KR20210096798A - Composition for Diagnosing Prognosis of Kidney Cancer and Kit Comprising Thereof - Google Patents

Abstract

The present invention provides a composition for diagnosing prognosis of kidney cancer, a kit for diagnosing prognosis of kidney cancer, comprising the same and a method for providing information necessary for prognostic diagnosis of kidney cancer using the same. Using the composition for prognostic diagnosis of the kidney cancer, the kit for diagnosing prognosis of kidney cancer, comprising the same, it is possible to help establish a treatment strategy for a kidney cancer patient by diagnosing and predicting the possibility of recurrence or prognosis after treatment of the kidney cancer patient.

Description

Kidney cancer prognosis diagnosis composition and kit comprising the same {Composition for Diagnosing Prognosis of Kidney Cancer and Kit Comprising Thereof}

The present invention relates to a composition for diagnosing the prognosis of kidney cancer, a kit for diagnosing the prognosis of kidney cancer including the same, and a method for providing information necessary for prognostic diagnosis of a kidney cancer patient using the same.

The kidney is an important urinary organ having a role of excreting wastes in the living body to the outside of the body by filtering blood and producing urine. At the same time, it is also an important endocrine organ that produces hormones such as angiotensin, which regulates blood pressure, and erythropoietin, a red blood cell hematopoietic factor.

Tumors that occur in the kidney include renal cell carcinoma (RCC) that occurs in adults, Wilms' tumor that occurs in children, and sarcoma as a rare tumor. Kidney cancer refers to renal cell carcinoma that occurs mostly in the parenchyma of the kidney (the part of the kidney that makes urine, which is composed of the medulla and the cortex). Although genetic factors are also known as risk factors for kidney cancer, in general, smoking and excessive fat intake are included. In addition, it is known that the incidence of tumors is high in patients receiving dialysis for a long time.

Renal cell carcinoma includes clear cell RCC, papillary RCC, chromophobe RCC, medullary RCC, and unclassifiable renal cell carcinoma. (unclassified RCC), and among them, papillary renal cell carcinoma is the second most common type, accounting for about 15-20% of all renal cell carcinomas.

Kidney cancer has almost no symptoms when the size of the tumor is small, and symptoms appear only when the tumor grows to a certain extent and pushes the organs away. Therefore, the diagnosis is often delayed, and when first diagnosed, about 30% of patients appear to have already metastasized. The most common symptom is hematuria, but this also occurs in only 60% of patients. Rather, symptoms such as shortness of breath, cough, and headache appear depending on the metastasized site, and the diagnosis of kidney cancer due to these metastases is up to 30% of all patients. Because kidney cancer can cause high blood pressure, hypercalcemia, and liver function abnormalities due to certain hormones produced by cancer cells, tumors are sometimes discovered while examining these other symptoms. Recently, it is often discovered incidentally on an imaging test while undergoing a medical examination without any symptoms.

Kidney cancer has a high survival rate due to tumor removal after onset, but it is difficult to diagnose at an early stage because there are no clear symptoms. For this reason, early diagnosis of kidney cancer and development of markers that can check the remaining lifespan after cancer onset is necessary.

Patent Document 1 discloses transglutaminase 2 as a marker used for detection or diagnosis of human kidney cancer. Although markers for diagnosing cancer including kidney cancer have been developed, studies have not yet been made on the relationship between the recurrence of kidney cancer patients or the survival rate of patients with recurrent kidney cancer and mutations in specific genes.

The present inventors need to develop a marker capable of diagnosing the prognosis of a recurrent renal cancer patient in order to determine a treatment strategy by discovering a marker for diagnosing the recurrence of renal cancer or a therapeutic agent for the recurrent renal cancer patient Based on this, we studied the relationship between a gene mutation found in patients with papillary renal cancer and survival or whether renal cancer recurs, and the relationship between a gene mutation and survival time found in patients with recurrent renal cancer.

Korean Patent Publication No. 1267580

In order to apply a therapeutic strategy suitable for renal cancer patients, it is necessary to develop a marker that can predict the prognosis of renal cancer patients and provide information to determine a treatment strategy. An object of the present invention is to provide a marker that helps in diagnosing whether renal cancer recurrence or prognosis in a patient, and a treatment strategy for a renal cancer patient.

One aspect of the present invention is ACTR1B gene mutation, BPNT1 gene mutation, BRD4 gene mutation, TSPOAP1 gene mutation, TMEM266 gene mutation, C16orf72 gene mutation, CD1C gene mutation, CEP128 gene mutation, CIITA gene mutation , COL5A1 gene mutation, CYP51A1 gene mutation, DNAAF2 gene mutation, EPHB1 gene mutation, ESRP2 gene mutation, FBXW9 gene mutation, ITGA3 gene mutation, ITGA4 gene mutation, ITGA8 gene mutation, KIF5C gene mutation , KPRP gene mutation, MAOB gene mutation, MUC17 gene mutation, MYH10 gene mutation, OGFR gene mutation, OR1S1 gene mutation, PCBP4 gene mutation, PCGF2 gene mutation, PCSK2 gene mutation, PLEKHB2 gene mutation , PPM1F gene mutation, RAB40B gene mutation, RRP36 gene mutation, RTL1 gene mutation, RYR1 gene mutation, SMARCA1 gene mutation, SNX7 gene mutation, SSX2IP gene mutation, TAS1R2 gene mutation, THUMPD2 gene mutation And it provides a composition for prognostic diagnosis of kidney cancer comprising a reagent capable of detecting a survival-specific marker of a kidney cancer patient comprising at least one selected from the group consisting of a mutation of the VPS13D gene.

Another aspect of the present invention is ACTR1B gene mutation, BPNT1 gene mutation, BRD4 gene mutation, TSPOAP1 gene mutation, TMEM266 gene mutation, C16orf72 gene mutation, CD1C gene mutation, CEP128 gene mutation, CIITA gene mutation , COL5A1 gene mutation, CYP51A1 gene mutation, DNAAF2 gene mutation, EPHB1 gene mutation, ESRP2 gene mutation, FBXW9 gene mutation, ITGA3 gene mutation, ITGA4 gene mutation, ITGA8 gene mutation, KIF5C gene mutation , KPRP gene mutation, MAOB gene mutation, MUC17 gene mutation, MYH10 gene mutation, OGFR gene mutation, OR1S1 gene mutation, PCBP4 gene mutation, PCGF2 gene mutation, PCSK2 gene mutation, PLEKHB2 gene mutation , PPM1F gene mutation, RAB40B gene mutation, RRP36 gene mutation, RTL1 gene mutation, RYR1 gene mutation, SMARCA1 gene mutation, SNX7 gene mutation, SSX2IP gene mutation, TAS1R2 gene mutation, THUMPD2 gene mutation And it provides a kit for prognostic diagnosis of kidney cancer comprising a reagent capable of detecting a survival-specific marker of a kidney cancer patient comprising at least one selected from the group consisting of a mutation of the VPS13D gene.

Another aspect of the present invention comprises the steps of preparing a sample DNA from a sample of a renal cancer patient; amplifying the sample DNA using the composition for diagnosing the prognosis of kidney cancer or the kit for diagnosing the prognosis of kidney cancer; and confirming the presence or absence of a survival-specific marker from the amplification result; provides a method for providing information necessary for prognostic diagnosis of renal cancer patients, including.

Using the composition for diagnosing the prognosis of kidney cancer of the present invention and the kit for diagnosing the prognosis of kidney cancer including the same, the possibility of recurrence or prognosis after treatment of a kidney cancer patient can be diagnosed and predicted. This can help establish a treatment strategy for kidney cancer patients.

1-40 show ACTR1B, BPNT1, BRD4, TSPOAP1, TMEM266, C16orf72, CD1C, CEP128, CIITA, COL5A1, CYP51A1, DNAAF2, EPHB1, ESRP2, FOBW9, ITGA3, ITGA4, ITGA8, KPUC For each gene MYH10, OGFR, OR1S1, PCBP4, PCGF2, PCSK2, PLEKHB2, PPM1F, RAB40B, RRP36, RTL1, RYR1, SMARCA1, SNX7, SSX2IP, TAS1R2, THUMPD2, VPS13D, kidney cancer patients with mutations in the corresponding gene A graph of the total survival and/or disease-free survival of (red) and renal cancer patients without mutations in the corresponding gene (blue) is shown.

In this specification, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In general, the nomenclature used herein and the experimental methods described below are those well known and commonly used in the art.

In the present invention, the term 'gene' and its variants include DNA fragments involved in polypeptide chain generation; It includes regions before and after the coding region, eg promoters and 3'-untranslated regions, respectively, as well as intervening sequences (introns) between individual coding fragments (exons).

As used herein, the term 'cancer' includes any member of a class of diseases characterized by the uncontrolled growth of abnormal cells. The term includes all known cancers and neoplastic conditions, whether characterized as malignant, benign, soft tissue or solid, and cancers of all stages and grades, including cancers before and after metastasis.

In the present invention, the term 'prognosis' refers to the progress and cure of neoplastic diseases such as cancer, such as the possibility of cancer-caused death or progression, including recurrence, metastatic spread, and drug resistance, for example. For the purpose of the present invention, it may be to predict the prognosis of kidney cancer, preferably to predict the disease-free survival rate or survival rate of renal cancer patients.

In the present invention, the term 'diagnosis' refers to confirming the presence or characteristics of a pathological condition, and for the purpose of the present invention, not only confirming whether or not cancer occurs, but also recurrence, metastasis, drug reactivity, resistance of the subject after treatment of cancer It means judging whether or not Preferably, when using the mutation of the gene of the present invention, it is possible to predict whether or not the subject will develop cancer, as well as whether the prognosis of the subject will be good in the future by checking whether the mutation is present from the subject's sample.

In the present invention, the term 'survival-specific marker' may refer to a mutation in a gene or mutations in a gene that can be an indicator for predicting the prognosis of kidney cancer in a subject after treatment of a kidney cancer patient. Also, in the present invention, the 'marker gene' may be used to refer to each gene mutation included in the survival-specific marker.

1. A composition for prognostic diagnosis of kidney cancer and a kit comprising the same

One aspect of the present invention provides a composition for prognostic diagnosis of renal cancer comprising a reagent capable of detecting a survival-specific marker of a renal cancer patient. The survival-specific marker of the composition for diagnosing the prognosis of renal cancer of the present invention may be an index predicting the prognosis of renal cancer in the subject after treatment of the renal cancer patient.

For example, when the survival-specific marker is identified, it can be determined that the survival rate is lower than the survival rate of a person for which the survival-specific marker is not identified, or when the survival-specific marker is identified, the recurrence rate of kidney cancer is the survival rate It can be determined that the specific marker is higher than that of an unidentified person.

Specifically, the survival-specific marker is a mutation of the ACTR1B gene (Gene bank accession number: NM_005735.4), a mutation of the BPNT1 gene (Gene bank accession number: NM_006085.6), and the BRD4 gene (Gene bank accession number: NM_058243.2) ) mutation, TSPOAP1 gene (Gene bank accession number: NM_004758.4) mutation, TMEM266 gene (Gene bank accession number: NM_152335.3) mutation, C16orf72 gene (Gene bank accession number: NM_014117.3) mutation, CD1C Gene (Gene bank accession number: NM_001765.3) mutation, CEP128 gene (Gene bank accession number: NM_152446.5) mutation, CIITA gene (Gene bank accession number: NM_001286402.1) mutation, COL5A1 gene (Gene bank accession) number: NM_000093.4) mutation, CYP51A1 gene (Gene bank accession number: NM_000786.4) mutation, DNAAF2 gene (Gene bank accession number: NM_018139.2) mutation, EPHB1 gene (Gene bank accession number: NM_004441.5) ) mutation, ESRP2 gene (Gene bank accession number: NM_024939.3) mutation, FBXW9 gene (Gene bank accession number: NM_032301.3) mutation, ITGA3 gene (Gene bank accession number: NM_002204.4) mutation, ITGA4 Gene bank accession number: NM_000885.6) mutation, ITGA8 gene (Gene bank accession number: NM_003638.3) mutation, KIF5C gene (Gene bank accession number: NM_004522.3) mutation, KPRP gene (Gene bank accession number: NM_001025231.2) Mutations, MAOB gene (Gene bank accession number: NM_000898.5) mutation, MUC17 gene (Gene bank accession number: NM_001040105.2) mutation, MYH10 gene (Gene bank accession number: NM_005964.4) mutation, OGFR gene ( Gene bank accession number: NM_007346.4) mutation, OR1S1 gene (Gene bank accession number: NM_001004458.1) mutation, PCBP4 gene (Gene bank accession number: NM_001174100.2) mutation, PCGF2 gene (Gene bank accession number: NM_007144.3) mutation, PCSK2 gene (Gene bank accession number: NM_002594.5) mutation, PLEKHB2 gene (Gene bank accession number: NM_001100623.1) mutation, PPM1F gene (Gene bank accession number: NM_014634.4) Mutation, RAB40B gene (Gene bank accession number: NM_006822.3) mutation, RRP36 gene (Gene bank accession number: NM_033112.4) mutation, RTL1 gene (Gene bank accession number: NM_001134888.2) mutation, RYR1 gene ( Gene bank access number r: NM_000540.2) mutation, SMARCA1 gene (Gene bank accession number: NM_003069.5) mutation, SNX7 gene (Gene bank accession number: NM_015976.5) mutation, SSX2IP gene (Gene bank accession number: NM_001166293.2) ), a mutation of the TAS1R2 gene (Gene bank accession number: NM_152232.2), a mutation of the THUMPD2 gene (Gene bank accession number: NM_025264.5) and a mutation of the VPS13D gene (Gene bank accession number: NM_015378.4). It provides a composition comprising at least one selected from the group.

Specifically, the survival-specific marker is ACTR1B gene mutation, BPNT1 gene mutation, BRD4 gene mutation, C16orf72 gene mutation, CD1C gene mutation, CEP128 gene mutation, CIITA gene mutation, CYP51A1 gene mutation, EPHB1 Gene mutation, FBXW9 gene mutation, ITGA3 gene mutation, ITGA8 gene mutation, KIF5C gene mutation, KPRP gene mutation, MAOB gene mutation, MUC17 gene mutation, MYH10 gene mutation, OR1S1 gene mutation, PCSK2 gene mutation, PLEKHB2 gene mutation, PPM1F gene mutation, RAB40B gene mutation, RTL1 gene mutation, RYR1 gene mutation, SMARCA1 gene mutation, SNX7 gene mutation, SSX2IP gene mutation, TAS1R2 gene mutation and THUMPD2 mutation It may be at least one selected from the group consisting of mutations of genes. For example, when at least one of the survival-specific markers is detected, the individual may determine that the survival rate is lower than that of a person for which the survival-specific marker is not identified, or it may be determined that the recurrence rate is high.

The full names of the abbreviations of the genes are ACTR1B (actin related protein 1B), BPNT1 (3' (2'), 5'-bisphosphate nucleotidase 1), BRD4 (bromodomain containing 4), TSPOAP1 (TSPO associated protein 1), TMEM266, respectively. (transmembrane protein 266), C16orf72 (chromosome 16 open reading frame 72), CD1C (CD1c molecule), CEP128 (centrosomal protein 128), CIITA (class II major histocompatibility complex transactivator), COL5A1 (collagen type V alpha 1 chain), CYP51A1 (cytochrome P450 family 51 subfamily A member 1), DNAAF2 (dynein axonemal assembly factor 2), EPHB1 (EPH receptor B1), ESRP2 (epithelial splicing regulatory protein 2), FBXW9 (F-box and WD repeat domain containing 9), ITGA3 (integrin subunit alpha 3), ITGA4 (integrin subunit alpha 4), ITGA8 (integrin subunit alpha 8), KIF5C (kinesin family member 5C), KPRP (keratinocyte proline rich protein), MAOB (monoamine oxidase B), MUC17 (mucin 17) , cell surface associated), MYH10 (myosin heavy chain 10), OGFR (opioid growth factor receptor), OR1S1 (olfactory receptor family 1 subfamily S member 1 (g) ene/pseudogene)), PCBP4(poly(rC) binding protein 4), PCGF2(polycomb group ring finger 2), PCSK2(proprotein convertase subtilisin/kexin type 2), PLEKHB2(pleckstrin homology domain containing B2), PPM1F(protein phosphatase) , Mg2+/Mn2+ dependent 1F), RAB40B (RAB40B, member RAS oncogene family), RRP36 (ribosomal RNA processing 36), RTL1 (retrotransposon Gag like 1), RYR1 (ryanodine receptor 1), SMARCA1 (SWI/SNF related, matrix associated) , actin dependent regulator of chromatin, subfamily a, member 1), SNX7 (sorting nexin 7), SSX2IP (SSX family member 2 interacting protein), TAS1R2 (taste 1 receptor member 2), THUMPD2 (THUMP domain containing 2), VPS13D ( vacuolar protein sorting 13 homolog D).

In the present invention, the reagent capable of detecting the survival-specific marker may include one or more selected from the group consisting of a primer, a probe, an antibody, and an aptamer for the survival-specific marker. The primer, probe, antibody or aptamer can be manufactured using a known technique, and a primer, probe, antibody or aptamer capable of detecting a mutation of a gene of the present invention is included in the scope of the present invention.

In the present invention, the term 'primer' is a nucleic acid sequence having a short free 3' hydroxyl group, which can form a base pair with a complementary template and is a starting point for template strand copying. It refers to a short nucleic acid sequence that functions as The primers are capable of initiating DNA synthesis in the presence of reagents for the polymerization reaction (ie, DNA polymerase or reverse transcriptase) and the four different nucleoside triphosphates in appropriate buffer solutions and temperatures. In the present invention, PCR amplification is performed using the forward and reverse primers of the mutant gene to determine the presence or absence of a corresponding gene marker through the generation of a desired product, and it can be used for diagnosis. For example, in the case of a forward primer, a primer corresponding to a mutant in which deletion, substitution, or insertion has occurred is designed, and a reverse primer is designed and PCR corresponding to a position where mutation does not occur, mutation of the gene of the present invention In the case of a chain, an amplification product will be generated by PCR, but if it is not a mutant of the gene of the present invention, no amplification product will be generated. PCR conditions, forward and reverse primer lengths can be modified based on those known in the art.

