg
Gln Val Leu Cys Leu Tyr 1985 1990
1995Asp Leu Ala Lys Glu Leu Gly Cys Ser Tyr Thr Asp Val Ala Ala
2000 2005 2010Gln Asp Gly Glu Ala Met
Leu Arg Lys Ile Leu Ala Ser Gln Gln 2015 2020
2025Pro Asp Arg Cys Lys Arg Ala Gln Ala Phe Ile Ser Thr Gln
Gly 2030 2035 2040Leu Lys Pro Asp Thr
Val Ala Glu Leu Val Ala Glu Glu Val Thr 2045 2050
2055Arg Glu Leu Leu Thr Ser Ser Gln Gly Thr Gly His Lys
Gln Met 2060 2065 2070Phe Asn Pro Thr
Glu Glu Ser Gln Thr Phe Leu Gln Leu Thr Thr 2075
2080 2085Leu Cys Gln Asp Arg Thr Leu Val Gly Met Lys
Leu Leu Asp Lys 2090 2095 2100Ile Ser
Ser Val Pro His Gly Glu Leu Ser Cys Thr Thr Glu Leu 2105
2110 2115Leu Ile Leu Ala His His Cys Phe Thr Leu
Thr Cys His Met Glu 2120 2125 2130Gly
Ile Ile Arg Val Leu Gln Ala Ala His Met Leu Thr Asp Asn 2135
2140 2145His Leu Ala Pro Ser Glu Glu Tyr Gly
Leu Val Val Arg Leu Leu 2150 2155
2160Thr Gly Ile Gly Arg Tyr Asn Glu Met Thr Tyr Ile Phe Asp Leu
2165 2170 2175Leu His Lys Lys His Tyr
Phe Glu Val Leu Met Arg Lys Lys Leu 2180 2185
2190Asp Pro Ser Gly Thr Leu Lys Thr Ala Leu Leu Asp Tyr Ile
Lys 2195 2200 2205Arg Cys Arg Pro Gly
Asp Ser Glu Lys His Asn Met Ile Ala Leu 2210 2215
2220Cys Phe Ser Met Cys Arg Glu Ile Gly Glu Asn His Glu
Ala Ala 2225 2230 2235Ala Arg Ile Gln
Leu Lys Leu Ile Leu Ser Pro Gly Arg Thr Ala 2240
2245 2250Ser Arg Met Gly Thr Ser 22551872285PRTHomo
sapiens 187Met Ala Ala Glu Glu Gly Val Ala Ser Ala Ala Ser Ala Gly Gly
Ser1 5 10 15Trp Gly Thr
Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro 20
25 30Val Pro Ala Glu Ala Met Gly Gln Leu Gly
Ser Arg Ala Gln Leu Arg 35 40
45Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser Leu Gln 50
55 60Val Leu Ser Leu Thr Pro Gly Ser Arg
Gly Gly Gly Arg Cys Cys Leu65 70 75
80Glu Gly Pro Phe Trp His Phe Leu Trp Glu Asp Ser Arg Asn
Ser Ser 85 90 95Thr Pro
Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu 100
105 110Leu Leu Ile Tyr Glu Phe Asn Leu Lys
Asp Gly Arg Cys Asp Ala Thr 115 120
125Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys Leu Ile Asp Asp
130 135 140Gln Asp Ile Ser Ile Ser Leu
Leu Ser Leu Arg Ile Leu Ser Phe His145 150
155 160Asn Asn Thr Ser Leu Leu Phe Ile Asn Lys Cys Val
Ile Leu His Ile 165 170
175Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu Asn Cys Phe Thr
180 185 190Leu Pro Leu Pro Ala Gln
Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195 200
205Cys Arg Gly Ile Leu Phe Val Leu Ser Ser Leu Gly Trp Ile
Tyr Ile 210 215 220Phe Asp Val Val Asp
Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu225 230
235 240His Lys Glu Asp Met Cys Asn Glu Gln Gln
Gln Glu Pro Ala Lys Ile 245 250
255Ser Ser Phe Thr Ser Leu Lys Val Ser Gln Asp Leu Asp Val Ala Val
260 265 270Ile Val Ser Ser Ser
Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr 275
280 285Phe Arg Gln His Pro Gly His Leu Leu Cys Glu Arg
Ile Leu Glu Asp 290 295 300Leu Pro Ile
Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val Asn305
310 315 320Ser Ala Tyr Asn Met Lys Leu
Ala Lys Phe Ser Phe Gln Ile Asp Arg 325
330 335Ser Trp Lys Ala Gln Leu Ser Ser Leu Asn Glu Thr
Ile Lys Asn Ser 340 345 350Lys
Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile Leu His 355
360 365Leu Glu Ser Pro Glu Ser Gly Asn His
Ser Thr Ser Val Gln Ser Trp 370 375
380Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr Asn Val Leu Gln385
390 395 400Lys Asp His Ala
Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met 405
410 415His Ile Ser Glu Gln Glu Glu Pro Ile Glu
Leu Lys Cys Val Ser Val 420 425
430Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu Arg Met Gly Tyr
435 440 445Thr Ile Thr Leu Trp Asp Leu
Glu Thr Gln Gly Met Gln Cys Ser Ser 450 455
460Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser Gly Asp Gln Gln
Leu465 470 475 480Cys Phe
Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu
485 490 495Thr Gln Glu Glu Phe Leu Asn
Arg Leu Met Ile His Gly Ser Ala Ser 500 505
510Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp Gly Arg Cys
Ser Ile 515 520 525Pro Ile His Ala
Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530
535 540Val Asn Phe Phe Leu Lys Ser Lys Glu Asn Leu Phe
Asn Pro Ser Ser545 550 555
560Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu Tyr
565 570 575Leu Arg Asn Val Glu
Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580
585 590Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln Ser Lys
His Phe Ser Glu 595 600 605Gln Leu
Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610
615 620Leu Phe Ile His Thr Glu Glu Leu Asp Glu His
Leu Gln Lys Gly Val625 630 635
640Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Arg Thr Phe Met Ile Lys
645 650 655Phe Pro Trp Lys
Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu 660
665 670Asn Val Pro Lys Val Lys Glu Ser Asn Ile Trp
Lys Lys Leu Ser Phe 675 680 685Glu
Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys Ile Pro Glu Ala 690
695 700Gln Thr Phe Phe Arg Ile Asp Ser His Ser
Ala Gln Lys Leu Glu Glu705 710 715