In the present invention, the term 'probe' refers to a nucleic acid fragment such as RNA or DNA capable of forming a specific binding with DNA, and consists of several bases to several hundred bases as long as possible. Since the probe is labeled, the presence or absence of a specific DNA can be confirmed. The probe may be manufactured in the form of an oligonucleotide probe, a single stranded DNA probe, a double stranded DNA probe, an RNA probe, or the like. In the present invention, by performing hybridization using a probe complementary to a mutation of a gene, it is possible to diagnose whether kidney cancer recurs based on whether or not hybridization occurs. For example, when a probe corresponding to a mutant having a deletion, substitution or insertion is synthesized and the probe is hybridized with the genomic DNA of a kidney cancer patient, hybridization will occur in the case of a mutant of the gene of the present invention, but the present invention If it is not a mutant of the gene, hybridization will not occur. Selection of suitable probes and hybridization conditions can be modified based on those known in the art.

In the present invention, the term 'antibody' is a term known in the art and refers to a specific protein molecule directed against an antigenic site. In the present invention, the antibody may refer to an antibody that specifically binds to each marker gene. Such an antibody can be prepared by cloning each marker gene into an expression vector according to a conventional method to obtain a protein encoded by the marker gene, and from the obtained protein by a conventional method. This also includes a partial peptide that can be made from the protein, and the partial peptide of the present invention contains at least 7 amino acids, preferably 9 amino acids, more preferably 12 or more amino acids. The form of the antibody of the present invention is not particularly limited, and a part thereof is included in the antibody of the present invention as long as it has polyclonal antibody, monoclonal antibody, or antigen-binding property, and all immunoglobulin antibodies are included. Furthermore, the antibody of the present invention includes a special antibody such as a humanized antibody. Antibodies used for the detection of marker genes of the present invention include functional fragments of antibody molecules as well as complete forms having two full-length light chains and two full-length heavy chains. A functional fragment of an antibody molecule refers to a fragment having at least an antigen-binding function, and includes Fab, F(ab'), F(ab') ₂ and Fv.

As used herein, the term 'aptamer' refers to a single-stranded nucleic acid (DNA, RNA, or modified nucleic acid) that has a stable tertiary structure by itself and can bind to a target molecule with high affinity and specificity. Aptamers can be synthesized by known chemical methods, for example, by a method called SELEX (Systematic Evolution of Ligands of Exponential enrichment) for various target substances (proteins, sugars, dyes, DNA, metal ions, cells, etc.) You can develop aptamers.

The mutation of the gene may include any one or more mutations, for example, a truncating mutation, a missense mutation (or a missense mutation), a nonsense mutation, a frame shift. ) mutation, in-frame mutation (or in-frame mutation), splice mutation, and splice_region mutation may have at least one mutation selected from the group consisting of mutations. The frameshift mutation may be at least one of a frame shift insert (FS ins) mutation and a frame shift delete mutation (FS del). The in-frame mutation may be at least one of an in-frame insertion (IF ins) mutation and an in-frame delete (IF del) mutation.

The term "X#Y" with respect to a mutation in a polypeptide sequence is self-recognized in the art, where "#" indicates the mutation site with respect to the amino acid number of the polypeptide, and "X" is that of the wild-type amino acid sequence. indicates the amino acid found at that position, and "Y" indicates the mutant amino acid at that position. For example, the designation "G67R" with respect to an ACTR1B polypeptide indicates that glycine is present at amino acid number 67 of the wild-type ACTR1B sequence and that glycine has been replaced by arginine in the mutant ACTR1B sequence. Mutations in these genes are as follows:

The mutation of the ACTR1B gene may be a frameshift deletion mutation of H178Pfs*140, a missense mutation of G67R, or a missense mutation of G40W in the amino acid sequence of SEQ ID NO: 1. The notation method for frameshift mutations is amino acid type (amino acid position) amino acid type fs* (number of nucleotides from the amino acid position to the stop codon in the downstream direction) explanation is omitted).

The mutation of the BPNT1 gene in the amino acid sequence of SEQ ID NO: 2 is a missense mutation of Y293C, a X260_splice (substitution of nucleotides from C to G at position 220232335 of chromosome 1) splice site mutation or a frameshift insertion mutation of S296Mfs*30 can be

The mutation of the BRD4 gene may be a nonsense mutation of Q1318* or a missense mutation of E1061K in the amino acid sequence of SEQ ID NO: 3. In the nonsense mutation, * indicates that the amino acid synthesis at the corresponding amino acid position is terminated (the description is omitted below).

The mutation of the TSPOAP1 gene may be a missense mutation of L1443M or a missense mutation of R56G in the amino acid sequence of SEQ ID NO: 4.

The mutation of the TMEM266 gene may be a missense mutation of E258K in the amino acid sequence of SEQ ID NO: 5.

The mutation of the C16orf72 gene may be a missense mutation of R110Q or a missense mutation of L100H in the amino acid sequence of SEQ ID NO: 6.

The CD1C gene mutation may be a missense mutation of G125E or a frameshift insertion mutation of N179Kfs*4 in the amino acid sequence of SEQ ID NO: 7.

The mutation of the CEP128 gene may be a nonsense mutation of S400* or a frameshift deletion mutation of F722Lfs*14 in the amino acid sequence of SEQ ID NO: 8.

The mutation of the CIITA gene may be a missense mutation of M132T or a missense mutation of Q143K in the amino acid sequence of SEQ ID NO: 9.

The mutation of the COL5A1 gene is, in the amino acid sequence of SEQ ID NO: 10, a frameshift deletion mutation that is K174Rfs*6, a nonsense mutation that is E1013*, a missense mutation that is P1445S, or X1791_splice (position of nucleotides from G to C at position 137734002 on chromosome 9) substitution) may be a splice site mutation.

The mutation of the CYP51A1 gene may be a missense mutation of A80D or a missense mutation of F256L in the amino acid sequence of SEQ ID NO: 11.

The mutation of the DNAAF2 gene may be a frameshift deletion mutation of V615Efs*12 or a missense mutation of F826L in the amino acid sequence of SEQ ID NO: 12.

The mutation of the EPHB1 gene may be a missense mutation of F146Y in the amino acid sequence of SEQ ID NO: 13.

The mutation of the ESRP2 gene may be a frameshift deletion mutation of K147Rfs*41 or a missense mutation of K423R in the amino acid sequence of SEQ ID NO: 14.

The mutation of the FBXW9 gene may be a missense mutation of P4H, a missense mutation of L199M, or a missense mutation of H369Y in the amino acid sequence of SEQ ID NO: 15.

The mutation of the ITGA3 gene may be a missense mutation of Y237C in the amino acid sequence of SEQ ID NO: 16.

The mutation of the ITGA4 gene may be a missense mutation of I981T in the amino acid sequence of SEQ ID NO: 17.

The mutation of the ITGA8 gene may be a missense mutation of D399G in the amino acid sequence of SEQ ID NO: 18.

The mutation of the KIF5C gene may be a nonsense mutation of Q452* or a missense mutation of Q683K in the amino acid sequence of SEQ ID NO: 19.

The mutation of the KPRP gene may be a missense mutation of R260Q or a missense mutation of G544D in the amino acid sequence of SEQ ID NO: 20.

The mutation of the MAOB gene may be an X47_splice (substitution of nucleotides from C to G at position 43702915 of chromosome 23) splice site mutation in the amino acid sequence of SEQ ID NO: 21, a missense mutation that is G213R, or a missense mutation that is R228L .

The mutation of the MUC17 gene is, in the amino acid sequence of SEQ ID NO: 22, a missense mutation of I3060S, a missense mutation of T1508M, a missense mutation of T2279N, a missense mutation of S2868C, a missense mutation of E704G, a missense mutation of T3421I, a missense mutation that is S30C, a frameshift deletion mutation that is S30Rfs*2, an S30del in-frame deletion mutation or a missense mutation that is E1765K. In the notation method of in-frame deletion mutations, del indicates that the corresponding amino acid is deleted at the corresponding amino acid sequence position (the description is omitted below).

The mutation of the MYH10 gene may be a missense mutation that is E1353Q, a missense mutation that is K1216T, a frameshift deletion mutation that is D324Ifs*12, or a missense mutation that is F463L in the amino acid sequence of SEQ ID NO: 23.

The mutation of the OGFR gene may be a missense mutation of A50P in the amino acid sequence of SEQ ID NO: 24.

The mutation of the OR1S1 gene may be a missense mutation of G54R in the amino acid sequence of SEQ ID NO: 25.

The mutation of the PCBP4 gene may be a missense mutation of G34W or a missense mutation of G114S in the amino acid sequence of SEQ ID NO: 26.

The mutation of the PCGF2 gene may be a missense mutation of E257G or a frameshift deletion mutation of T344Rfs*43 in the amino acid sequence of SEQ ID NO: 27.

The mutation of the PCSK2 gene may be a missense mutation of L284F or a G4dup in-frame insertion mutation in the amino acid sequence of SEQ ID NO: 28.

The mutation of the PLEKHB2 gene may be a missense mutation that is V159L, a missense mutation that is L203V, or a frameshift deletion mutation that is A202Dfs*14 in the amino acid sequence of SEQ ID NO: 29.

The mutation of the PPM1F gene may be a frameshift deletion mutation of 1278Ffs*9 or a missense mutation of F194S in the amino acid sequence of SEQ ID NO: 30.

The mutation of the RAB40B gene may be a missense mutation of G37R or a missense mutation of D95V in the amino acid sequence of SEQ ID NO: 31.

The mutation of the RRP36 gene may be a missense mutation of E190D or a nonsense mutation of R17* in the amino acid sequence of SEQ ID NO: 32.

The mutation of the RTL1 gene may be, in the amino acid sequence of SEQ ID NO: 33, a frameshift deletion mutation of K923Rfs*24, a N331_E332del in-frame deletion mutation, a frameshift deletion mutation of L330Sfs*18, or a frameshift deletion mutation of L330Gfs*102. .

The mutation of the RYR1 gene is, in the amino acid sequence of SEQ ID NO: 34, a missense mutation that is S1770L, a missense mutation that is V742G, a missense mutation that is D618Y, a missense mutation that is Q4203H, a nonsense mutation that is Y694*, a missense mutation that is M3652L, or R2415Q, a missense mutation.

The mutation of the SMARCA1 gene may be a missense mutation that is L805P, a missense mutation that is K1039N, or a nonsense mutation that is Q65* in the amino acid sequence of SEQ ID NO: 35.

The mutation of the SNX7 gene may be a frameshift insertion mutation of S8Ifs*81 or a missense mutation of A62D in the amino acid sequence of SEQ ID NO: 36.

The mutation of the SSX2IP gene may be a missense mutation of S544L or a missense mutation of L432F in the amino acid sequence of SEQ ID NO: 37.

The mutation of the TAS1R2 gene may be a missense mutation of N428K or a missense mutation of M45K in the amino acid sequence of SEQ ID NO: 38.

The mutation of the THUMPD2 gene is a frameshift insertion mutation of I312Nfs*7 in the amino acid sequence of SEQ ID NO: 39, X396_splice (a nucleotide substitution from C to G at position 39964200 of chromosome 2) splice site mutation or a frame with R396Sfs*13 It may be a shift deletion mutation.

The mutation of the VPS13D gene may be a missense mutation of Y4304C or a missense mutation of E317V in the amino acid sequence of SEQ ID NO: 40.

Next generation sequencing (NGS), RT-PCR, direct nucleic acid sequencing method, and microarray can be used as an analysis method for diagnosing the prognosis of kidney cancer using the mutation of the gene. Any method that can confirm the existence of a mutation using a mutation of a gene can be applied without limitation. In one embodiment, the presence of a mutation is determined using an anti-(mutant of each gene) antibody or nucleic acid probe that hybridizes under stringent conditions to the polynucleotide of the mutant of each gene. In another embodiment, the antibody or nucleic acid probe is detectably labeled. In another embodiment, the label is selected from the group consisting of an immunofluorescent label, a chemiluminescent label, a phosphorescent label, an enzymatic label, a radioactive label, avidin/biotin, colloidal gold particles, colored particles, and magnetic particles. In another embodiment, the presence of the mutation is determined by radioimmunoassay, western blot assay, immunofluorescence assay, enzymatic immunoassay, immunoprecipitation assay, chemiluminescence assay, immunohistochemical assay, dot blot assay, slot blot assay or flow cytometry. determined by the assay. In another embodiment, the presence of the mutation is determined by RT-PCR. In another embodiment, the presence of a mutation is determined by nucleic acid sequencing.

As used herein, the term 'polynucleotide' generally refers to any polyribonucleotide or polydeoxyribonucleotide, which may be unmodified RNA or DNA or modified RNA or DNA. Thus, for example, polynucleotides as defined herein include, but are not limited to, single- and double-stranded DNA, DNA comprising single- and double-stranded regions, single- and double-stranded RNA, and single- and double-stranded DNA. - RNA comprising a region, single-stranded or more typically double-stranded, or hybrid molecule comprising DNA and RNA, which may comprise single- and double-stranded regions. Thus, DNA or RNA having a backbone that has been modified for stability or other reasons is a 'polynucleotide' as the term is intended herein. Also included in the term 'polynucleotide' as defined herein is DNA or RNA comprising an unconventional base such as inosine or a modified base such as a tritiated base. In general, the term 'polynucleotide' includes all chemically, enzymatically and/or metabolically modified forms of unmodified polynucleotides. Polynucleotides can be prepared by a variety of methods, including in vitro recombinant DNA-mediated techniques, and by expression of DNA in cells and organisms.

Another aspect of the present invention is ACTR1B gene mutation, BPNT1 gene mutation, BRD4 gene mutation, TSPOAP1 gene mutation, TMEM266 gene mutation, C16orf72 gene mutation, CD1C gene mutation, CEP128 gene mutation, CIITA gene mutation , COL5A1 gene mutation, CYP51A1 gene mutation, DNAAF2 gene mutation, EPHB1 gene mutation, ESRP2 gene mutation, FBXW9 gene mutation, ITGA3 gene mutation, ITGA4 gene mutation, ITGA8 gene mutation, KIF5C gene mutation , KPRP gene mutation, MAOB gene mutation, MUC17 gene mutation, MYH10 gene mutation, OGFR gene mutation, OR1S1 gene mutation, PCBP4 gene mutation, PCGF2 gene mutation, PCSK2 gene mutation, PLEKHB2 gene mutation , PPM1F gene mutation, RAB40B gene mutation, RRP36 gene mutation, RTL1 gene mutation, RYR1 gene mutation, SMARCA1 gene mutation, SNX7 gene mutation, SSX2IP gene mutation, TAS1R2 gene mutation, THUMPD2 gene mutation And it provides a kit for prognostic diagnosis of kidney cancer comprising a reagent capable of detecting a survival-specific marker of a kidney cancer patient comprising at least one selected from the group consisting of a mutation of the VPS13D gene.

The survival-specific marker is ACTR1B gene mutation, BPNT1 gene mutation, BRD4 gene mutation, C16orf72 gene mutation, CD1C gene mutation, CEP128 gene mutation, CIITA gene mutation, CYP51A1 gene mutation, EPHB1 gene mutation , FBXW9 gene mutation, ITGA3 gene mutation, ITGA8 gene mutation, KIF5C gene mutation, KPRP gene mutation, MAOB gene mutation, MUC17 gene mutation, MYH10 gene mutation, OR1S1 gene mutation, PCSK2 gene mutation , PLEKHB2 gene mutation, PPM1F gene mutation, RAB40B gene mutation, RTL1 gene mutation, RYR1 gene mutation, SMARCA1 gene mutation, SNX7 gene mutation, SSX2IP gene mutation, TAS1R2 gene mutation, and THUMPD2 gene mutation It may be at least one selected from the group consisting of.

For example, when at least one of the survival-specific markers is detected, the individual may determine that the survival rate is lower than that of a person for which the survival-specific marker is not identified, or it may be determined that the recurrence rate is high.

The reagent capable of detecting the survival-specific marker may include one or more selected from the group consisting of a primer, a probe, an antibody, and an aptamer, and the specific details are the same as described above, and thus a detailed description thereof will be omitted.

The kit of the present invention may be an RT-PCR kit, a DNA chip kit or a protein chip kit. As an example, the RT-PCR kit for measuring the mRNA expression level of the marker gene of the present invention may be a kit including essential elements necessary for performing RT-PCR. The RT-PCR kit contains, in addition to each primer pair specific for the marker gene, a test tube or other suitable container, reaction buffer (with varying pH and magnesium concentration), deoxynucleotides (dNTPs), Taq-polymerase and enzymes such as reverse transcriptase, DNase, RNAse inhibitors, DEPC-water, sterile water, and the like. In addition, a pair of primers specific to a gene used as a quantitative control may be included.

As another example, the DNA chip kit of the present invention may include essential elements necessary for performing a DNA chip analysis method. The DNA chip kit may include a substrate to which cDNA corresponding to a marker gene or a fragment thereof is attached as a probe, and reagents, agents, enzymes, etc. for preparing a fluorescently labeled probe. In addition, the substrate may include cDNA corresponding to a quantitative control gene or a fragment thereof.

As another example, the kit of the present invention is a protein chip kit for measuring the level of a protein expressed from the marker gene, and the kit is not particularly limited thereto, but includes a substrate, an appropriate buffer, It may include a chromogenic enzyme or a secondary antibody labeled with a fluorescent substance, a chromogenic substrate, and the like. The substrate is not particularly limited thereto, but a nitrocellulose membrane, a 96-well plate synthesized from a polyvinyl resin, a 96-well plate synthesized from a polystyrene resin, a glass slide glass, etc. may be used, and the chromogenic enzyme is not particularly limited thereto. However, peroxidase and alkaline phosphatase may be used, and the fluorescent material may be FITC, RITC, etc., but is not particularly limited thereto, and the color development substrate solution is not particularly limited thereto, but ABTS (2, 2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)) or OPD (o-phenylenediamine), TMB (tetramethyl benzidine).

In addition, the kit of the present invention may further include a buffer, an indicator, or a combination thereof as a reagent.

The kit for prognostic diagnosis of kidney cancer of the present invention is very economical because it saves time and money compared to the existing general gene mutation detection method. Using existing gene mutation detection methods such as Single Strand Conformational Polymorphism (SSCP), Protein Truncation Test (PTT), cloning, and direct sequencing, it takes several days on average to test all one gene. It takes several months. In addition, gene mutations can be precisely tested quickly and simply through next generation sequencing (NGS). When mutations are tested by conventional analysis methods such as SSCP, cloning, direct sequencing, and Restriction Fragment Length Polymorphism (RFLP), it takes about a month to complete the test, whereas using the kit of the present invention, sample DNA is prepared If it is done, results can be obtained within about 10 to 11 hours, and since a primer set capable of detecting mutations is integrated on one chip, not only time but also cost can be reduced compared to the conventional method. Compared to the conventional method, the average cost of reagents is less than half per experiment, so even greater cost savings can be expected when the researcher's labor costs are taken into account.