720Leu Ile Gly Ile Gly Leu Asn Leu Val Phe Asp Asn Leu Lys Lys
Asn 725 730 735Asn Ile Lys
Glu Ala Ser Glu Leu Leu Lys Asn Met Gly Phe Asp Val 740
745 750Lys Gly Gln Leu Leu Lys Ile Cys Phe Tyr
Thr Thr Asn Lys Asn Ile 755 760
765Arg Asp Phe Leu Val Glu Ile Leu Lys Glu Lys Asn Tyr Phe Ser Glu 770
775 780Lys Glu Lys Arg Thr Ile Asp Phe
Val His Gln Val Glu Lys Leu Tyr785 790
795 800Leu Gly His Phe Gln Glu Asn Met Gln Ile Gln Ser
Phe Pro Arg Tyr 805 810
815Trp Ile Lys Glu Gln Asp Phe Phe Lys His Lys Ser Val Leu Asp Ser
820 825 830Phe Leu Lys Tyr Asp Cys
Lys Asp Glu Phe Asn Lys Gln Asp His Arg 835 840
845Ile Val Leu Asn Trp Ala Leu Trp Trp Asp Gln Leu Thr Gln
Glu Ser 850 855 860Ile Leu Leu Pro Arg
Ile Ser Pro Glu Glu Tyr Lys Ser Tyr Ser Pro865 870
875 880Glu Ala Leu Trp Arg Tyr Leu Thr Ala Arg
His Asp Trp Leu Asn Ile 885 890
895Ile Leu Trp Ile Gly Glu Phe Gln Thr Gln His Ser Tyr Ala Ser Leu
900 905 910Gln Gln Asn Lys Trp
Pro Leu Leu Thr Val Asp Val Ile Asn Gln Asn 915
920 925Thr Ser Cys Asn Asn Tyr Met Arg Asn Glu Ile Leu
Asp Lys Leu Ala 930 935 940Arg Asn Gly
Val Phe Leu Ala Ser Glu Leu Glu Asp Phe Glu Cys Phe945
950 955 960Leu Leu Arg Leu Ser Arg Ile
Gly Gly Val Ile Gln Asp Thr Leu Pro 965
970 975Val Gln Asn Tyr Lys Thr Lys Glu Gly Trp Asp Phe
His Ser Gln Phe 980 985 990Ile
Leu Tyr Cys Leu Glu His Ser Leu Gln His Leu Leu Tyr Val Tyr 995
1000 1005Leu Asp Cys Tyr Lys Leu Ser Pro
Glu Asn Cys Pro Phe Leu Glu 1010 1015
1020Lys Lys Glu Leu His Glu Ala His Pro Trp Phe Glu Phe Leu Val
1025 1030 1035Gln Cys Arg Gln Val Ala
Ser Asn Leu Thr Asp Pro Lys Leu Ile 1040 1045
1050Phe Gln Ala Ser Leu Ala Asn Ala Gln Ile Leu Ile Pro Thr
Asn 1055 1060 1065Gln Ala Ser Val Ser
Ser Met Leu Leu Glu Gly His Thr Leu Leu 1070 1075
1080Ala Leu Ala Thr Thr Met Tyr Ser Pro Gly Gly Val Ser
Gln Val 1085 1090 1095Val Gln Asn Glu
Glu Asn Glu Asn Cys Leu Lys Lys Val Asp Pro 1100
1105 1110Gln Leu Leu Lys Met Ala Leu Thr Pro Tyr Pro
Lys Leu Lys Thr 1115 1120 1125Ala Leu
Phe Pro Gln Cys Thr Pro Pro Ser Val Leu Pro Ser Asp 1130
1135 1140Ile Thr Ile Tyr His Leu Ile Gln Ser Leu
Ser Pro Phe Asp Pro 1145 1150 1155Ser
Arg Leu Phe Gly Trp Gln Ser Ala Asn Thr Leu Ala Ile Gly 1160
1165 1170Asp Ala Trp Ser His Leu Pro His Phe
Ser Ser Pro Asp Leu Val 1175 1180
1185Asn Lys Tyr Ala Ile Val Glu Arg Leu Asn Phe Ala Tyr Tyr Leu
1190 1195 1200His Asn Gly Arg Pro Ser
Phe Ala Phe Gly Thr Phe Leu Val Gln 1205 1210
1215Glu Leu Ile Lys Ser Lys Thr Pro Lys Gln Leu Ile Gln Gln
Val 1220 1225 1230Gly Asn Glu Ala Tyr
Val Ile Gly Leu Ser Ser Phe His Ile Pro 1235 1240
1245Ser Ile Gly Ala Ala Cys Val Cys Phe Leu Glu Leu Leu
Gly Leu 1250 1255 1260Asp Ser Leu Lys
Leu Arg Val Asp Met Lys Val Ala Asn Ile Ile 1265
1270 1275Leu Ser Tyr Lys Cys Arg Asn Glu Asp Ala Gln
Tyr Ser Phe Ile 1280 1285 1290Arg Glu
Ser Val Ala Glu Lys Leu Ser Lys Leu Ala Asp Gly Glu 1295
1300 1305Lys Thr Thr Thr Glu Glu Leu Leu Val Leu
Leu Glu Glu Gly Thr 1310 1315 1320Trp
Asn Ser Ile Gln Gln Gln Glu Ile Lys Arg Leu Ser Ser Glu 1325
1330 1335Ser Ser Ser Gln Trp Ala Leu Val Val
Gln Phe Cys Arg Leu His 1340 1345
1350Asn Met Lys Leu Ser Ile Ser Tyr Leu Arg Glu Cys Ala Lys Ala
1355 1360 1365Asn Asp Trp Leu Gln Phe
Ile Ile His Ser Gln Leu His Asn Tyr 1370 1375
1380His Pro Ala Glu Val Lys Ser Leu Ile Gln Tyr Phe Ser Pro
Val 1385 1390 1395Ile Gln Asp His Leu
Arg Leu Ala Phe Glu Asn Leu Pro Ser Val 1400 1405
1410Pro Thr Ser Lys Met Asp Ser Asp Gln Val Cys Asn Lys
Cys Pro 1415 1420 1425Gln Glu Leu Gln
Gly Ser Lys Gln Glu Met Thr Asp Leu Phe Glu 1430
1435 1440Ile Leu Leu Gln Cys Ser Glu Glu Pro Asp Ser
Trp His Trp Leu 1445 1450 1455Leu Val
Glu Ala Val Lys Gln Gln Ala Pro Ile Leu Ser Val Leu 1460
1465 1470Ala Ser Cys Leu Gln Gly Ala Ser Ala Ile
Ser Cys Leu Cys Val 1475 1480 1485Trp
Ile Ile Thr Ser Val Glu Asp Asn Val Ala Thr Glu Ala Met 1490
1495 1500Gly His Ile Gln Asp Ser Thr Glu Asp
His Thr Trp Asn Leu Glu 1505 1510
1515Asp Leu Ser Val Ile Trp Arg Thr Leu Leu Thr Arg Gln Lys Ser
1520 1525 1530Lys Thr Leu Ile Arg Gly
Phe Gln Leu Phe Phe Lys Asp Ser Pro 1535 1540
1545Leu Leu Leu Val Met Glu Met Tyr Glu Leu Cys Met Phe Phe
Arg 1550 1555 1560Asn Tyr Lys Glu Ala
Glu Ala Lys Leu Leu Glu Phe Gln Lys Ser 1565 1570
1575Leu Glu Thr Leu Asn Thr Ala Ala Thr Lys Val His Pro
Val Ile 1580 1585 1590Pro Ala Met Trp
Leu Glu Asp Gln Val Cys Phe Leu Leu Lys Leu 1595
1600 1605Met Leu Gln Gln Cys Lys Thr Gln Tyr Glu Leu
Gly Lys Leu Leu 1610 1615 1620Gln Leu
Phe Val Glu Arg Glu His Leu Phe Ser Asp Gly Pro Asp 1625
1630 1635Val Lys Lys Leu Cys Ile Leu Cys Gln Ile
Leu Lys Asp Thr Ser 1640 1645 1650Ile
Ala Ile Asn His Thr Ile Ile Thr Ser Tyr Ser Ile Glu Asn 1655
1660 1665Leu Gln His Glu Cys Arg Ser Ile Leu
Glu Arg Leu Gln Thr Asp 1670 1675
1680Gly Gln Phe Ala Leu Ala Arg Arg Val Ala Glu Leu Ala Glu Leu
1685 1690 1695Pro Val Asp Asn Leu Val
Ile Lys Glu Ile Thr Gln Glu Met Gln 1700 1705
1710Thr Leu Lys His Ile Glu Gln Trp Ser Leu Lys Gln Ala Arg