2. A method of providing information necessary for prognostic diagnosis of kidney cancer

Another aspect of the present invention comprises the steps of preparing a sample DNA from a sample of a renal cancer patient; It provides a method of providing information necessary for prognostic diagnosis of a renal cancer patient, comprising the step of checking the presence or absence of a survival-specific marker using the composition or kit for prognostic diagnosis of renal cancer with respect to the sample DNA.

The method may further include amplifying the sample DNA prepared from the renal cancer patient sample using a composition or kit for prognostic diagnosis of renal cancer.

The description of the 'composition and kit for prognostic diagnosis of kidney cancer' is the same as that described in ' 1. Composition for prognostic diagnosis of kidney cancer and kit including the same', and thus a detailed description thereof will be omitted.

The term 'patient' usually includes humans as well as other animals, such as other primates, rodents, dogs, cats, horses, sheep, pigs, and the like.

The term 'sample' refers to a sample of an individual or tissue in which cancer or tumor has already occurred or is expected to occur, and a target sample for diagnosing its prognosis. Specifically, it may refer to a tumor lysate or extract prepared from frozen tissue obtained from a patient with renal cancer.

The term 'subject' includes a subject diagnosed with or suspected of having kidney cancer.

The method can predict the overall survival or disease-free survival of renal cancer patients.

As used herein, the term 'overall survival (OS)' includes a clinical endpoint describing a patient who is alive for a finite time after being diagnosed with or treated for a disease, such as cancer, regardless of whether the cancer recurs or not. means the possibility of surviving.

In the present invention, the term 'disease-free survival (DFS)' includes a period in which a patient survives without cancer recurrence after treatment for a specific disease (eg, cancer).

According to the present invention, by confirming the presence of a mutation in the gene of the present invention in a sample of a kidney cancer patient, it is possible to predict what prognosis an individual having the target sample has for cancer. This method can also be achieved by comparing the total survival or disease-free survival of subjects in a control group that does not have a mutation known to have a good prognosis. In the present invention, an individual known to have a good prognosis means an individual without a history of metastasis, recurrence, death, etc. after cancer has developed.

The survival-specific marker is ACTR1B gene mutation, BPNT1 gene mutation, BRD4 gene mutation, TSPOAP1 gene mutation, TMEM266 gene mutation, C16orf72 gene mutation, CD1C gene mutation, CEP128 gene mutation, CIITA gene mutation , COL5A1 gene mutation, CYP51A1 gene mutation, DNAAF2 gene mutation, EPHB1 gene mutation, ESRP2 gene mutation, FBXW9 gene mutation, ITGA3 gene mutation, ITGA4 gene mutation, ITGA8 gene mutation, KIF5C gene mutation , KPRP gene mutation, MAOB gene mutation, MUC17 gene mutation, MYH10 gene mutation, OGFR gene mutation, OR1S1 gene mutation, PCBP4 gene mutation, PCGF2 gene mutation, PCSK2 gene mutation, PLEKHB2 gene mutation , PPM1F gene mutation, RAB40B gene mutation, RRP36 gene mutation, RTL1 gene mutation, RYR1 gene mutation, SMARCA1 gene mutation, SNX7 gene mutation, SSX2IP gene mutation, TAS1R2 gene mutation, THUMPD2 gene mutation And it may include at least one selected from the group consisting of a mutation of the VPS13D gene.

The survival-specific marker is ACTR1B gene mutation, BPNT1 gene mutation, BRD4 gene mutation, C16orf72 gene mutation, CD1C gene mutation, CEP128 gene mutation, CIITA gene mutation, CYP51A1 gene mutation, EPHB1 gene mutation , FBXW9 gene mutation, ITGA3 gene mutation, ITGA8 gene mutation, KIF5C gene mutation, KPRP gene mutation, MAOB gene mutation, MUC17 gene mutation, MYH10 gene mutation, OR1S1 gene mutation, PCSK2 gene mutation , PLEKHB2 gene mutation, PPM1F gene mutation, RAB40B gene mutation, RTL1 gene mutation, RYR1 gene mutation, SMARCA1 gene mutation, SNX7 gene mutation, SSX2IP gene mutation, TAS1R2 gene mutation, and THUMPD2 gene mutation It may be at least one selected from the group consisting of.

The method of providing information necessary for prognostic diagnosis of the renal cancer patient may predict the total survival rate or disease-free survival rate of the renal cancer patient. For example, the method may include, when the survival-specific marker is identified, determining that the survival rate is lower than that of a person whose survival-specific marker is not identified. Or vice versa.

In addition, the method may include; when the survival-specific marker is identified, determining that the recurrence rate of kidney cancer is higher than that of a person for which the survival-specific marker is not identified. Or vice versa.

As such, the mutants of the genes of the present invention, ACTR1B, BPNT1, BRD4, TSPOAP1, TMEM266, C16orf72, CD1C, CEP128, CIITA, CYP51A1, EPHB1, FBXW9, ITGA3, ITGA8, KIF5C, KPRP, MAOB, MUC17, MYH, PCSK2, PLEKHB2, PPM1F, RAB40B, RTL1, RYR1, SMARCA1, SNX7, SSX2IP, TAS1R2 and THUMPD2 Using a mutation of at least one gene selected from the gene group consisting of Nothing has been revealed about it as of yet. In addition, it has not been reported that the total survival rate or disease-free survival rate may be different for each gene. The present inventors have identified for the first time that the mutation of the above genes can be used as a diagnostic marker for predicting the difference in therapeutic effect of kidney cancer patients or diagnosing the prognosis of kidney cancer patients.

The method of providing information necessary for predicting the difference in the therapeutic effect of renal cancer patients of the present invention can be used to diagnose gene mutations in kidney cancer, to increase the survival rate of kidney cancer patients, or to lower the recurrence rate. Through the method for prognostic diagnosis of renal cancer of the present invention, it is possible to predict the therapeutic effect of renal cancer, or the survival rate or recurrence rate of renal cancer patients, using information on the occurrence of mutations in the gene of renal cancer, so a therapeutic agent suitable for each patient It can provide information not only in the discovery but also in the selection of treatments, so that it is possible to efficiently design a therapeutic strategy for kidney cancer.

Hereinafter, the present invention will be described in detail by way of Examples and Experimental Examples.

However, the following examples and experimental examples are only for illustrating the present invention, and the content of the present invention is not limited by the following examples and experimental examples.

Example

Securing genetic and clinical information

In order to derive a survival-specific marker for diagnosing the prognosis of kidney cancer, recurrence, metastasis, death, and observation time of 291 patients with papillary renal cancer who have both genetic and clinical information from The Cancer Genome Atlas (TCGA). Data were obtained and used for analysis. Table 1 below shows data on the gender and survival of patients with papillary renal cancer.

number of patients ratio(%) gender male 214 73.5 female 77 26.5 survival O 247 84.9 X 44 15.1 Sum 291 100

Selection of genes relevant to survival

For the data of the 291 people, divided into two groups of survival (S0)/death (S1) according to the presence or absence of survival, and machine learning was performed with three Feature Selection (Information Gain, Chi-Square, MR) methods, The following 47 genes were derived that were survival-related:

ABCB1, ACTR1B, ATP6V0A1, BPNT1, BRD4, TSPOAP1, TMEM266, C16orf72, CD1C, CEP128, CIITA, COL5A1, CPEB3, CYP51A1, DNA ITAF2, EPHB1, ESRP2, FBXW9, ITRPGA8, KIF5C, KPUC17, ITRPGA8, MYH10, OGFR, OR1S1, PCBP4, PCGF2, PCSK2, PLEKHB2, PPM1F, RAB40B, RBP5, RRP36, RTL1, RYR1, SLC36A3, SMARCA1, SNX7, SSX2IP, TAS1R2, THOC1, THUMPD2, USP3, VPS13.

Screening and review of survival-specific markers for prognosis

The present inventors performed comparative analysis on the data of the 291 subject patients in order to confirm the applicability as a survival-specific marker for 47 genes related to survival, missing values, specificity values were excluded.

Based on the clinical information (event (death or recurrence), observation time) of the patients, overall survival or disease-free survival was calculated by Kaplan Meier survival analysis using SPSS. In the total survival period, the event was defined as death, and in the disease-free survival period, the event was defined as the recurrence of renal cancer. In order to determine whether the occurrence of mutations in each of the genes is correlated with death or recurrence of kidney cancer, based on the event time of each group obtained in the Kaplan Meier survival assay, The association of total survival and the association of mutagenesis and disease-free survival were confirmed by log rank test. A p-value of less than 0.05 was considered statistically significant.

The experimental group was defined as the case with alterations in query gene, and the control group was the case without alterations in query gene. The median months survival means a value located at the center when the survival periods of patients in the corresponding group are listed. The slope in the survival curve by the Kaplan Meier survival assay is determined by the duration of survival. The p values of the analysis results are specifically shown in Table 2 below.

number of mutations Mutation (%) Cyto band Mutation type Total survival (p-value) Disease-free survival (p-value) cut missense in-frame ABCB1 2 0.72 7q21.12 0 2 0 0.0716 null ACTR1B 3 1.08 2q11.2 One 2 0 0.00359 0.00343 ATP6V0A1 2 0.72 17q21.2 One One 0 0.0753 null BPNT1 2 0.72 1q41 2 0 0 0.0118 0 BRD4 2 0.72 19p13.12 One One 0 0.0218 0.0156 TSPOAP1 2 0.72 17q22 0 2 0 0.00337 null TMEM266 One 0.36 15q24.2 0 One 0 0.0195 null C16orf72 2 0.72 16p13.2 0 2 0 0.00184 5.22E-15 CD1C 2 0.72 1q23.1 One One 0 0.0185 0.00191 CEP128 2 0.72 14q31.1 2 0 0 0.019 3.21E-10 CIITA 2 0.72 16p13.13 0 2 0 2.18E-06 0.000102 COL5A1 4 1.44 9q34.3 3 One 0 0.000778 0.712 CPEB3 One 0.36 10q23.32 0 One 0 0.152 null CYP51A1 2 0.72 7q21.2 0 2 0 0.00163 0 DNAAF2 2 0.72 14q21.3 One One 0 0.00143 null EPHB1 One 0.36 3q22.2 0 One 0 0.005 0.00468 ESRP2 2 0.72 16q22.1 One One 0 0.0175 null FBXW9 3 1.08 19p13.13 0 3 0 0.0000685 0.0000333 ITGA3 One 0.36 17q21.33 0 One 0 4.42E-07 5.08E-07 ITGA4 One 0.36 2q31.3 0 One 0 6.45E-06 null ITGA8 One 0.36 10p13 0 One 0 4.42E-07 5.08E-07 KIF5C 2 0.72 2q23.1-q23.2 One One 0 0.000146 0.000195 KPRP 2 0.72 1q21.3 0 2 0 3.62E-08 1.12E-09 MAOB 2 0.72 Xp11.3 One One 0 0.0000594 0.000642 MUC17 9 3.24 7q22.1 One 8 0 1.83E-06 0.000195 MYH10 4 0.72 17p13.1 One 3 0 0.0000734 3.02E-06 OGFR One 0.36 20q13.33 0 One 0 0.000614 null OR1S1 One 0.36 11q12.1 0 One 0 0.0000177 0.00133 PCBP4 2 0.72 3p21.2 0 2 0 0.0275 null PCGF2 2 0.72 17q12 One One 0 0.0457 0.14 PCSK2 2 0.72 20p12.1 0 One One 0.0111 0.00191 PLEKHB2 2 0.72 2q21.1 One One 0 0.00174 2.21E-06 PPM1F 2 0.72 22q11.22 One One 0 0.000179 7.47E-06 RAB40B 2 0.72 17q25.3 0 2 0 0.000166 0 RBP5 2 0.72 12p13.31 One One 0 0.0775 null RRP36 2 0.72 6p21.1 One One 0 0.00633 0.0529 RTL1 2 0.72 14q32.2 2 0 0 7.48E-08 0.00468 RYR1 7 2.52 19q13.2 One 6 0 0.00065 0.0346 SLC36A3 One 0.36 5q33.1 One 0 0 0.13 null SMARCA1 3 1.08 Xq25-q26.1 One 2 0 4.25E-09 1.97E-12 SNX7 2 0.72 1p21.3 One One 0 0.000412 0.000102 SSX2IP 2 0.72 1p22.3 0 2 0 4.80E-10 0 TAS1R2 2 0.72 1p36.13 0 2 0 3.95E-12 0.000342 THOC1 2 0.72 18p11.32 One One 0 0.0625 null THUMPD2 2 0.72 2p22.1; 2p22-p21 2 0 0 0.0000227 3.59E-14 USP3 2 0.72 15q22.31 0 2 0 0.13 null VPS13D 2 0.72 1p36.22-p36.21 0 2 0 0.0457 0.14

Among the genes in Table 2, the following 7 genes have p values of over 0.05 or null values of overall survival and disease free survival, indicating that the correlation with total survival or recurrence is low. It is judged:

ABCB1, ATP6V0A1, CPEB3, RBP5, SLC36A3, THOC1, USP3.

In addition, the following 40 genes (candidate gene group 1) have a p-value of less than 0.05 for total survival or disease-free survival, and are considered genes highly correlated with survival or recurrence rates. Specifically, if there is a mutation in the gene, the survival rate It is judged to be low or the recurrence rate is high.

Candidate gene group 1: ACTR1B, BPNT1, BRD4, TSPOAP1, TMEM266, C16orf72, CD1C, CEP128, CIITA, COL5A1, CYP51A1, DNAAF2, EPHB1, ESRP2, FBXW9, ITGA3, ITGA4, ITGA8, KIPIF5C MYH10, OGFR, OR1S1, PCBP4, PCGF2, PCSK2, PLEKHB2, PPM1F, RAB40B, RRP36, RTL1, RYR1, SMARCA1, SNX7, SSX2IP, TAS1R2, THUMPD2, VPS13D.

In addition, among the first group of candidate genes, when there were mutations in the following 29 genes (candidate gene group 2), the survival rate was low, and the recurrence rate of kidney cancer was high or the disease-free survival period was short.

Candidate gene group 2: ACTR1B, BPNT1, BRD4, C16orf72, CD1C, CEP128, CIITA, CYP51A1, EPHB1, FBXW9, ITGA3, ITGA8, KIF5C, KPRP, MAOB, MUC17, MYH10, OR1S1, PCSK2, PPM1F RTL1, RYR1, SMARCA1, SNX7, SSX2IP, TAS1R2, THUMPD2.

1 to 40 show, for each gene of the first group of candidate genes, the total survival rate and/or of a kidney cancer patient having a mutation in the corresponding gene (red) and a kidney cancer patient without a mutation in the corresponding gene (blue) A graph of disease-free survival is shown.

Specifically, the data of FIGS. 1 to 40 are as follows:

ACTR1B, as can be seen in (A) of FIG. 1 , in the case of kidney cancer patients in which the ACTR1B gene mutation did not occur, approximately 86% survived (blue), whereas the ACTR1B gene mutation occurred kidney cancer patients. Because 100% of the patients died, it was confirmed that the survival rate was lower than that of renal cancer patients without mutation (red). According to (B) of FIG. 1 , in the case of kidney cancer patients in which the ACTR1B gene mutation did not occur, approximately 82% of the patients had no recurrence for more than 100 months (blue), but if there was a mutation in the ACTR1B gene, 100% recurrence occurred in less than 20 months appeared (red). Therefore, when there is a mutation in the ACTR1B gene, the probability of death or recurrence due to kidney cancer increases, so it can be seen that the mutation in the ACTR1B gene is significant as a predictive marker for the survival rate of kidney cancer patients or recurrence of kidney cancer.

As can be seen from (A) of FIG. 2 , BPNT1 is a kidney cancer patient with a mutation in the BPNT1 gene, whereas approximately 86% of patients with kidney cancer in which the BPNT1 gene is not mutated survive (blue). Because 100% of the patients died, it was confirmed that the survival rate was lower than that of renal cancer patients without mutation (red). According to (B) of Figure 2, in the case of kidney cancer patients in which the mutation in the BPNT1 gene did not occur, approximately 82% of the patients had no recurrence for more than 100 months (blue), but if there was a mutation in the BPNT1 gene, 100% recurrence in less than 1 month appeared (red). Therefore, when there is a mutation in the BPNT1 gene, the probability of death or recurrence due to kidney cancer increases, so it can be seen that the mutation of the BPNT1 gene is significant as a predictive marker for the survival rate of kidney cancer patients or recurrence of kidney cancer.

As can be seen from (A) of FIG. 3 , in the case of renal cancer patients in which the BRD4 gene is not mutated, approximately 86% of the patients with BRD4 survived (blue), whereas the renal cancer patients in which the BRD4 gene is mutated. Because 100% of the patients died, it was confirmed that the survival rate was lower than that of renal cancer patients without mutation (red). According to (B) of FIG. 3 , in the case of kidney cancer patients in which the mutation in the BRD4 gene did not occur, approximately 82% did not have recurrence for more than 100 months (blue), but if there was a mutation in the BRD4 gene, 100% recurrence was not achieved within 24 months. appeared (red). Therefore, when there is a mutation in the BRD4 gene, the probability of death or recurrence due to kidney cancer increases, so it can be seen that the mutation of the BRD4 gene is significant as a predictive marker for the survival rate of kidney cancer patients or recurrence of kidney cancer.

As can be seen from FIG. 4 , TSPOAP1 is approximately 86% of patients with renal cancer in which the TSPOAP1 gene is not mutated (blue), whereas 100% of patients with renal cancer in which the TSPOAP1 gene is mutated survive. Because he died, it was confirmed that the survival rate was lower than that of the renal cancer patient without the mutation (red). Therefore, it can be seen that the mutation of the TSPOAP1 gene is significant as a marker for predicting the survival rate of renal cancer patients.

As can be seen from FIG. 5, in TMEM266, approximately 85% of kidney cancer patients with no mutation in the TMEM266 gene survived (blue), whereas 100% of kidney cancer patients with a mutation in the TMEM266 gene. Because he died, it was confirmed that the survival rate was lower than that of the renal cancer patient without the mutation (red). Therefore, it can be seen that the mutation of the TMEM266 gene is significant as a marker for predicting the survival rate of renal cancer patients.

As can be seen from (A) of FIG. 6, about 86% of C16orf72 kidney cancer patients in which the C16orf72 gene mutation did not occur survived (blue), whereas the C16orf72 gene mutation occurred kidney cancer patients. Because 100% of the patients died, it was confirmed that the survival rate was lower than that of renal cancer patients without mutation (red). According to (B) of Figure 6, in the case of kidney cancer patients in which the mutation in the C16orf72 gene did not occur, approximately 82% did not have recurrence for more than 100 months (blue), but if there was a mutation in the C16orf72 gene, 100% recurrence occurred in less than 2 months appeared (red). Therefore, when there is a mutation in the C16orf72 gene, the probability of death or recurrence due to kidney cancer increases, so it can be seen that the mutation in the C16orf72 gene is significant as a predictive marker for the survival rate of kidney cancer patients or recurrence of kidney cancer.