Ile 1715 1720 1725Asp Phe Trp Lys Lys
Cys His Glu Asn Phe Lys Lys Asn Ser Ile 1730 1735
1740Ser Ser Lys Ala Ala Ser Ser Phe Phe Ser Thr Gln Ala
His Val 1745 1750 1755Ala Cys Glu His
Pro Thr Gly Trp Ser Ser Met Glu Glu Arg His 1760
1765 1770Leu Leu Leu Thr Leu Ala Gly His Trp Leu Ala
Gln Glu Asp Val 1775 1780 1785Val Pro
Leu Asp Lys Leu Glu Glu Leu Glu Lys Gln Ile Trp Leu 1790
1795 1800Cys Arg Ile Thr Gln His Thr Leu Gly Arg
Asn Gln Glu Glu Thr 1805 1810 1815Glu
Pro Arg Phe Ser Arg Gln Ile Ser Thr Ser Gly Glu Leu Ser 1820
1825 1830Phe Asp Ser Leu Ala Ser Glu Phe Ser
Phe Ser Lys Leu Ala Ala 1835 1840
1845Leu Asn Thr Ser Lys Tyr Leu Glu Leu Asn Ser Leu Pro Ser Lys
1850 1855 1860Glu Thr Cys Glu Asn Arg
Leu Asp Trp Lys Glu Gln Glu Ser Leu 1865 1870
1875Asn Phe Leu Ile Gly Arg Leu Leu Asp Asp Gly Cys Val His
Glu 1880 1885 1890Ala Ser Arg Val Cys
Arg Tyr Phe His Phe Tyr Asn Pro Asp Val 1895 1900
1905Ala Leu Val Leu His Cys Arg Ala Leu Ala Ser Gly Glu
Ala Ser 1910 1915 1920Met Glu Asp Leu
His Pro Glu Ile His Ala Leu Leu Gln Ser Ala 1925
1930 1935Glu Leu Leu Glu Glu Glu Ala Pro Asp Ile Pro
Leu Arg Arg Val 1940 1945 1950His Ser
Thr Ser Ser Leu Asp Ser Gln Lys Phe Val Thr Val Pro 1955
1960 1965Ser Ser Asn Glu Val Val Thr Asn Leu Glu
Val Leu Thr Ser Lys 1970 1975 1980Cys
Leu His Gly Lys Asn Tyr Cys Arg Gln Val Leu Cys Leu Tyr 1985
1990 1995Asp Leu Ala Lys Glu Leu Gly Cys Ser
Tyr Thr Asp Val Ala Ala 2000 2005
2010Gln Asp Gly Glu Ala Met Leu Arg Lys Ile Leu Ala Ser Gln Gln
2015 2020 2025Pro Asp Arg Cys Lys Arg
Ala Gln Ala Phe Ile Ser Thr Gln Gly 2030 2035
2040Leu Lys Pro Asp Thr Val Ala Glu Leu Val Ala Glu Glu Val
Thr 2045 2050 2055Arg Glu Leu Leu Thr
Ser Ser Gln Gly Thr Gly His Lys Gln Met 2060 2065
2070Phe Asn Pro Thr Glu Glu Ser Gln Thr Phe Leu Gln Leu
Thr Thr 2075 2080 2085Leu Cys Gln Asp
Arg Thr Leu Val Gly Met Lys Leu Leu Asp Lys 2090
2095 2100Ile Ser Ser Val Pro His Gly Glu Leu Ser Cys
Thr Thr Glu Leu 2105 2110 2115Leu Ile
Leu Ala His His Cys Phe Thr Leu Thr Cys His Met Glu 2120
2125 2130Gly Ile Ile Arg Val Leu Gln Ala Ala His
Met Leu Thr Asp Asn 2135 2140 2145His
Leu Ala Pro Ser Glu Glu Tyr Gly Leu Val Val Arg Leu Leu 2150
2155 2160Thr Gly Ile Gly Arg Tyr Asn Glu Met
Thr Tyr Ile Phe Asp Leu 2165 2170
2175Leu His Lys Lys His Tyr Phe Glu Val Leu Met Arg Lys Lys Leu
2180 2185 2190Asp Pro Ser Gly Thr Leu
Lys Thr Ala Leu Leu Asp Tyr Ile Lys 2195 2200
2205Arg Cys Arg Pro Gly Asp Ser Glu Lys His Asn Met Ile Ala
Leu 2210 2215 2220Cys Phe Ser Met Cys
Arg Glu Ile Gly Glu Asn His Glu Ala Ala 2225 2230
2235Ala Arg Ile Gln Leu Lys Leu Ile Glu Ser Gln Pro Trp
Glu Asp 2240 2245 2250Ser Leu Lys Asp
Gly His Gln Leu Lys Gln Leu Leu Leu Lys Ala 2255
2260 2265Leu Thr Leu Met Leu Asp Ala Ala Glu Ser Tyr
Ala Lys Asp Ser 2270 2275 2280Cys Val
2285188949PRTHomo sapiens 188Met Ala Ala Glu Glu Gly Val Ala Ser Ala
Ala Ser Ala Gly Gly Ser1 5 10
15Trp Gly Thr Ala Ala Met Gly Arg Val Leu Pro Met Leu Leu Val Pro
20 25 30Val Pro Ala Glu Ala Met
Gly Gln Leu Gly Ser Arg Ala Gln Leu Arg 35 40
45Thr Gln Pro Glu Ala Leu Gly Ser Leu Thr Ala Ala Gly Ser
Leu Gln 50 55 60Val Leu Ser Leu Thr
Pro Gly Ser Arg Gly Gly Gly Arg Cys Cys Leu65 70
75 80Glu Gly Pro Phe Trp His Phe Leu Trp Glu
Asp Ser Arg Asn Ser Ser 85 90
95Thr Pro Thr Glu Lys Pro Lys Leu Leu Ala Leu Gly Glu Asn Tyr Glu
100 105 110Leu Leu Ile Tyr Glu
Phe Asn Leu Lys Asp Gly Arg Cys Asp Ala Thr 115
120 125Ile Leu Tyr Ser Cys Ser Arg Glu Ala Leu Gln Lys
Leu Ile Asp Asp 130 135 140Gln Asp Ile
Ser Ile Ser Leu Leu Ser Leu Arg Ile Leu Ser Phe His145
150 155 160Asn Asn Thr Ser Leu Leu Phe
Ile Asn Lys Cys Val Ile Leu His Ile 165
170 175Ile Phe Pro Glu Arg Asp Ala Ala Ile Arg Val Leu
Asn Cys Phe Thr 180 185 190Leu
Pro Leu Pro Ala Gln Ala Val Asp Met Ile Ile Asp Thr Gln Leu 195
200 205Cys Arg Gly Ile Leu Phe Val Leu Ser
Ser Leu Gly Trp Ile Tyr Ile 210 215
220Phe Asp Val Val Asp Gly Thr Tyr Val Ala His Val Asp Leu Ala Leu225
230 235 240His Lys Glu Asp
Met Cys Asn Glu Gln Gln Gln Glu Pro Ala Lys Ile 245
250 255Ser Ser Phe Thr Ser Leu Lys Val Ser Gln
Asp Leu Asp Val Ala Val 260 265
270Ile Val Ser Ser Ser Asn Ser Ala Val Ala Leu Asn Leu Asn Leu Tyr
275 280 285Phe Arg Gln His Pro Gly His
Leu Leu Cys Glu Arg Ile Leu Glu Asp 290 295
300Leu Pro Ile Gln Gly Pro Lys Gly Val Asp Glu Asp Asp Pro Val
Asn305 310 315 320Ser Ala
Tyr Asn Met Lys Leu Ala Lys Phe Ser Phe Gln Ile Asp Arg
325 330 335Ser Trp Lys Ala Gln Leu Ser
Ser Leu Asn Glu Thr Ile Lys Asn Ser 340 345
350Lys Leu Glu Val Ser Cys Cys Ala Pro Trp Phe Gln Asp Ile
Leu His 355 360 365Leu Glu Ser Pro
Glu Ser Gly Asn His Ser Thr Ser Val Gln Ser Trp 370
375 380Ala Phe Ile Pro Gln Asp Ile Met His Gly Gln Tyr
Asn Val Leu Gln385 390 395
400Lys Asp His Ala Lys Thr Ser Asp Pro Gly Arg Ser Trp Lys Ile Met
405 410 415His Ile Ser Glu Gln
Glu Glu Pro Ile Glu Leu Lys Cys Val Ser Val 420
425 430Thr Gly Phe Thr Ala Leu Phe Thr Trp Glu Val Glu