As can be seen from (A) of FIG. 7, about 86% of CD1C patients with kidney cancer without mutation in the CD1C gene survived (blue), whereas kidney cancer patients with mutation in the CD1C gene. Because 100% of the patients died, it was confirmed that the survival rate was lower than that of renal cancer patients without mutation (red). According to (B) of FIG. 7 , in the case of kidney cancer patients in which the CD1C gene mutation did not occur, approximately 82% had no recurrence for more than 100 months (blue). appeared (red). Therefore, it can be seen that the CD1C gene mutation is significant as a predictive marker for the survival rate of kidney cancer patients or recurrence of kidney cancer because the probability of death or recurrence due to kidney cancer increases when there is a mutation in the CD1C gene.

As can be seen from (A) of FIG. 8 , in the case of kidney cancer patients in which the CEP128 gene is not mutated, approximately 86% of CEP128 survives (blue), whereas the CEP128 gene is mutated in kidney cancer patients. Because 100% of the patients died, it was confirmed that the survival rate was lower than that of renal cancer patients without mutation (red). According to (B) of Figure 8, in the case of kidney cancer patients in which the mutation in the CEP128 gene did not occur, approximately 82% had no recurrence for more than 100 months (blue). appeared (red). Therefore, when there is a mutation in the CEP128 gene, the probability of death or recurrence due to kidney cancer increases, so it can be seen that the mutation of the CEP128 gene is significant as a predictive marker for the survival rate of kidney cancer patients or recurrence of kidney cancer.

As can be seen from (A) of FIG. 9 , CIITA is a kidney cancer patient with a mutation in the CIITA gene, whereas approximately 86% of patients with kidney cancer in which the CIITA gene is not mutated survive (blue). Because 100% of the patients died, it was confirmed that the survival rate was lower than that of renal cancer patients without mutation (red). According to (B) of FIG. 9 , in the case of kidney cancer patients in which the mutation in the CIITA gene did not occur, approximately 82% did not have recurrence for more than 100 months (blue), but if there was a mutation in the CIITA gene, 100% recurrence was less than 7 months appeared (red). Therefore, when there is a mutation in the CIITA gene, the probability of death or recurrence due to kidney cancer increases, so it can be seen that the mutation in the CIITA gene is significant as a predictive marker for the survival rate of kidney cancer patients or recurrence of kidney cancer.

As can be seen in FIG. 10, about 86% of COL5A1 kidney cancer patients without mutation in the COL5A1 gene survived (blue), whereas 75% of kidney cancer patients with a mutation in the COL5A1 gene survived. Since he died within 36 months, it was confirmed that the survival rate was lower than that of patients with non-mutated kidney cancer (red). Therefore, it can be seen that the mutation of the COL5A1 gene is significant as a marker for predicting the survival rate of renal cancer patients.

As can be seen from (A) of FIG. 11 , CYP51A1 survives approximately 86% of kidney cancer patients in which the CYP51A1 gene is not mutated (blue), whereas renal cancer patients in which the CYP51A1 gene mutation occurs. Because 100% of the patients died, it was confirmed that the survival rate was lower than that of renal cancer patients without mutation (red). According to (B) of Figure 11, in the case of kidney cancer patients in which the mutation in the CYP51A1 gene did not occur, approximately 82% of patients had no recurrence for more than 100 months (blue). appeared (red). Therefore, when there is a mutation in the CYP51A1 gene, the probability of death or recurrence due to kidney cancer increases, so it can be seen that the mutation of the CYP51A1 gene is significant as a predictive marker for the survival rate of kidney cancer patients or recurrence of kidney cancer.

As can be seen from FIG. 12, in the case of kidney cancer patients with no mutation in the DNAAF2 gene, approximately 86% of DNAAF2 survived (blue), whereas 100% of kidney cancer patients with mutation in the DNAAF2 gene survived. Because he died, it was confirmed that the survival rate was lower than that of the renal cancer patient without the mutation (red). Therefore, it can be seen that the mutation of the DNAAF2 gene is significant as a marker for predicting the survival rate of renal cancer patients.

As can be seen from (A) of FIG. 13 , in the case of kidney cancer patients in which the EPHB1 gene is not mutated, approximately 86% of EPHB1 survives (blue), whereas the EPHB1 gene is mutated in kidney cancer patients. Because 100% of the patients died, it was confirmed that the survival rate was lower than that of renal cancer patients without mutation (red). According to (B) of FIG. 13 , in the case of kidney cancer patients in which the mutation in the EPHB1 gene did not occur, approximately 82% did not have recurrence for more than 100 months (blue), but if there was a mutation in the EPHB1 gene, 100% recurrence occurred in less than 12 months appeared (red). Therefore, when there is a mutation in the EPHB1 gene, the probability of death or recurrence due to kidney cancer increases. Therefore, it can be seen that the mutation of the EPHB1 gene is significant as a predictive marker for the survival rate of kidney cancer patients or recurrence of kidney cancer.

As can be seen from FIG. 14 , ESRP2 is approximately 86% of renal cancer patients in which the ESRP2 gene is not mutated (blue), whereas 100% of renal cancer patients in which the ESRP2 gene is mutated survive. Because he died, it was confirmed that the survival rate was lower than that of the renal cancer patient without the mutation (red). Therefore, it can be seen that the mutation of the ESRP2 gene is significant as a marker for predicting the survival rate of renal cancer patients.

As can be seen from (A) of FIG. 15 , in the case of kidney cancer patients in which the FBXW9 gene is not mutated, approximately 86% of FBXW9 survived (blue), whereas the FBXW9 gene mutated kidney cancer patients survived (blue). Because 100% of the patients died, it was confirmed that the survival rate was lower than that of renal cancer patients without mutation (red). According to (B) of Figure 15, in the case of kidney cancer patients in which the mutation in the FBXW9 gene did not occur, approximately 82% did not have a recurrence for more than 100 months (blue), but if there is a mutation in the FBXW9 gene, 100% recurrence is less than 17 months appeared (red). Therefore, when there is a mutation in the FBXW9 gene, the probability of death or recurrence due to kidney cancer increases, so it can be seen that the mutation of the FBXW9 gene is significant as a survival rate of kidney cancer patients or a predictive marker of kidney cancer recurrence.

As can be seen from (A) of FIG. 16, in the case of kidney cancer patients in which the ITGA3 gene mutation did not occur, about 86% of ITGA3 survived (blue), whereas the ITGA3 gene mutation occurred kidney cancer patients. Because 100% of the patients died, it was confirmed that the survival rate was lower than that of renal cancer patients without mutation (red). According to (B) of Figure 16, in the case of kidney cancer patients in which the mutation in the ITGA3 gene did not occur, approximately 82% of the patients had no recurrence for more than 100 months (blue), but if there was a mutation in the ITGA3 gene, 100% recurrence occurred in less than 4 months. appeared (red). Therefore, when there is a mutation in the ITGA3 gene, the probability of death or recurrence due to kidney cancer increases, so it can be seen that the mutation in the ITGA3 gene is significant as a predictive marker for the survival rate of kidney cancer patients or recurrence of kidney cancer.

As can be seen from FIG. 17, in the case of kidney cancer patients in which the ITGA4 gene mutation does not occur, approximately 86% of ITGA4 survives (blue), whereas 100% of the kidney cancer patients in which the ITGA4 gene mutation occurs. Because he died, it was confirmed that the survival rate was lower than that of the renal cancer patient without the mutation (red). Therefore, it can be seen that the mutation of the ITGA4 gene is significant as a marker for predicting the survival rate of renal cancer patients.

As can be seen from (A) of FIG. 18, in the case of kidney cancer patients in which the ITGA8 gene mutation did not occur, about 86% of ITGA8 survived (blue), whereas the ITGA8 gene mutation occurred in kidney cancer patients. Because 100% of the patients died, it was confirmed that the survival rate was lower than that of renal cancer patients without mutation (red). According to (B) of FIG. 18 , in the case of kidney cancer patients in which the mutation in the ITGA8 gene did not occur, approximately 82% did not have recurrence for more than 100 months (blue), but if there was a mutation in the ITGA8 gene, 100% recurrence occurred in less than 4 months appeared (red). Therefore, when there is a mutation in the ITGA8 gene, the probability of death or recurrence due to kidney cancer increases, so it can be seen that the mutation of the ITGA8 gene is significant as a predictive marker for the survival rate of kidney cancer patients or recurrence of kidney cancer.

As can be seen from (A) of FIG. 19(A) in KIF5C, approximately 86% of kidney cancer patients in which the KIF5C gene mutation did not occur survived (blue), whereas the kidney cancer patients in which the KIF5C gene mutation occurred. Because 100% of the patients died, it was confirmed that the survival rate was lower than that of renal cancer patients without mutation (red). According to (B) of FIG. 19 , in the case of kidney cancer patients in which the mutation in the KIF5C gene did not occur, approximately 82% had no recurrence for more than 100 months (blue), but if there was a mutation in the KIF5C gene, there was a 100% recurrence in less than 7 months. appeared (red). Therefore, when there is a mutation in the KIF5C gene, the probability of death or recurrence due to kidney cancer increases, so it can be seen that the mutation in the KIF5C gene is significant as a predictive marker for the survival rate of kidney cancer patients or recurrence of kidney cancer.

As can be seen from (A) of FIG. 20, in the case of kidney cancer patients in which the KPRP gene mutation does not occur, approximately 86% of KPRP survives (blue), whereas the KPRP gene mutation occurs in kidney cancer patients. Because 100% of the patients died, it was confirmed that the survival rate was lower than that of renal cancer patients without mutation (red). According to (B) of Figure 20, in the case of kidney cancer patients in which the mutation in the KPRP gene did not occur, approximately 82% did not have recurrence for more than 100 months (blue), but if there was a mutation in the KPRP gene, 100% recurrence occurred in less than 2 months appeared (red). Therefore, when there is a mutation in the KPRP gene, the probability of death or recurrence due to kidney cancer increases, so it can be seen that the mutation in the KPRP gene is significant as a predictive marker for the survival rate of kidney cancer patients or recurrence of kidney cancer.

As can be seen from (A) of FIG. 21 , in the case of kidney cancer patients in which the MAOB gene is not mutated, approximately 86% survived (blue), whereas the MAOB gene mutation occurred in kidney cancer patients. Because 100% of the patients died, it was confirmed that the survival rate was lower than that of renal cancer patients without mutation (red). According to (B) of FIG. 21 , in the case of kidney cancer patients in which the MAOB gene mutation did not occur, approximately 82% had no recurrence for more than 100 months (blue), but if there was a mutation in the MAOB gene, 100% recurrence occurred in less than 5 months appeared (red). Therefore, when there is a mutation in the MAOB gene, the probability of death or recurrence due to kidney cancer increases, so it can be seen that the mutation in the MAOB gene is significant as a predictive marker for the survival rate of kidney cancer patients or recurrence of kidney cancer.

As can be seen from (A) of FIG. 22 , MUC17 is approximately 87% of patients with renal cancer in which the MUC17 gene is not mutated (blue), whereas renal cancer patients in which the MUC17 gene is mutated. was confirmed that the survival rate was lower than that of renal cancer patients without mutations because more than 50% of the patients died (red). According to (B) of FIG. 22 , in the case of kidney cancer patients in which the MUC17 gene mutation did not occur, approximately 83% had no recurrence for more than 100 months (blue), but if there was a mutation in the MUC17 gene, it was less than 26 months and more than 50% appeared to recur (red). Therefore, when there is a mutation in the MUC17 gene, the probability of death or recurrence due to kidney cancer increases. Therefore, it can be seen that the mutation of the MUC17 gene is significant as a predictive marker for the survival rate of kidney cancer patients or recurrence of kidney cancer.

As can be seen from (A) of FIG. 23 , MYH10 is approximately 86% of patients with renal cancer in which the MYH10 gene is not mutated (blue), whereas renal cancer patients in which the MYH10 gene is mutated. As 75% of the patients died, it was confirmed that the survival rate was lower than that of patients with non-mutated kidney cancer (red). According to (B) of FIG. 23 , in the case of kidney cancer patients in which the mutation in the MYH10 gene did not occur, approximately 82% had no recurrence for more than 100 months (blue), but if there was a mutation in the MYH10 gene, 75% recurrence occurred in less than 2 months appeared (red). Therefore, when there is a mutation in the MYH10 gene, the probability of death or recurrence due to kidney cancer increases. Therefore, it can be seen that the mutation in the MYH10 gene is significant as a predictive marker for the survival rate of kidney cancer patients or recurrence of kidney cancer.

As can be seen in FIG. 24 , OGFR is approximately 86% of patients with kidney cancer in which the mutation in the OGFR gene does not occur (blue), whereas 100% of patients with kidney cancer in which the mutation in the OGFR gene occurs. Because he died, it was confirmed that the survival rate was lower than that of the renal cancer patient without the mutation (red). Therefore, it can be seen that the mutation of the OGFR gene is significant as a marker for predicting the survival rate of renal cancer patients.

As can be seen from (A) of FIG. 25, OR1S1 is a kidney cancer patient with a mutation in the OR1S1 gene, whereas approximately 86% of patients with kidney cancer in which the OR1S1 gene is not mutated survive (blue). Because 100% of the patients died, it was confirmed that the survival rate was lower than that of renal cancer patients without mutation (red). According to (B) of Figure 25, in the case of kidney cancer patients in which the mutation in the OR1S1 gene did not occur, approximately 82% did not have recurrence for more than 100 months (blue), but if there is a mutation in the OR1S1 gene, 100% recurrence occurred in less than 10 months appeared (red). Therefore, when there is a mutation in the OR1S1 gene, the probability of death or recurrence due to kidney cancer increases, so it can be seen that the mutation of the OR1S1 gene is significant as a predictive marker for the survival rate of kidney cancer patients or recurrence of kidney cancer.

As can be seen in FIG. 26 , in the case of kidney cancer patients in which the PCBP4 gene is not mutated, approximately 86% survive (blue), whereas 100% of the kidney cancer patients in which the PCBP4 gene is mutated survive. Because he died, it was confirmed that the survival rate was lower than that of the renal cancer patient without the mutation (red). It can be seen that the mutation of the PCBP4 gene is significant as a predictive marker for the survival rate of renal cancer patients.

As can be seen from FIG. 27, PCGF2 survives in approximately 86% of renal cancer patients in which the PCGF2 gene is not mutated (blue), whereas 100% in renal cancer patients in which the PCGF2 gene is mutated. Because he died, it was confirmed that the survival rate was lower than that of the renal cancer patient without the mutation (red). It can be seen that the mutation of the PCGF2 gene is significant as a marker for predicting the survival rate of renal cancer patients.

As can be seen from (A) of FIG. 28, PCSK2 is a renal cancer patient with a mutation in the PCSK2 gene, whereas approximately 86% of patients with renal cancer in which the PCSK2 gene is not mutated survive (blue). Because 100% of the patients died, it was confirmed that the survival rate was lower than that of renal cancer patients without mutation (red). According to (B) of Figure 28, in the case of kidney cancer patients in which the mutation in the PCSK2 gene did not occur, approximately 82% had no recurrence for more than 100 months (blue). appeared (red). Therefore, when there is a mutation in the PCSK2 gene, the probability of death or recurrence due to kidney cancer increases. Therefore, it can be seen that the mutation of the PCSK2 gene is significant as a predictive marker for the survival rate of kidney cancer patients or recurrence of kidney cancer.

As can be seen from (A) of FIG. 29 , PLEKHB2 is about 86% of patients with kidney cancer in which the PLEKHB2 gene is not mutated (blue), whereas kidney cancer patients in which the PLEKHB2 gene is mutated. Because 100% of the patients died, it was confirmed that the survival rate was lower than that of renal cancer patients without mutation (red). According to (B) of Figure 29, in the case of kidney cancer patients in which the mutation in the PLEKHB2 gene did not occur, approximately 82% did not have recurrence for more than 100 months (blue), but if there was a mutation in the PLEKHB2 gene, 100% recurrence was less than 4 months appeared to be (red). Therefore, when there is a mutation in the PLEKHB2 gene, the probability of death or recurrence due to kidney cancer increases. Therefore, it can be seen that the mutation of the PLEKHB2 gene is significant as a predictive marker for the survival rate of kidney cancer patients or recurrence of kidney cancer.

As can be seen from (A) of FIG. 30 , in the case of renal cancer patients in which the PPM1F gene is not mutated, approximately 86% of PPM1F survives (blue), whereas the PPM1F gene is mutated in renal cancer patients. Because 100% of the patients died, it was confirmed that the survival rate was lower than that of renal cancer patients without mutation (red). According to (B) of Figure 30, in the case of kidney cancer patients in which the mutation in the PPM1F gene did not occur, approximately 82% of the patients had no recurrence for more than 100 months (blue), but if there was a mutation in the PPM1F gene, 100% recurrence in less than 5 months appeared (red). Therefore, when there is a mutation in the PPM1F gene, the probability of death or recurrence due to kidney cancer increases. Therefore, it can be seen that the mutation in the PPM1F gene is significant as a predictive marker for the survival rate of kidney cancer patients or recurrence of kidney cancer.

As can be seen from (A) of FIG. 31 (A), RAB40B is approximately 86% of patients with renal cancer in which the RAB40B gene is not mutated (blue), whereas renal cancer patients in which the RAB40B gene is mutated (blue). Because 100% of the patients died, it was confirmed that the survival rate was lower than that of renal cancer patients without mutation (red). According to (B) of Figure 31, in the case of kidney cancer patients in which the mutation in the RAB40B gene did not occur, approximately 82% did not have a recurrence for more than 100 months (blue), but if there is a mutation in the RAB40B gene, 100% recurrence in less than 1 month appeared (red). Therefore, when there is a mutation in the RAB40B gene, the probability of death or recurrence due to kidney cancer increases, so it can be seen that the mutation in the RAB40B gene is significant as a predictive marker for the survival rate of kidney cancer patients or recurrence of kidney cancer.

As can be seen from FIG. 32, in the case of kidney cancer patients in which the RRP36 gene mutation does not occur, approximately 86% of RRP36 survives (blue), whereas 100% of the kidney cancer patients in which the RRP36 gene mutation occurs. Because he died, it was confirmed that the survival rate was lower than that of the renal cancer patient without the mutation (red). It can be seen that the mutation of the RRP36 gene is significant as a marker for predicting the survival rate of renal cancer patients.

As can be seen from (A) of FIG. 33 , in the case of kidney cancer patients in which the RTL1 gene is not mutated, approximately 86% of RTL1 survives (blue), whereas the RTL1 gene is mutated in kidney cancer patients. Because 100% of the patients died, it was confirmed that the survival rate was lower than that of renal cancer patients without mutation (red). According to (B) of Figure 33, in the case of kidney cancer patients in which the mutation in the RTL1 gene did not occur, approximately 82% of the patients did not have a recurrence for more than 100 months (blue), but if there is a mutation in the RTL1 gene, 100% recurrence is less than 12 months appeared (red). Therefore, when there is a mutation in the RTL1 gene, the probability of death or recurrence due to kidney cancer increases. Therefore, it can be seen that the mutation in the RTL1 gene is significant as a predictive marker for the survival rate of kidney cancer patients or recurrence of kidney cancer.

As can be seen from (A) of FIG. 34 , RYR1 survives approximately 86% of renal cancer patients in which the RYR1 gene is not mutated (blue), whereas renal cancer patients in which the RYR1 gene is mutated. was confirmed that the survival rate was lower than that of renal cancer patients without mutations because more than 50% of the patients died (red). According to (B) of Figure 34, in the case of kidney cancer patients in which the mutation in the RYR1 gene did not occur, approximately 82% had no recurrence for more than 100 months (blue), but if there was a mutation in the RYR1 gene, it was less than 52 months and more than 50% appeared to recur (red). Therefore, when there is a mutation in the RYR1 gene, the probability of death or recurrence due to kidney cancer increases. Therefore, it can be seen that the mutation of the RYR1 gene is significant as a predictive marker for the survival rate of kidney cancer patients or recurrence of kidney cancer.

As can be seen from (A) of FIG. 35 , in SMARCA1, approximately 86% of renal cancer patients without mutation in the SMARCA1 gene survived (blue), whereas renal cancer patients with mutation in the SMARCA1 gene. Because 100% of the patients died, it was confirmed that the survival rate was lower than that of renal cancer patients without mutation (red). According to (B) of FIG. 35 , in the case of kidney cancer patients in which the SMARCA1 gene mutation did not occur, approximately 82% did not have recurrence for more than 100 months (blue), but if there was a mutation in the SMARCA1 gene, 100% recurrence occurred in less than 1 month appeared (red). Therefore, when there is a mutation in the SMARCA1 gene, the probability of death or recurrence due to kidney cancer increases, so it can be seen that the mutation in the SMARCA1 gene is significant as a predictive marker for the survival rate of kidney cancer patients or recurrence of kidney cancer.

As can be seen from (A) of FIG. 36 , about 86% of renal cancer patients in which the SNX7 gene mutation did not occur in SNX7 survived (blue), whereas kidney cancer patients in which the SNX7 gene mutation occurred. Because 100% of the patients died, it was confirmed that the survival rate was lower than that of renal cancer patients without mutation (red). According to (B) of FIG. 36, in the case of kidney cancer patients in which the mutation in the SNX7 gene did not occur, approximately 82% had no recurrence for more than 100 months (blue). appeared (red). Therefore, when there is a mutation in the SNX7 gene, the probability of death or recurrence due to kidney cancer increases. Therefore, it can be seen that the mutation in the SNX7 gene is significant as a survival rate of kidney cancer patients or a predictive marker of kidney cancer recurrence.

As can be seen from (A) of FIG. 37 , in SSX2IP, approximately 86% of renal cancer patients without mutation in the SSX2IP gene survived (blue), whereas renal cancer patients with mutation in the SSX2IP gene. Because 100% of the patients died, it was confirmed that the survival rate was lower than that of renal cancer patients without mutation (red). According to (B) of Figure 37, in the case of kidney cancer patients in which the mutation in the SSX2IP gene did not occur, approximately 82% did not have a recurrence for more than 100 months (blue), but if there is a mutation in the SSX2IP gene, 100% recurrence in less than 1 month appeared (red). Therefore, when there is a mutation in the SSX2IP gene, the probability of death or recurrence due to kidney cancer increases. Therefore, it can be seen that the mutation of the SSX2IP gene is significant as a predictive marker for the survival rate of kidney cancer patients or recurrence of kidney cancer.

As can be seen from (A) of FIG. 38 (A), in TAS1R2, approximately 86% of renal cancer patients in which the TAS1R2 gene is not mutated survive (blue), whereas the TAS1R2 gene is mutated in renal cancer patients. Because 100% of the patients died, it was confirmed that the survival rate was lower than that of renal cancer patients without mutation (red). According to (B) of FIG. 38 , in the case of kidney cancer patients in which the TAS1R2 gene mutation did not occur, approximately 82% of patients had no recurrence for more than 100 months (blue), but if there was a mutation in the TAS1R2 gene, 100% recurrence occurred in less than 8 months appeared (red). Therefore, when there is a mutation in the TAS1R2 gene, the probability of death or recurrence due to kidney cancer increases, so it can be seen that the mutation in the TAS1R2 gene is significant as a predictive marker for the survival rate of kidney cancer patients or recurrence of kidney cancer.

As can be seen from (A) of FIG. 39, about 86% of THUMPD2 kidney cancer patients without mutation in the THUMPD2 gene survived (blue), whereas kidney cancer patients in which the THUMPD2 gene mutation occurred. Because 100% of the patients died, it was confirmed that the survival rate was lower than that of renal cancer patients without mutation (red). According to (B) of FIG. 39, in the case of kidney cancer patients in which the THUMPD2 gene mutation did not occur, approximately 82% of patients had no recurrence for more than 100 months (blue), but if there was a mutation in the THUMPD2 gene, 100% recurrence occurred in less than 2 months appeared to be (red). Therefore, when there is a mutation in the THUMPD2 gene, the probability of death or recurrence due to kidney cancer increases. Therefore, it can be seen that the mutation of the THUMPD2 gene is significant as a predictive marker for the survival rate of kidney cancer patients or recurrence of kidney cancer.

As can be seen from FIG. 40, in the case of VPS13D gene mutation, approximately 86% of patients with kidney cancer survived (blue), whereas 100% of kidney cancer patients with mutation in the VPS13D gene survived. Because he died, it was confirmed that the survival rate was lower than that of the renal cancer patient without the mutation (red). It can be seen that the mutation of the VPS13D gene is significant as a marker for predicting the survival rate of renal cancer patients.

Detection of marker genes using mutation position information

The mutated position information of the genes of the first group of candidate genes is shown in Table 3 below.

Gene AA change Type Copy # COSMIC Chr Start Pos End Pos HGVSc ACTR1B H178Pfs*140 Frame_Shift_Del diploid chr2 98275011 98275014 ENST00000289228.5:c.533_536delACTC G67R Missense diploid One chr2 98275931 98275931 ENST00000289228.5:c.199G>A G40W Missense gain chr2 98277105 98277105 ENST00000289228.5:c.118G>T BPNT1 Y293C Missense diploid chr1 220232235 220232235 ENST00000322067.7:c.878A>G X260_splice Splice_Site diploid chr1 220232335 220232335 ENST00000322067.7:c.779-1G>C S296Mfs*30 Frame_Shift_Ins diploid chr1 220232228 220232229 ENST00000322067.7:c.880_884dupTATGC BRD4 Q1318* Nonsense diploid chr19 15349622 15349622 ENST00000263377.2:c.3952C>T E1061K Missense shallowdel chr19 15350822 15350822 ENST00000263377.2:c.3181G>A TSPOAP1 L1443M Missense gain chr17 56386306 56386306 ENST00000343736.4:c.4327C>A R56G Missense gain chr17 56405116 56405116 ENST00000343736.4:c.166A>G TMEM266 E258K Missense diploid chr15 76484312 76484312 ENST00000388942.3:c.772G>A C16orf72 R110Q Missense gain chr16 9196862 9196862 ENST00000327827.7:c.329G>A L100H Missense diploid chr16 9186850 9186850 ENST00000327827.7:c.299T>A CD1C G125E Missense gain One chr1 158261919 158261919 ENST00000368170.3:c.374G>A N179Kfs*4 Frame_Shift_Ins diploid chr1 158262079 15826080 ENST00000368170.3:c.535_536dupAA CEP128 S400* Nonsense diploid chr14 81297497 81297497 ENST00000281129.3:c.1199C>A F722Lfs*14 Frame_Shift_Del shallowdel chr14 81251281 81251284 ENST00000281129.3:c.2166_2169delTAAG CIITA M132T Missense gain chr16 10992818 10992818 ENST00000324288.8:c.395T>C Q143K Missense amp chr16 10992850 10992850 ENST00000324288.8:c.427C>A COL5A1 K174Rfs*6 Frame_Shift_Del diploid chr9 137593045 137593045 ENST00000371817.3:c.521delA E1013* Nonsense diploid chr9 137694764 137694764 ENST00000371817.3:c.3037G>T P1445S Missense diploid chr9 137710604 137710604 ENST00000371817.3:c.4333C>T X1791_splice Splice_Site diploid chr9 137734002 137734002 ENST00000371817.3:c.5371-1G>C CYP51A1 A80D Missense gain chr7 91761140 91761140 ENST00000003100.8:c.239C>A F256L Missense diploid chr7 91755569 91755569 ENST00000003100.8:c.768C>A DNAAF2 V615Efs*12 Frame_Shift_Del diploid chr14 50100020 50100024 ENST00000298292.8:c.1844_1848delTAAAC F826L Missense shallowdel chr14 50092296 50092296 ENST00000298292.8:c.2478C>A EPHB1 F146Y Missense shallowdel One chr3 134670526 134670526 ENST00000398015.3:c.437T>A ESRP2 K147Rfs*41 Frame_Shift_Del gain chr16 68267898 68267898 ENST00000565858.1:c.440delA K423R Missense diploid chr16 68265766 68265766 ENST00000565858.1:c.1268A>G FBXW9 P4H Missense diploid chr19 12807385 12807385 ENST0000393261.3:c.11C>A L199M Missense diploid chr19 12805491 12805491 ENST0000393261.3:c.595T>A H369Y Missense diploid chr19 12800616 12800616 ENST0000393261.3:c.1105C>T ITGA3 Y237C Missense diploid One chr17 48148253 48148253 ENST00000320031.8:c.710A>G ITGA4 I981T Missense diploid One chr2 182399601 182399601 ENST00000397033.2:c.2942T>C ITGA8 D399G Missense diploid One chr10 15688856 15688856 ENST000003378076.3:c.1196A>G KIF5C Q452* Nonsense gain chr2 149835496 149835496 ENST00000435030.1:c.1354C>T Q683K Missense diploid chr2 149853801 149853801 ENST00000435030.1:c.2047C>A KPRP R260Q Missense diploid chr1 152732843 152732843 ENST00000606109.1:c.779G>A G544D Missense diploid One chr1 152733695 152733695 ENST00000606109.1:c.1631G>A MAOB X47_splice Splice_Site diploid chrX 43702915 43702915 ENST00000378069.4:c.141+1G>C G213R Missense shallowdel One chrX 43655117 43655117 ENST00000378069.4:c.637G>A R228L Missense gain chrX 43655071 43655071 ENST00000378069.4:c.683G>T MUC17 I3060S Missense gain One chr7 100683876 100683876 ENST00000306151.4:c.9179T>G I3060S Missense gain One chr7 100683876 100683876 ENST00000306151.4:c.9179T>G T1508M Missense diploid chr7 100679220 100679220 ENST00000306151.4:c.4523C>T T2279N Missense gain chr7 100681533 100681533 ENST00000306151.4:c.6836C>A S2868C Missense gain chr7 100683299 100683299 ENST00000306151.4:c.8602A>T E704G Missense gain One chr7 100676808 100676808 ENST00000306151.4:c.2111A>G T3421I Missense diploid chr7 100684959 100684959 ENST00000306151.4:c.10262C>T S30C Missense gain chr7 100674406 100674406 ENST00000306151.4:c.88A>T S30Rfs*2 Frame_Shift_Del gain chr7 100674408 100674408 ENST00000306151.4:c.90delT S30del In_Frame_Del gain chr7 100674406 100674408 ENST00000306151.4:c.88_90delAGT E1765K Missense One chr7 100679990 100679990 ENST00000306151.4:c.5293G>A MYH10 E1353Q Missense gain 5 chr17 8397110 8397110 ENST00000269243.4:c.4057G>C K1216T Missense diploid chr17 8404148 8404148 ENST00000269243.4:c.3647A>C D324Ifs*12 Frame_Shift_Del diploid chr17 8452026 8452026 ENST00000269243.4:c.969delA F463L Missense diploid chr17 8448780 8448780 ENST00000269243.4:c.1387T>C OGFR A50P Missense gain chr20 61436359 61436359 ENST00000290291.6:c.148G>C OR1S1 G54R Missense diploid One chr11 57982376 57982376 ENST00000309433.6:c.160G>A PCBP4 G34W Missense gain chr3 51995031 51995031 ENST00000322099.7:c.100G>T G114S Missense diploid chr3 51994252 51994252 ENST00000322099.7:c.340G>A PCGF2 E257G Missense diploid chr17 36891741 36891741 ENST000000580830.1:c.770A>G T344Rfs*43 Frame_Shift_Del gain chr17 36891478 36891482 ENST00000580830.1:c.1029_1033delAACTT PCSK2 L284F Missense gain One chr20 17417493 17417493 ENST00000262545.2:c.850C>T G4dup In_Frame_Ins gain chr20 17207956 17207957 ENST00000262545.2:c.10_12dupGGT PLEKHB2 V159L Missense diploid chr2 131897791 131897791 ENST00000409279.1:c.475G>C L203V Missense diploid chr2 131904284 131904284 ENST00000409279.1:c.607C>G A202Dfs*14 Frame_Shift_Del diploid chr2 131904282 131904282 ENST00000409279.1:c.605delC PPM1F I278Ffs*9 Frame_Shift_Del shallowdel chr22 22285579 22285579 ENST00000263212.5:c.832delA F194S Missense diploid One chr22 22287929 22287929 ENST00000263212.5:c.581T>C RAB40B G37R Missense gain chr17 80656364 80656364 ENST00000571995.1:c.109G>C D95V Missense diploid chr17 80617514 80617514 ENST00000571995.1:c.284A>T RRP36 E190D Missense diploid chr6 42995142 42995142 ENST00000244496.5:c.570G>C R17* Nonsense diploid chr6 42989441 42989441 ENST00000244496.5:c.49C>T RTL1 K923Rfs*24 Frame_Shift_Del diploid chr14 101348358 101348358 ENST000000534062.1:c.2768delA N331_E332del In_Frame_Del diploid chr14 101350131 101350136 ENST000000534062.1:c.990_995delCAACGA L330Sfs*18 Frame_Shift_Del diploid chr14 101350138 101350138 ENST000000534062.1:c.988delC L330Gfs*102 Frame_Shift_Del diploid chr14 101350131 101350138 ENST000000534062.1:c.988_995delCTCAACGA RYR1 S1770L Missense diploid 2 chr19 38976604 38976604 ENST00000359596.3:c.5309C>T V742G Missense diploid chr19 38949843 38949843 ENST00000359596.3:c.2225T>G D618Y Missense diploid 2 chr19 38948197 38948197 ENST00000359596.3:c.1852G>T Q4203H Missense diploid chr19 39052079 39052079 ENST00000359596.3:c.12609G>C Y694* Nonsense diploid One chr19 38948847 38948847 ENST00000359596.3:c.2082C>G M3652L Missense diploid One chr19 39019255 39019255 ENST00000359596.3:c.10954A>T R2415Q Missense diploid One chr19 38990577 38990577 ENST00000359596.3:c.7244G>A SMARCA1 L805P Missense gain chrX 128614706 128614706 ENST00000371122.4:c.2414T>C K1039N Missense shallowdel chrX 128582334 128582334 ENST00000371122.4:c.3117G>C Q65* Nonsense shallowdel chrX 128652406 128652406 ENST00000371122.4:c.193C>T SNX7 S8Ifs*81 Frame_Shift_Ins shallowdel chr1 99127306 99127307 ENST00000306121.3:c.20dupC A62D Missense diploid chr1 99150445 99150445 ENST00000306121.3:c.185C>A SSX2IP S544L Missense diploid One chr1 85116084 85116084 ENST00000342203.3:c.1631C>T L432F Missense diploid One chr1 85121610 85121610 ENST00000342203.3:c.1294C>T TAS1R2 N428K Missense shallowdel One chr1 19176018 19176018 ENST00000375371.3:c.1284C>A M45K Missense diploid One chr1 19186021 19186021 ENST00000375371.3:c.134T>A THUMPD2 I312Nfs*7 Frame_Shift_Ins diploid chr2 39983057 39983058 ENST00000505747.1:c.934dupA X396_splice Splice_Site gain chr2 39964200 39964200 ENST00000505747.1:c.1188-1G>C R396Sfs*13 Frame_Shift_Del gain chr2 39964198 39964199 ENST00000505747.1:c.1188_1189delAG VPS13D Y4304C Missense diploid chr1 12567023 12567023 ENST00000358136.3:c.12911A>G E317V Missense shallowdel chr1 12318000 12318000 ENST00000358136.3:c.950A>T

Based on the mutation position information, it is possible to manufacture a microchip using a primer, a probe, an antibody, or an aptamer capable of detecting the marker gene, and the specific method may be according to a conventional technique.

In the above, preferred embodiments of the present invention have been exemplarily described, but the scope of the present invention is not limited to the specific embodiments as described above, and those of ordinary skill in the art will It can be appropriately changed within.