Arg Met Gly Tyr 435 440 445Thr Ile
Thr Leu Trp Asp Leu Glu Thr Gln Gly Met Gln Cys Ser Ser 450
455 460Leu Gly Thr Lys Cys Ile Pro Val Asp Ser Ser
Gly Asp Gln Gln Leu465 470 475
480Cys Phe Val Leu Thr Glu Asn Gly Leu Ser Leu Ile Leu Phe Gly Leu
485 490 495Thr Gln Glu Glu
Phe Leu Asn Arg Leu Met Ile His Gly Ser Ala Ser 500
505 510Thr Val Asp Thr Leu Cys His Leu Asn Gly Trp
Gly Arg Cys Ser Ile 515 520 525Pro
Ile His Ala Leu Glu Ala Gly Ile Glu Asn Arg Gln Leu Asp Thr 530
535 540Val Asn Phe Phe Leu Lys Ser Lys Glu Asn
Leu Phe Asn Pro Ser Ser545 550 555
560Lys Ser Ser Val Ser Asp Gln Phe Asp His Leu Ser Ser His Leu
Tyr 565 570 575Leu Arg Asn
Val Glu Glu Leu Ile Pro Ala Leu Asp Leu Leu Cys Ser 580
585 590Ala Ile Arg Glu Ser Tyr Ser Glu Pro Gln
Ser Lys His Phe Ser Glu 595 600
605Gln Leu Leu Asn Leu Thr Leu Ser Phe Leu Asn Asn Gln Ile Lys Glu 610
615 620Leu Phe Ile His Thr Glu Glu Leu
Asp Glu His Leu Gln Lys Gly Val625 630
635 640Asn Ile Leu Thr Ser Tyr Ile Asn Glu Leu Arg Thr
Phe Met Ile Lys 645 650
655Phe Pro Trp Lys Leu Thr Asp Ala Ile Asp Glu Tyr Asp Val His Glu
660 665 670Asn Val Pro Lys Val Lys
Glu Ser Asn Ile Trp Lys Lys Leu Ser Phe 675 680
685Glu Glu Val Ile Ala Ser Ala Ile Leu Asn Asn Lys Ile Pro
Glu Ala 690 695 700Gln Thr Phe Phe Arg
Ile Asp Ser His Ser Ala Gln Lys Leu Glu Glu705 710
715 720Leu Ile Gly Ile Gly Leu Asn Leu Val Phe
Asp Asn Leu Lys Lys Asn 725 730
735Asn Ile Lys Glu Ala Ser Glu Leu Leu Lys Asn Met Gly Phe Asp Val
740 745 750Lys Gly Gln Leu Leu
Lys Ile Cys Phe Tyr Thr Thr Asn Lys Asn Ile 755
760 765Arg Asp Phe Leu Val Glu Ile Leu Lys Glu Lys Asn
Tyr Phe Ser Glu 770 775 780Lys Glu Lys
Arg Thr Ile Asp Phe Val His Gln Val Glu Lys Leu Tyr785
790 795 800Leu Gly His Phe Gln Glu Asn
Met Gln Ile Gln Ser Phe Pro Arg Tyr 805
810 815Trp Ile Lys Glu Gln Asp Phe Phe Lys His Lys Ser
Val Leu Asp Ser 820 825 830Phe
Leu Lys Tyr Asp Cys Lys Asp Glu Phe Asn Lys Gln Asp His Arg 835
840 845Ile Val Leu Asn Trp Ala Leu Trp Trp
Asp Gln Leu Thr Gln Glu Ser 850 855
860Ile Leu Leu Pro Arg Ile Ser Pro Glu Glu Tyr Lys Ser Tyr Ser Pro865
870 875 880Glu Ala Leu Trp
Arg Tyr Leu Thr Ala Arg His Asp Trp Leu Asn Ile 885
890 895Ile Leu Trp Ile Gly Glu Phe Gln Thr Gln
His Ser Tyr Ala Ser Leu 900 905
910Gln Gln Asn Lys Trp Pro Leu Leu Thr Val Asp Val Ile Asn Gln Asn
915 920 925Thr Ser Cys Asn Asn Tyr Met
Arg Asn Glu Ile Leu Asp Lys Leu Ala 930 935
940Gly Tyr Tyr Asn Cys945
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