<110> THE CATHOLIC UNIVERSITY OF KOREA INDUSTRY-ACADEMIC COOPERATION FOUNDATION <120> Composition for Diagnosing Prognosis of Kidney Cancer and Kit Comprising Thereof <130> 2019-DPA-3291 <160> 40 <170> KoPatentIn 3.0 <210> 1 <211> 376 <212> PRT <213> Homo sapiens <400> 1 Met Glu Ser Tyr Asp Ile Ile Ala Asn Gln Pro Val Val Ile Asp Asn 1 5 10 15 Gly Ser Gly Val Ile Lys Ala Gly Phe Ala Gly Asp Gln Ile Pro Lys 20 25 30 Tyr Cys Phe Pro Asn Tyr Val Gly Arg Pro Lys His Met Arg Val Met 35 40 45 Ala Gly Ala Leu Glu Gly Asp Leu Phe Ile Gly Pro Lys Ala Glu Glu 50 55 60 His Arg Gly Leu Leu Thr Ile Arg Tyr Pro Met Glu His Gly Val Val 65 70 75 80 Arg Asp Trp Asn Asp Met Glu Arg Ile Trp Gln Tyr Val Tyr Ser Lys 85 90 95 Asp Gln Leu Gln Thr Phe Ser Glu Glu His Pro Val Leu Leu Thr Glu 100 105 110 Ala Pro Leu Asn Pro Ser Lys Asn Arg Glu Lys Ala Ala Glu Val Phe 115 120 125 Phe Glu Thr Phe Asn Val Pro Ala Leu Phe Ile Ser Met Gln Ala Val 130 135 140 Leu Ser Leu Tyr Ala Thr Gly Arg Thr Thr Gly Val Val Leu Asp Ser 145 150 155 160 Gly Asp Gly Val Thr His Ala Val Pro Ile Tyr Glu Gly Phe Ala Met 165 170 175 Pro His Ser Ile Met Arg Val Asp Ile Ala Gly Arg Asp Val Ser Arg 180 185 190 Tyr Leu Arg Leu Leu Leu Arg Lys Glu Gly Val Asp Phe His Thr Ser 195 200 205 Ala Glu Phe Glu Val Val Arg Thr Ile Lys Glu Arg Ala Cys Tyr Leu 210 215 220 Ser Ile Asn Pro Gln Lys Asp Glu Ala Leu Glu Thr Glu Lys Val Gln 225 230 235 240 Tyr Thr Leu Pro Asp Gly Ser Thr Leu Asp Val Gly Pro Ala Arg Phe 245 250 255 Arg Ala Pro Glu Leu Leu Phe Gln Pro Asp Leu Val Gly Asp Glu Ser 260 265 270 Glu Gly Leu His Glu Val Val Ala Phe Ala Ile His Lys Ser Asp Met 275 280 285 Asp Leu Arg Arg Thr Leu Phe Ala Asn Ile Val Leu Ser Gly Gly Ser 290 295 300 Thr Leu Phe Lys Gly Phe Gly Asp Arg Leu Leu Ser Glu Val Lys Lys 305 310 315 320 Leu Ala Pro Lys Asp Ile Lys Ile Lys Ile Ser Ala Pro Gln Glu Arg 325 330 335 Leu Tyr Ser Thr Trp Ile Gly Gly Ser Ile Leu Ala Ser Leu Asp Thr 340 345 350 Phe Lys Lys Met Trp Val Ser Lys Lys Glu Tyr Glu Glu Asp Gly Ser 355 360 365 Arg Ala Ile His Arg Lys Thr Phe 370 375 <210> 2 <211> 308 <212> PRT <213> Homo sapiens <400> 2 Met Ala Ser Ser Asn Thr Val Leu Met Arg Leu Val Ala Ser Ala Tyr 1 5 10 15 Ser Ile Ala Gln Lys Ala Gly Met Ile Val Arg Arg Val Ile Ala Glu 20 25 30 Gly Asp Leu Gly Ile Val Glu Lys Thr Cys Ala Thr Asp Leu Gln Thr 35 40 45 Lys Ala Asp Arg Leu Ala Gln Met Ser Ile Cys Ser Ser Leu Ala Arg 50 55 60 Lys Phe Pro Lys Leu Thr Ile Ile Gly Glu Glu Asp Leu Pro Ser Glu 65 70 75 80 Glu Val Asp Gln Glu Leu Ile Glu Asp Ser Gln Trp Glu Glu Ile Leu 85 90 95 Lys Gln Pro Cys Pro Ser Gln Tyr Ser Ala Ile Lys Glu Glu Asp Leu 100 105 110 Val Val Trp Val Asp Pro Leu Asp Gly Thr Lys Glu Tyr Thr Glu Gly 115 120 125 Leu Leu Asp Asn Val Thr Val Leu Ile Gly Ile Ala Tyr Glu Gly Lys 130 135 140 Ala Ile Ala Gly Val Ile Asn Gln Pro Tyr Tyr Asn Tyr Glu Ala Gly 145 150 155 160 Pro Asp Ala Val Leu Gly Arg Thr Ile Trp Gly Val Leu Gly Leu Gly 165 170 175 Ala Phe Gly Phe Gln Leu Lys Glu Val Pro Ala Gly Lys His Ile Ile 180 185 190 Thr Thr Thr Arg Ser His Ser Asn Lys Leu Val Thr Asp Cys Val Ala 195 200 205 Ala Met Asn Pro Asp Ala Val Leu Arg Val Gly Gly Ala Gly Asn Lys 210 215 220 Ile Ile Gln Leu Ile Glu Gly Lys Ala Ser Ala Tyr Val Phe Ala Ser 225 230 235 240 Pro Gly Cys Lys Lys Trp Asp Thr Cys Ala Pro Glu Val Ile Leu His 245 250 255 Ala Val Gly Gly Lys Leu Thr Asp Ile His Gly Asn Val Leu Gln Tyr 260 265 270 His Lys Asp Val Lys His Met Asn Ser Ala Gly Val Leu Ala Thr Leu 275 280 285 Arg Asn Tyr Asp Tyr Tyr Ala Ser Arg Val Pro Glu Ser Ile Lys Asn 290 295 300 Ala Leu Val Pro 305 <210> 3 <211> 1362 <212> PRT <213> Homo sapiens <400> 3 Met Ser Ala Glu Ser Gly Pro Gly Thr Arg Leu Arg Asn Leu Pro Val 1 5 10 15 Met Gly Asp Gly Leu Glu Thr Ser Gln Met Ser Thr Thr Gln Ala Gln 20 25 30 Ala Gln Pro Gln Pro Ala Asn Ala Ala Ser Thr Asn Pro Pro Pro Pro 35 40 45 Glu Thr Ser Asn Pro Asn Lys Pro Lys Arg Gln Thr Asn Gln Leu Gln 50 55 60 Tyr Leu Leu Arg Val Val Leu Lys Thr Leu Trp Lys His Gln Phe Ala 65 70 75 80 Trp Pro Phe Gln Gln Pro Val Asp Ala Val Lys Leu Asn Leu Pro Asp 85 90 95 Tyr Tyr Lys Ile Ile Lys Thr Pro Met Asp Met Gly Thr Ile Lys Lys 100 105 110 Arg Leu Glu Asn Asn Tyr Tyr Trp Asn Ala Gln Glu Cys Ile Gln Asp 115 120 125 Phe Asn Thr Met Phe Thr Asn Cys Tyr Ile Tyr Asn Lys Pro Gly Asp 130 135 140 Asp Ile Val Leu Met Ala Glu Ala Leu Glu Lys Leu Phe Leu Gln Lys 145 150 155 160 Ile Asn Glu Leu Pro Thr Glu Glu Thr Glu Ile Met Ile Val Gln Ala 165 170 175 Lys Gly Arg Gly Arg Gly Arg Lys Glu Thr Gly Thr Ala Lys Pro Gly 180 185 190 Val Ser Thr Val Pro Asn Thr Thr Gln Ala Ser Thr Pro Pro Gln Thr 195 200 205 Gln Thr Pro Gln Pro Asn Pro Pro Pro Val Gln Ala Thr Pro His Pro 210 215 220 Phe Pro Ala Val Thr Pro Asp Leu Ile Val Gln Thr Pro Val Met Thr 225 230 235 240 Val Val Pro Pro Gln Pro Leu Gln Thr Pro Pro Val Pro Pro Gln 245 250 255 Pro Gln Pro Pro Pro Ala Pro Ala Pro Gln Pro Val Gln Ser His Pro 260 265 270 Pro Ile Ile Ala Ala Thr Pro Gln Pro Val Lys Thr Lys Lys Gly Val 275 280 285 Lys Arg Lys Ala Asp Thr Thr Thr Pro Thr Thr Ile Asp Pro Ile His 290 295 300 Glu Pro Pro Ser Leu Pro Pro Glu Pro Lys Thr Thr Lys Leu Gly Gln 305 310 315 320 Arg Arg Glu Ser Ser Arg Pro Val Lys Pro Pro Lys Lys Asp Val Pro 325 330 335 Asp Ser Gln Gln His Pro Ala Pro Glu Lys Ser Ser Lys Val Ser Glu 340 345 350 Gln Leu Lys Cys Cys Ser Gly Ile Leu Lys Glu Met Phe Ala Lys Lys 355 360 365 His Ala Ala Tyr Ala Trp Pro Phe Tyr Lys Pro Val Asp Val Glu Ala 370 375 380 Leu Gly Leu His Asp Tyr Cys Asp Ile Ile Lys His Pro Met Asp Met 385 390 395 400 Ser Thr Ile Lys Ser Lys Leu Glu Ala Arg Glu Tyr Arg Asp Ala Gln 405 410 415 Glu Phe Gly Ala Asp Val Arg Leu Met Phe Ser Asn Cys Tyr Lys Tyr 420 425 430 Asn Pro Pro Asp His Glu Val Val Ala Met Ala Arg Lys Leu Gln Asp 435 440 445 Val Phe Glu Met Arg Phe Ala Lys Met Pro Asp Glu Pro Glu Glu Pro 450 455 460 Val Val Ala Val Ser Ser Pro Ala Val Pro Pro Thr Lys Val Val 465 470 475 480 Ala Pro Pro Ser Ser Ser Asp Ser Ser Ser Asp Ser Ser Ser Asp Ser 485 490 495 Asp Ser Ser Thr Asp Asp Ser Glu Glu Glu Arg Ala Gln Arg Leu Ala 500 505 510 Glu Leu Gln Glu Gln Leu Lys Ala Val His Glu Gln Leu Ala Ala Leu 515 520 525 Ser Gln Pro Gln Gln Asn Lys Pro Lys Lys Lys Glu Lys Asp Lys Lys 530 535 540 Glu Lys Lys Lys Glu Lys His Lys Arg Lys Glu Glu Val Glu Glu Asn 545 550 555 560 Lys Lys Ser Lys Ala Lys Glu Pro Pro Lys Lys Thr Lys Lys Asn 565 570 575 Asn Ser Ser Asn Ser Asn Val Ser Lys Lys Glu Pro Ala Pro Met Lys 580 585 590 Ser Lys Pro Pro Thr Tyr Glu Ser Glu Glu Glu Asp Lys Cys Lys 595 600 605 Pro Met Ser Tyr Glu Glu Lys Arg Gln Leu Ser Leu Asp Ile Asn Lys 610 615 620 Leu Pro Gly Glu Lys Leu Gly Arg Val Val His Ile Ile Gln Ser Arg 625 630 635 640 Glu Pro Ser Leu Lys Asn Ser Asn Pro Asp Glu Ile Glu Ile Asp Phe 645 650 655 Glu Thr Leu Lys Pro Ser Thr Leu Arg Glu Leu Glu Arg Tyr Val Thr 660 665 670 Ser Cys Leu Arg Lys Lys Arg Lys Pro Gln Ala Glu Lys Val Asp Val 675 680 685 Ile Ala Gly Ser Ser Lys Met Lys Gly Phe Ser Ser Ser Glu Ser Glu 690 695 700 Ser Ser Ser Glu Ser Ser Ser Ser Ser Asp Ser Glu Asp Ser Glu Thr Glu 705 710 715 720 Met Ala Pro Lys Ser Lys Lys Lys Gly His Pro Gly Arg Glu Gln Lys 725 730 735 Lys His His His His His His Gln Gln Met Gln Gln Ala Pro Ala Pro 740 745 750 Val Pro Gln Gln Pro Pro Pro Pro Pro Gln Gln Pro Pro Pro Pro Pro 755 760 765 Pro Pro Gln Gln Gln Gln Gln Pro Pro Pro Pro Pro Pro Pro Pro Ser 770 775 780 Met Pro Gln Gln Ala Ala Pro Ala Met Lys Ser Ser Pro Pro Pro Phe 785 790 795 800 Ile Ala Thr Gln Val Pro Val Leu Glu Pro Gln Leu Pro Gly Ser Val 805 810 815 Phe Asp Pro Ile Gly His Phe Thr Gln Pro Ile Leu His Leu Pro Gln 820 825 830 Pro Glu Leu Pro Pro His Leu Pro Gln Pro Pro Glu His Ser Thr Pro 835 840 845 Pro His Leu Asn Gln His Ala Val Val Ser Pro Ala Leu His Asn 850 855 860 Ala Leu Pro Gln Gln Pro Ser Arg Pro Ser Asn Arg Ala Ala Ala Leu 865 870 875 880 Pro Pro Lys Pro Ala Arg Pro Pro Ala Val Ser Pro Ala Leu Thr Gln 885 890 895 Thr Pro Leu Leu Pro Gln Pro Pro Met Ala Gln Pro Pro Gln Val Leu 900 905 910 Leu Glu Asp Glu Glu Pro Pro Ala Pro Pro Leu Thr Ser Met Gln Met 915 920 925 Gln Leu Tyr Leu Gln Gln Leu Gln Lys Val Gln Pro Pro Thr Pro Leu 930 935 940 Leu Pro Ser Val Lys Val Gln Ser Gln Pro Pro Pro Leu Pro Pro 945 950 955 960 Pro Pro His Pro Ser Val Gln Gln Gln Leu Gln Gln Gln Pro Pro Pro 965 970 975 Pro Pro Pro Pro Gln Pro Gln Pro Pro Pro Gln Gln Gln His Gln Pro 980 985 990 Pro Pro Arg Pro Val His Leu Gln Pro Met Gln Phe Ser Thr His Ile 995 1000 1005 Gln Gln Pro Pro Pro Pro Gln Gly Gln Gln Pro Pro His Pro Pro Pro 1010 1015 1020 Gly Gln Gln Pro Pro Pro Pro Gln Pro Ala Lys Pro Gln Gln Val Ile 1025 1030 1035 1040 Gln His His His Ser Pro Arg His His Lys Ser Asp Pro Tyr Ser Thr 1045 1050 1055 Gly His Leu Arg Glu Ala Pro Ser Pro Leu Met Ile His Ser Pro Gln 1060 1065 1070 Met Ser Gln Phe Gln Ser Leu Thr His Gln Ser Pro Pro Gln Gln Asn 1075 1080 1085 Val Gln Pro Lys Lys Gln Glu Leu Arg Ala Ala Ser Val Val Gln Pro 1090 1095 1100 Gln Pro Leu Val Val Val Lys Glu Glu Lys Ile His Ser Pro Ile Ile 1105 1110 1115 1120 Arg Ser Glu Pro Phe Ser Pro Ser Leu Arg Pro Glu Pro Pro Lys His 1125 1130 1135 Pro Glu Ser Ile Lys Ala Pro Val His Leu Pro Gln Arg Pro Glu Met 1140 1145 1150 Lys Pro Val Asp Val Gly Arg Pro Val Ile Arg Pro Pro Glu Gln Asn 1155 1160 1165 Ala Pro Pro Pro Gly Ala Pro Asp Lys Asp Lys Gln Lys Gln Glu Pro 1170 1175 1180 Lys Thr Pro Val Ala Pro Lys Lys Asp Leu Lys Ile Lys Asn Met Gly 1185 1190 1195 1200 Ser Trp Ala Ser Leu Val Gln Lys His Pro Thr Thr Pro Ser Ser Thr 1205 1210 1215 Ala Lys Ser Ser Ser Asp Ser Phe Glu Gln Phe Arg Arg Ala Ala Arg 1220 1225 1230 Glu Lys Glu Glu Arg Glu Lys Ala Leu Lys Ala Gln Ala Glu His Ala 1235 1240 1245 Glu Lys Glu Lys Glu Arg Leu Arg Gln Glu Arg Met Arg Ser Arg Glu 1250 1255 1260 Asp Glu Asp Ala Leu Glu Gln Ala Arg Arg Ala His Glu Glu Ala Arg 1265 1270 1275 1280 Arg Arg Gln Glu Gln Gln Gln Gln Gln Arg Gln Glu Gln Gln Gln Gln 1285 1290 1295 Gln Gln Gln Gln Ala Ala Ala Val Ala Ala Ala Ala Thr Pro Gln Ala 1300 1305 1310 Gln Ser Ser Gln Pro Gln Ser Met Leu Asp Gln Gln Arg Glu Leu Ala 1315 1320 1325 Arg Lys Arg Glu Gln Glu Arg Arg Arg Arg Arg Glu Ala Met Ala Ala Thr 1330 1335 1340 Ile Asp Met Asn Phe Gln Ser Asp Leu Leu Ser Ile Phe Glu Glu Asn 1345 1350 1355 1360 Leu Phe <210> 4 <211> 1857 <212> PRT <213> Homo sapiens <400> 4 Met Glu Gln Leu Thr Thr Leu Pro Arg Pro Gly Asp Pro Gly Ala Met 14 18 23 28 Glu Pro Trp Ala Leu Pro Thr Trp His Ser Trp Thr Pro Gly Arg Gly 33 38 43 Gly Glu Pro Ser Ser Ala Ala Pro Ser Ile Ala Asp Thr Pro Pro Ala 48 53 58 Ala Leu Gln Leu Gln Glu Leu Arg Ser Glu Glu Ser Ser Ser Lys Pro Lys 63 68 73 Gly Asp Gly Ser Ser Arg Pro Val Gly Gly Thr Asp Pro Glu Gly Ala 78 83 88 93 Glu Ala Cys Leu Pro Ser Leu Gly Gln Gln Ala Ser Ser Ser Ser Gly Pro 98 103 108 Ala Cys Gln Arg Pro Glu Asp Glu Glu Val Glu Ala Phe Leu Lys Ala 113 118 123 Lys Leu Asn Met Ser Phe Gly Asp Arg Pro Asn Leu Glu Leu Leu Arg 128 133 138 Ala Leu Gly Glu Leu Arg Gln Arg Cys Ala Ile Leu Lys Glu Glu Asn 143 148 153 Gln Met Leu Arg Lys Ser Ser Phe Pro Glu Thr Glu Glu Lys Val Arg 158 163 168 173 Arg Leu Lys Arg Lys Asn Ala Glu Leu Ala Val Ile Ala Lys Arg Leu 178 183 188 Glu Glu Arg Ala Arg Lys Leu Gln Glu Thr Asn Leu Arg Val Val Ser 193 198 203 Ala Pro Leu Pro Arg Pro Gly Thr Ser Leu Glu Leu Cys Arg Lys Ala 208 213 218 Leu Ala Arg Gln Arg Ala Arg Asp Leu Ser Glu Thr Ala Ser Ala Leu 223 228 233 Leu Ala Lys Asp Lys Gln Ile Ala Ala Leu Gln Arg Glu Cys Arg Glu 238 243 248 253 Leu Gln Ala Arg Leu Thr Leu Val Gly Lys Glu Gly Pro Gln Trp Leu 258 263 268 His Val Arg Asp Phe Asp Arg Leu Leu Arg Glu Ser Gln Arg Glu Val 273 278 283 Leu Arg Leu Gln Arg Gln Ile Ala Leu Arg Asn Gln Arg Glu Thr Leu 288 293 298 Pro Leu Pro Pro Ser Trp Pro Pro Gly Pro Ala Leu Gln Ala Arg Ala 303 308 313 Gly Ala Pro Ala Pro Gly Ala Pro Gly Glu Ala Thr Pro Gln Glu Asp 318 323 328 333 Ala Asp Asn Leu Pro Val Ile Leu Gly Glu Pro Glu Lys Glu Gln Arg 338 343 348 Val Gln Gln Leu Glu Ser Glu Leu Ser Lys Lys Arg Lys Lys Cys Glu 353 358 363 Ser Leu Glu Gln Glu Ala Arg Lys Lys Gln Arg Arg Cys Glu Glu Leu 368 373 378 Glu Leu Gln Leu Arg Gln Ala Gln Asn Glu Asn Ala Arg Leu Val Glu 383 388 393 Glu Asn Ser Arg Leu Ser Gly Arg Ala Thr Glu Lys Glu Gln Val Glu 398 403 408 413 Trp Glu Asn Ala Glu Leu Arg Gly Gln Leu Leu Gly Val Thr Gln Glu 418 423 428 Arg Asp Ser Ala Leu Arg Lys Ser Gln Gly Leu Gln Ser Lys Leu Glu 433 438 443 Ser Leu Glu Gln Val Leu Lys His Met Arg Glu Val Ala Gln Arg Arg 448 453 458 Gln Gln Leu Glu Val Glu His Glu Gln Ala Arg Leu Ser Leu Arg Glu 463 468 473 Lys Gln Glu Glu Val Arg Arg Leu Gln Gln Ala Gln Ala Glu Ala Gln 478 483 488 493 Arg Glu His Glu Gly Ala Val Gln Leu Leu Glu Ser Thr Leu Asp Ser 498 503 508 Met Gln Ala Arg Val Arg Glu Leu Glu Glu Gln Cys Arg Ser Gln Thr 513 518 523 Glu Gln Phe Ser Leu Leu Ala Gln Glu Leu Gln Ala Phe Arg Leu His 528 533 538 Pro Gly Pro Leu Asp Leu Leu Thr Ser Ala Leu Asp Cys Gly Ser Leu 543 548 553 Gly Asp Cys Pro Pro Pro Pro Cys Cys Cys Ser Ile Pro Gln Pro Cys 558 563 568 573 Arg Gly Ser Gly Pro Lys Asp Leu Asp Leu Pro Pro Gly Ser Pro Gly 578 583 588 Arg Cys Thr Pro Lys Ser Ser Glu Pro Ala Pro Ala Thr Leu Thr Gly 593 598 603 Val Pro Arg Arg Thr Ala Lys Lys Ala Glu Ser Leu Ser Asn Ser Ser 608 613 618 His Ser Glu Ser Ile His Asn Ser Pro Lys Ser Cys Pro Thr Pro Glu 623 628 633 Val Asp Thr Ala Ser Glu Val Glu Glu Leu Glu Ala Asp Ser Val Ser 638 643 648 653 Leu Leu Pro Ala Ala Pro Glu Gly Ser Arg Gly Gly Ala Arg Ile Gln 658 663 668 Val Phe Leu Ala Arg Tyr Ser Tyr Asn Pro Phe Glu Gly Pro Asn Glu 673 678 683 Asn Pro Glu Ala Glu Leu Pro Leu Thr Ala Gly Glu Tyr Ile Tyr Ile 688 693 698 Tyr Gly Asn Met Asp Glu Asp Gly Phe Phe Glu Gly Glu Leu Met Asp 703 708 713 Gly Arg Arg Gly Leu Val Pro Ser Asn Phe Val Glu Arg Val Ser Asp 718 723 728 733 Asp Asp Leu Leu Thr Ser Leu Pro Pro Glu Leu Ala Asp Leu Ser His 738 743 748 Ser Ser Gly Pro Glu Leu Ser Phe Leu Ser Val Gly Gly Gly Gly Ser 753 758 763 Ser Ser Gly Gly Gln Ser Ser Val Gly Arg Ser Gln Pro Arg Pro Glu 768 773 778 Glu Glu Asp Ala Gly Asp Glu Leu Ser Leu Ser Pro Ser Pro Glu Gly 783 788 793 Leu Gly Glu Pro Pro Ala Val Pro Tyr Pro Arg Arg Leu Val Val Leu 798 803 808 813 Lys Gln Leu Ala His Ser Val Val Leu Ala Trp Glu Pro Pro Pro Glu 818 823 828 Gln Val Glu Leu His Gly Phe His Ile Cys Val Asn Gly Glu Leu Arg 833 838 843 Gln Ala Leu Gly Pro Gly Ala Pro Pro Lys Ala Val Leu Glu Asn Leu 848 853 858 Asp Leu Trp Ala Gly Pro Leu His Ile Ser Val Gln Ala Leu Thr Ser 863 868 873 Arg Gly Ser Ser Asp Pro Leu Arg Cys Cys Leu Ala Val Gly Ala Arg 878 883 888 893 Ala Gly Val Val Pro Ser Gln Leu Arg Val His Arg Leu Thr Ala Thr 898 903 908 Ser Ala Glu Ile Thr Trp Val Pro Gly Asn Ser Asn Leu Ala His Ala 913 918 923 Ile Tyr Leu Asn Gly Glu Glu Cys Pro Pro Ala Ser Pro Ser Thr Tyr 928 933 938 Trp Ala Thr Phe Cys His Leu Arg Pro Gly Thr Pro Tyr Gln Ala Gln 943 948 953 Val Glu Ala Gln Leu Pro Pro Gln Gly Pro Trp Glu Pro Gly Trp Glu 958 963 968 973 Arg Leu Glu Gln Arg Ala Ala Thr Leu Gln Phe Thr Thr Leu Pro Ala 978 983 988 Gly Pro Pro Asp Ala Pro Leu Asp Val Gln Ile Glu Pro Gly Pro Ser 993 998 1003 Pro Gly Ile Leu Ile Ile Ser Trp Leu Pro Val Thr Ile Asp Ala Ala 1008 1013 1018 Gly Thr Ser Asn Gly Val Arg Val Thr Gly Tyr Ala Ile Tyr Ala Asp 1023 1028 1033 Gly Gln Lys Ile Met Glu Val Ala Ser Pro Thr Ala Gly Ser Val Leu 1038 1043 1048 1053 Val Glu Leu Ser Gln Leu Gln Leu Leu Gln Val Cys Arg Glu Val Val 1058 1063 1068 Val Arg Thr Met Ser Pro His Gly Glu Ser Ala Asp Ser Ile Pro Ala 1073 1078 1083 Pro Ile Thr Pro Ala Leu Ala Pro Ala Ser Leu Pro Ala Arg Val Ser 1088 1093 1098 Cys Pro Ser Pro His Pro Ser Pro Glu Ala Arg Ala Pro Leu Ala Ser 1103 1108 1113 Ala Ser Pro Gly Pro Gly Asp Pro Ser Ser Pro Leu Gln His Pro Ala 1118 1123 1128 1133 Pro Leu Gly Thr Gln Glu Pro Pro Gly Ala Pro Pro Ala Ser Pro Ser 1138 1143 1148 Arg Glu Met Ala Lys Gly Ser His Glu Asp Pro Pro Ala Pro Cys Ser 1153 1158 1163 Gln Glu Glu Ala Gly Ala Ala Val Leu Gly Thr Ser Glu Glu Arg Thr 1168 1173 1178 Ala Ser Thr Ser Thr Leu Gly Glu Lys Asp Pro Gly Pro Ala Ala Pro 1183 1188 1193 Ser Leu Ala Lys Gln Glu Ala Glu Trp Thr Ala Gly Glu Ala Cys Pro 1198 1203 1208 1213 Ala Ser Ser Ser Thr Gln Gly Ala Arg Ala Gln Gln Ala Pro Asn Thr 1218 1223 1228 Glu Met Cys Gln Gly Gly Asp Pro Gly Ser Gly Leu Arg Pro Arg Ala 1233 1238 1243 Glu Lys Glu Asp Thr Ala Glu Leu Gly Val His Leu Val Asn Ser Leu 1248 1253 1258 Val Asp His Gly Arg Asn Ser Asp Leu Ser Asp Ile Gln Glu Glu Glu 1263 1268 1273 Glu Glu Glu Glu Glu Glu Glu Glu Glu Glu Glu Leu Gly Ser Arg Thr Cys 1278 1283 1288 1293 Ser Phe Gln Lys Gln Val Ala Gly Asn Ser Ile Arg Glu Asn Gly Ala 1298 1303 1308 Lys Ser Gln Pro Asp Pro Phe Cys Glu Thr Asp Ser Asp Glu Glu Ile 1313 1318 1323 Leu Glu Gln Ile Leu Glu Leu Pro Leu Gln Gln Phe Cys Ser Lys Lys 1328 1333 1338 Leu Phe Ser Ile Pro Glu Glu Glu Glu Glu Glu Glu Glu Asp Glu Glu 1343 1348 1353 Glu Glu Lys Ser Gly Ala Gly Cys Ser Ser Arg Asp Pro Gly Pro Pro 1358 1363 1368 1373 Glu Pro Ala Leu Leu Gly Leu Gly Cys Asp Ser Gly Gln Pro Arg Arg 1378 1383 1388 Pro Gly Gln Cys Pro Leu Ser Pro Glu Ser Ser Arg Ala Gly Asp Cys 1393 1398 1403 Leu Glu Asp Met Pro Gly Leu Val Gly Gly Ser Ser Arg Arg Arg Gly 1408 1413 1418 Gly Gly Ser Pro Glu Lys Pro Pro Ser Arg Arg Arg Pro Pro Asp Pro 1423 1428 1433 Arg Glu His Cys Ser Arg Leu Leu Ser Asn Asn Gly Pro Gln Ala Ser 1438 1443 1448 1453 Gly Arg Leu Gly Pro Thr Arg Glu Arg Gly Gly Leu Pro Val Ile Glu 1458 1463 1468 Gly Pro Arg Thr Gly Leu Glu Ala Ser Gly Arg Gly Arg Leu Gly Pro 1473 1478 1483 Ser Arg Arg Cys Ser Arg Gly Arg Ala Leu Glu Pro Gly Leu Ala Ser 1488 1493 1498 Cys Leu Ser Pro Lys Cys Leu Glu Ile Ser Ile Glu Tyr Asp Ser Glu 1503 1508 1513 Asp Glu Gln Glu Ala Gly Ser Gly Gly Ile Ser Ile Thr Ser Ser Cys 1518 1523 1528 1533 Tyr Pro Gly Asp Gly Glu Ala Trp Gly Thr Ala Thr Val Gly Arg Pro 1538 1543 1548 Arg Gly Pro Pro Lys Ala Asn Ser Gly Pro Lys Pro Tyr Pro Arg Leu 1553 1558 1563 Pro Ala Trp Glu Lys Gly Glu Pro Glu Arg Arg Gly Arg Ser Ala Thr 1568 1573 1578 Gly Arg Ala Lys Glu Pro Leu Ser Arg Ala Thr Glu Thr Gly Glu Ala 1583 1588 1593 Arg Gly Gln Asp Gly Ser Gly Arg Arg Gly Pro Gln Lys Arg Gly Val 1598 1603 1608 1613 Arg Val Leu Arg Pro Ser Thr Ala Glu Leu Val Pro Ala Arg Ser Pro 1618 1623 1628 Ser Glu Thr Leu Ala Tyr Gln His Leu Pro Val Arg Ile Phe Val Ala 1633 1638 1643 Leu Phe Asp Tyr Asp Pro Val Ser Met Ser Pro Asn Pro Asp Ala Gly 1648 1653 1658 Glu Glu Glu Leu Pro Phe Arg Glu Gly Gln Ile Leu Lys Val Phe Gly 1663 1668 1673 Asp Lys Asp Ala Asp Gly Phe Tyr Gln Gly Glu Gly Gly Gly Arg Thr 1678 1683 1688 1693 Gly Tyr Ile Pro Cys Asn Met Val Ala Glu Val Ala Val Asp Ser Pro 1698 1703 1708 Ala Gly Arg Gln Gln Leu Leu Gln Arg Gly Tyr Leu Ser Pro Asp Ile 1713 1718 1723 Leu Leu Glu Gly Ser Gly Asn Gly Pro Phe Val Tyr Ser Thr Ala His 1728 1733 1738 Thr Thr Gly Pro Pro Lys Pro Arg Arg Ser Lys Lys Ala Glu Ser 1743 1748 1753 Glu Gly Pro Ala Gln Pro Cys Pro Gly Pro Pro Lys Leu Val Pro Ser 1758 1763 1768 1773 Ala Asp Leu Lys Ala Pro His Ser Met Val Ala Ala Phe Asp Tyr Asn 1778 1783 1788 Pro Gln Glu Ser Ser Pro Asn Met Asp Val Glu Ala Glu Leu Pro Phe 1793 1798 1803 Arg Ala Gly Asp Val Ile Thr Val Phe Gly Gly Met Asp Asp Asp Gly 1808 1813 1818 Phe Tyr Tyr Gly Glu Leu Asn Gly Gln Arg Gly Leu Val Pro Ser Asn 1823 1828 1833 Phe Leu Glu Gly Pro Gly Pro Glu Ala Gly Gly Leu Asp Arg Glu Pro 1838 1843 1848 1853 Arg Thr Pro Gln Ala Glu Ser Gln Arg Thr Arg Arg Arg Arg Val Gln 1858 1863 1868 Cys <210> 5 <211> 531 <212> PRT <213> Homo sapiens <400> 5 Met Ala Val Ala Pro Ser Phe Asn Met Thr Asn Pro Gln Pro Ala Ile 1 5 10 15 Glu Gly Gly Ile Ser Glu Val Glu Ile Ile Ser Gln Gln Val Asp Glu 20 25 30 Glu Thr Lys Ser Ile Ala Pro Val Gln Leu Val Asn Phe Ala Tyr Arg 35 40 45 Asp Leu Pro Leu Ala Ala Val Asp Leu Ser Thr Ala Gly Ser Gln Leu 50 55 60 Leu Ser Asn Leu Asp Glu Asp Tyr Gln Arg Glu Gly Ser Asn Trp Leu 65 70 75 80 Lys Pro Cys Cys Gly Lys Arg Ala Ala Val Trp Gln Val Phe Leu Leu 85 90 95 Ser Ala Ser Leu Asn Ser Phe Leu Val Ala Cys Val Ile Leu Val Val 100 105 110 Ile Leu Leu Thr Leu Glu Leu Leu Ile Asp Ile Lys Leu Leu Gln Phe 115 120 125 Ser Ser Ala Phe Gln Phe Ala Gly Val Ile His Trp Ile Ser Leu Val 130 135 140 Ile Leu Ser Val Phe Phe Ser Glu Thr Val Leu Arg Ile Val Val Leu 145 150 155 160 Gly Ile Trp Asp Tyr Ile Glu Asn Lys Ile Glu Val Phe Asp Gly Ala 165 170 175 Val Ile Ile Leu Ser Leu Ala Pro Met Val Ala Ser Thr Val Ala Asn 180 185 190 Gly Pro Arg Ser Pro Trp Asp Ala Ile Ser Leu Ile Ile Met Leu Arg 195 200 205 Ile Trp Arg Val Lys Arg Val Ile Asp Ala Tyr Val Leu Pro Val Lys 210 215 220 Leu Glu Met Glu Met Val Ile Gln Gln Tyr Glu Lys Ala Lys Val Ile 225 230 235 240 Gln Asp Glu Gln Leu Glu Arg Leu Thr Gln Ile Cys Gln Glu Gln Gly 245 250 255 Phe Glu Ile Arg Gln Leu Arg Ala His Leu Ala Gln Gln Asp Leu Asp 260 265 270 Leu Ala Ala Glu Arg Glu Ala Ala Leu Gln Ala Pro His Val Leu Ser 275 280 285 Gln Pro Arg Ser Arg Phe Lys Val Leu Glu Ala Gly Thr Trp Asp Glu 290 295 300 Glu Thr Ala Ala Glu Ser Val Val Glu Glu Leu Gln Pro Ser Gln Glu 305 310 315 320 Ala Thr Met Lys Asp Asp Met Asn Ser Tyr Ile Ser Gln Tyr Tyr Asn 325 330 335 Gly Pro Ser Ser Asp Ser Gly Val Pro Glu Pro Ala Val Cys Met Val 340 345 350 Thr Thr Ala Ala Ile Asp Ile His Gln Pro Asn Ile Ser Ser Asp Leu 355 360 365 Phe Ser Leu Asp Met Pro Leu Lys Leu Gly Gly Asn Gly Thr Ser Ala 370 375 380 Thr Ser Glu Ser Ala Ser Arg Ser Ser Val Thr Arg Ala Gln Ser Asp 385 390 395 400 Ser Ser Gln Thr Leu Gly Ser Ser Met Asp Cys Ser Thr Ala Arg Glu 405 410 415 Glu Pro Ser Ser Glu Pro Gly Pro Ser Pro Pro Leu Pro Ser Gln 420 425 430 Gln Gln Val Glu Glu Ala Thr Val Gln Asp Leu Leu Ser Ser Leu Ser 435 440 445 Glu Asp Pro Cys Pro Ser Gln Lys Ala Leu Asp Pro Ala Pro Leu Ala 450 455 460 Arg Pro Ser Pro Ala Gly Ser Ala Gln Thr Ser Pro Glu Leu Glu His 465 470 475 480 Arg Val Ser Leu Phe Asn Gln Lys Asn Gln Glu Gly Phe Thr Val Phe 485 490 495 Gln Ile Arg Pro Val Ile His Phe Gln Pro Thr Val Pro Met Leu Glu 500 505 510 Asp Lys Phe Arg Ser Leu Glu Ser Lys Glu Gln Lys Leu His Arg Val 515 520 525 Pro Glu Ala 530 <210> 6 <211> 275 <212> PRT <213> Homo sapiens <400> 6 Met Glu Glu Arg Lys Glu Glu Gly Glu Ala Glu Ile Gln Glu His Gly 1 5 10 15 Pro Glu His Trp Phe Ser Lys Trp Glu Arg Gln Cys Leu Ala Glu Ala 20 25 30 Glu Gln Asp Glu Gln Leu Pro Pro Glu Leu Gln Glu Glu Ala Ala Ala 35 40 45 Ala Ala Gln Pro Glu His Lys Gln Gln Lys Leu Trp His Leu Phe Gln 50 55 60 Asn Ser Ala Thr Ala Val Ala Gln Leu Tyr Lys Asp Arg Val Cys Gln 65 70 75 80 Gln Pro Gly Leu Ser Leu Trp Val Pro Phe Gln Asn Ala Ala Thr Ala 85 90 95 Val Thr Asn Leu Tyr Lys Glu Ser Val Asp Thr His Gln Arg Ser Phe 100 105 110 Asp Ile Gly Ile Gln Ile Gly Tyr Gln Arg Arg Asn Lys Asp Val Leu 115 120 125 Ala Trp Val Lys Lys Arg Arg Arg Thr Ile Arg Arg Glu Asp Leu Ile 130 135 140 Ser Phe Leu Cys Gly Lys Val Pro Pro Arg Asn Ser Arg Ala Pro 145 150 155 160 Pro Arg Leu Thr Val Val Ser Pro Asn Arg Ala Thr Ser Thr Glu Thr 165 170 175 Ser Ser Ser Val Glu Thr Asp Leu Gln Pro Phe Arg Glu Ala Ile Ala 180 185 190 Leu His Gly Leu Ser Gly Ala Met Ala Ser Ile Ser Val Arg Ser Ser 195 200 205 Thr Pro Gly Ser Pro Thr His Val Ser Ser Gly Ser Asn Ala Ser Arg 210 215 220 Arg Arg Asn Gly Leu His Asp Val Asp Leu Asn Thr Phe Ile Ser Glu 225 230 235 240 Glu Met Ala Leu His Leu Asp Asn Gly Gly Thr Arg Lys Arg Thr Ser 245 250 255 Ala Gln Cys Gly Asp Val Ile Thr Asp Ser Pro Thr His Lys Arg Asn 260 265 270 Arg Met Ile 275 <210> 7 <211> 333 <212> PRT <213> Homo sapiens <400> 7 Met Leu Phe Leu Gln Phe Leu Leu Leu Ala Leu Leu Leu Pro Gly Gly 1 5 10 15 Asp Asn Ala Asp Ala Ser Gln Glu His Val Ser Phe His Val Ile Gln 20 25 30 Ile Phe Ser Phe Val Asn Gln Ser Trp Ala Arg Gly Gln Gly Ser Gly 35 40 45 Trp Leu Asp Glu Leu Gln Thr His Gly Trp Asp Ser Glu Ser Gly Thr 50 55 60 Ile Ile Phe Leu His Asn Trp Ser Lys Gly Asn Phe Ser Asn Glu Glu 65 70 75 80 Leu Ser Asp Leu Glu Leu Leu Phe Arg Phe Tyr Leu Phe Gly Leu Thr 85 90 95 Arg Glu Ile Gln Asp His Ala Ser Gln Asp Tyr Ser Lys Tyr Pro Phe 100 105 110 Glu Val Gln Val Lys Ala Gly Cys Glu Leu His Ser Gly Lys Ser Pro 115 120 125 Glu Gly Phe Phe Gln Val Ala Phe Asn Gly Leu Asp Leu Leu Ser Phe 130 135 140 Gln Asn Thr Thr Trp Val Pro Ser Pro Gly Cys Gly Ser Leu Ala Gln 145 150 155 160 Ser Val Cys His Leu Leu Asn His Gln Tyr Glu Gly Val Thr Glu Thr 165 170 175 Val Tyr Asn Leu Ile Arg Ser Thr Cys Pro Arg Phe Leu Leu Gly Leu 180 185 190 Leu Asp Ala Gly Lys Met Tyr Val His Arg Gln Val Arg Pro Glu Ala 195 200 205 Trp Leu Ser Ser Arg Pro Ser Leu Gly Ser Gly Gln Leu Leu Leu Val 210 215 220 Cys His Ala Ser Gly Phe Tyr Pro Lys Pro Val Trp Val Thr Trp Met 225 230 235 240 Arg Asn Glu Gln Glu Gln Leu Gly Thr Lys His Gly Asp Ile Leu Pro 245 250 255 Asn Ala Asp Gly Thr Trp Tyr Leu Gln Val Ile Leu Glu Val Ala Ser 260 265 270 Glu Glu Pro Ala Gly Leu Ser Cys Arg Val Arg His Ser Ser Leu Gly 275 280 285 Gly Gln Asp Ile Ile Leu Tyr Trp Gly His His Phe Ser Met Asn Trp 290 295 300 Ile Ala Leu Val Val Ile Val Pro Leu Val Ile Leu Ile Val Leu Val 305 310 315 320 Leu Trp Phe Lys Lys His Cys Ser Tyr Gln Asp Ile Leu 325 330 <210> 8 <211> 1094 <212> PRT <213> Homo sapiens <400> 8 Met Ala Glu Ser Ser Ser Glu Ser Asp His Phe Arg Cys Arg Asp Arg 1 5 10 15 Leu Ser Pro Trp Ala Ala Arg Ser Thr His Arg Gly Thr Arg Ser Leu 20 25 30 Pro Thr Val Glu Val Thr Glu Lys Val Asn Thr Ile Thr Ser Thr Leu 35 40 45 Gln Asp Thr Ser Arg Asn Leu Arg Gln Val Asp Gln Met Leu Gly Arg 50 55 60 Tyr Arg Glu Tyr Ser Asn Gly Gln Ala Gly Ala Ile Glu His Leu Lys 65 70 75 80 Glu Ser Leu Glu Gln Ser Ile Asp Gln Leu Arg Ser Gln Arg Leu Leu 85 90 95 Arg Asn Ser Gly Gly Arg Ser Ile Ser Val Thr Ser Leu Ser Ala Ser 100 105 110 Asp Leu Asp Gly Gly Thr Gly Ser Glu Leu His His Phe Pro Pro Thr 115 120 125 Ser Pro Leu Lys Asp Tyr Gly Asp Pro Gln Gly Ile Lys Arg Met Arg 130 135 140 Ser Arg Thr Gly Val Arg Phe Val Gln Glu Thr Asp Asp Met Thr Gln 145 150 155 160 Leu His Gly Phe His Gln Ser Leu Arg Asp Leu Ser Ser Glu Gln Ile 165 170 175 Arg Leu Gly Asp Asp Phe Asn Arg Glu Leu Ser Arg Arg Ser Arg Ser 180 185 190 Asp Ala Glu Thr Lys Arg Ala Leu Glu Glu Leu Thr Glu Lys Leu Asn 195 200 205 Glu Ala Gln Lys Gln Glu Val Val Ser Asp Arg Val Glu Arg Arg Leu 210 215 220 Gln Glu Leu Glu Arg Glu Met Arg Thr Glu Arg Glu Leu Val Glu Arg 225 230 235 240 Arg Gln Asp Gln Leu Gly Leu Met Ser Leu Gln Leu Gln Glu Ala Leu 245 250 255 Lys Lys Gln Glu Ala Lys Ala Asp Glu His Glu Gly Ala Ile Lys Asn 260 265 270 Lys Leu Arg Gln Thr Glu Thr Glu Lys Asn Gln Leu Glu Gln Glu Leu 275 280 285 Glu Leu Ser Arg Arg Leu Leu Asn Gln Ser Glu Gly Ser Arg Glu Thr 290 295 300 Leu Leu His Gln Val Glu Glu Leu Arg Thr Gln Leu Thr Lys Ala Glu 305 310 315 320 Gly Asp Arg Lys Gly Leu Gln His Gln Val Ser Gln Ile Ser Lys Gln 325 330 335 Gln Ser Asn Tyr Gln Asp Glu Gln Gly Glu Asp Trp Arg Phe Arg Arg 340 345 350 Gly Val Glu Arg Glu Lys Gln Asp Leu Glu Lys Gln Met Ser Asp Leu 355 360 365 Arg Val Gln Leu Asn Phe Ser Ala Met Ala Ser Glu Leu Glu Glu Val 370 375 380 Lys Arg Cys Met Glu Arg Lys Asp Lys Glu Lys Ala His Leu Ala Ser 385 390 395 400 Gln Val Glu Asn Leu Thr Arg Glu Leu Glu Asn Gly Glu Lys Gln Gln 405 410 415 Leu Gln Met Leu Asp Arg Leu Lys Glu Ile Gln Asn His Phe Asp Thr 420 425 430 Cys Glu Ala Glu Arg Lys His Ala Asp Leu Gln Ile Ser Glu Leu Thr 435 440 445 Arg His Ala Glu Asp Ala Thr Lys Gln Ala Glu Arg Tyr Leu Ser Glu 450 455 460 Leu Gln Gln Ser Glu Ala Leu Lys Glu Glu Ala Glu Lys Arg Arg Glu 465 470 475 480 Asp Leu Lys Leu Lys Ala Gln Glu Ser Ile Arg Gln Trp Lys Leu Lys 485 490 495 His Lys Lys Leu Glu Arg Ala Leu Glu Lys Gln Ser Glu Thr Val Asp 500 505 510 Glu Leu Thr Gly Lys Asn Asn Gln Ile Leu Lys Glu Lys Asp Glu Leu 515 520 525 Lys Thr Gln Leu Tyr Ala Ala Leu Gln Gln Ile Glu Asn Leu Arg Lys 530 535 540 Glu Leu Asn Asp Val Leu Thr Lys Arg Ala Leu Gln Glu Glu Glu Leu 545 550 555 560 His Ser Lys Glu Glu Lys Leu Arg Asp Ile Lys Ser His Gln Ala Asp 565 570 575 Leu Glu Leu Glu Val Lys Asn Ser Leu Asp Thr Ile His Arg Leu Glu 580 585 590 Ser Glu Leu Lys Lys Gln Ser Lys Ile Gln Ser Gln Met Lys Val Glu 595 600 605 Lys Ala His Leu Glu Glu Glu Ile Ala Glu Leu Lys Lys Ser Gln Ala 610 615 620 Gln Asp Lys Ala Lys Leu Leu Glu Met Gln Glu Ser Ile Lys Asp Leu 625 630 635 640 Ser Ala Ile Arg Ala Asp Leu Ala Asn Lys Leu Ala Glu Glu Glu Arg 645 650 655 Ala Lys Lys Ala Val Leu Lys Asp Leu Ser Asp Leu Thr Ala Gln Ala 660 665 670 Lys Ser Arg Asp Glu Glu Thr Ala Thr Ile Ile Thr Gln Leu Lys Leu 675 680 685 Glu Arg Asp Val His Gln Arg Glu Leu Lys Asp Leu Thr Ser Ser Leu 690 695 700 Gln Ser Val Lys Thr Lys His Glu Gln Asn Ile Gln Glu Leu Met Lys 705 710 715 720 His Phe Lys Lys Glu Lys Ser Glu Ala Glu Asn His Ile Arg Thr Leu 725 730 735 Lys Ala Glu Ser Leu Glu Glu Lys Asn Met Ala Lys Ile His Arg Gly 740 745 750 Gln Leu Glu Lys Leu Lys Ser Gln Cys Asp Arg Leu Thr Glu Glu Leu 755 760 765 Thr Gln Asn Glu Asn Glu Asn Lys Lys Leu Lys Leu Lys Tyr Gln Cys 770 775 780 Leu Lys Asp Gln Leu Glu Glu Arg Glu Lys His Ile Ser Ile Glu Glu 785 790 795 800 Glu His Leu Arg Arg Met Glu Glu Ala Arg Leu Gln Leu Lys Asp Gln 805 810 815 Leu Leu Cys Leu Glu Thr Glu Gln Glu Ser Ile Leu Gly Val Ile Gly 820 825 830 Lys Glu Ile Asp Ala Ala Cys Lys Thr Phe Ser Lys Asp Ser Val Glu 835 840 845 Lys Leu Lys Val Phe Ser Ser Gly Pro Asp Ile His Tyr Asp Pro His 850 855 860 Arg Trp Leu Ala Glu Ser Lys Thr Lys Leu Gln Trp Leu Cys Glu Glu 865 870 875 880 Leu Lys Glu Arg Glu Asn Arg Glu Lys Asn Leu Arg His Gln Leu Met 885 890 895 Leu Cys Arg Gln Gln Leu Arg Asn Leu Thr Glu Asn Lys Glu Ser Glu 900 905 910 Leu Gln Cys Leu Phe Gln Gln Ile Glu Arg Gln Glu Gln Leu Leu Asp 915 920 925 Glu Ile His Arg Glu Lys Arg Asp Leu Leu Glu Glu Thr Gln Arg Lys 930 935 940 Asp Glu Glu Met Gly Ser Leu Gln Asp Arg Val Ile Ala Leu Glu Thr 945 950 955 960 Ser Thr Gln Val Ala Leu Asp His Leu Glu Ser Val Pro Glu Lys Leu 965 970 975 Ser Leu Leu Glu Asp Phe Lys Asp Phe Arg Asp Ser Cys Ser Ser Ser 980 985 990 Glu Arg Thr Asp Gly Arg Tyr Ser Lys Tyr Arg Val Arg Arg Asn Ser 995 1000 1005 Leu Gln His His Gln Asp Asp Thr Lys Tyr Arg Thr Lys Ser Phe Lys 1010 1015 1020 Gly Asp Arg Thr Phe Leu Glu Gly Ser His Thr Arg Gly Leu Asp His 1025 1030 1035 1040 Ser Ser Ser Trp Gln Asp His Ser Arg Phe Leu Ser Ser Pro Arg Phe 1045 1050 1055 Ser Tyr Val Asn Ser Phe Thr Lys Arg Thr Val Ala Pro Asp Ser Ala 1060 1065 1070 Ser Asn Lys Glu Asp Ala Thr Met Asn Gly Thr Ser Ser Gln Pro Lys 1075 1080 1085 Lys Glu Glu Tyr Gly Ser 1090 <210> 9 <211> 1131 <212> PRT <213> Homo sapiens <400> 9 Met Arg Cys Leu Ala Pro Arg Pro Ala Gly Ser Tyr Leu Ser Glu Pro 1 5 10 15 Gln Gly Ser Ser Gln Cys Ala Thr Met Glu Leu Gly Pro Leu Glu Gly 20 25 30 Gly Tyr Leu Glu Leu Leu Asn Ser Asp Ala Asp Pro Leu Cys Leu Tyr 35 40 45 His Phe Tyr Asp Gln Met Asp Leu Ala Gly Glu Glu Glu Ile Glu Leu 50 55 60 Tyr Ser Glu Pro Asp Thr Asp Thr Ile Asn Cys Asp Gln Phe Ser Arg 65 70 75 80 Leu Leu Cys Asp Met Glu Gly Asp Glu Glu Thr Arg Glu Ala Tyr Ala 85 90 95 Asn Ile Ala Glu Leu Asp Gln Tyr Val Phe Gln Asp Ser Gln Leu Glu 100 105 110 Gly Leu Ser Lys Asp Ile Phe Ile Glu His Ile Gly Pro Asp Glu Val 115 120 125 Ile Gly Glu Ser Met Glu Met Pro Ala Glu Val Gly Gln Lys Ser Gln 130 135 140 Lys Arg Pro Phe Pro Glu Glu Leu Pro Ala Asp Leu Lys His Trp Lys 145 150 155 160 Pro Ala Glu Pro Pro Thr Val Val Thr Gly Ser Leu Leu Val Gly Pro 165 170 175 Val Ser Asp Cys Ser Thr Leu Pro Cys Leu Pro Leu Pro Ala Leu Phe 180 185 190 Asn Gln Glu Pro Ala Ser Gly Gln Met Arg Leu Glu Lys Thr Asp Gln 195 200 205 Ile Pro Met Pro Phe Ser Ser Ser Ser Leu Ser Cys Leu Asn Leu Pro 210 215 220 Glu Gly Pro Ile Gln Phe Val Pro Thr Ile Ser Thr Leu Pro His Gly 225 230 235 240 Leu Trp Gln Ile Ser Glu Ala Gly Thr Gly Val Ser Ser Ile Phe Ile 245 250 255 Tyr His Gly Glu Val Pro Gln Ala Ser Gln Val Pro Pro Ser Gly 260 265 270 Phe Thr Val His Gly Leu Pro Thr Ser Pro Asp Arg Pro Gly Ser Thr 275 280 285 Ser Pro Phe Ala Pro Ser Ala Thr Asp Leu Pro Ser Met Pro Glu Pro 290 295 300 Ala Leu Thr Ser Arg Ala Asn Met Thr Glu His Lys Thr Ser Pro Thr 305 310 315 320 Gln Cys Pro Ala Ala Gly Glu Val Ser Asn Lys Leu Pro Lys Trp Pro 325 330 335 Glu Pro Val Glu Gln Phe Tyr Arg Ser Leu Gln Asp Thr Tyr Gly Ala 340 345 350 Glu Pro Ala Gly Pro Asp Gly Ile Leu Val Glu Val Asp Leu Val Gln 355 360 365 Ala Arg Leu Glu Arg Ser Ser Ser Lys Ser Leu Glu Arg Glu Leu Ala 370 375 380 Thr Pro Asp Trp Ala Glu Arg Gln Leu Ala Gln Gly Gly Leu Ala Glu 385 390 395 400 Val Leu Leu Ala Ala Lys Glu His Arg Arg Pro Arg Glu Thr Arg Val 405 410 415 Ile Ala Val Leu Gly Lys Ala Gly Gln Gly Lys Ser Tyr Trp Ala Gly 420 425 430 Ala Val Ser Arg Ala Trp Ala Cys Gly Arg Leu Pro Gln Tyr Asp Phe 435 440 445 Val Phe Ser Val Pro Cys His Cys Leu Asn Arg Pro Gly Asp Ala Tyr 450 455 460 Gly Leu Gln Asp Leu Leu Phe Ser Leu Gly Pro Gln Pro Leu Val Ala 465 470 475 480 Ala Asp Glu Val Phe Ser His Ile Leu Lys Arg Pro Asp Arg Val Leu 485 490 495 Leu Ile Leu Asp Gly Phe Glu Glu Leu Glu Ala Gln Asp Gly Phe Leu 500 505 510 His Ser Thr Cys Gly Pro Ala Pro Ala Glu Pro Cys Ser Leu Arg Gly 515 520 525 Leu Leu Ala Gly Leu Phe Gln Lys Lys Leu Leu Arg Gly Cys Thr Leu 530 535 540 Leu Leu Thr Ala Arg Pro Arg Gly Arg Leu Val Gln Ser Leu Ser Lys 545 550 555 560 Ala Asp Ala Leu Phe Glu Leu Ser Gly Phe Ser Met Glu Gln Ala Gln 565 570 575 Ala Tyr Val Met Arg Tyr Phe Glu Ser Ser Gly Met Thr Glu His Gln 580 585 590 Asp Arg Ala Leu Thr Leu Leu Arg Asp Arg Pro Leu Leu Leu Ser His 595 600 605 Ser His Ser Pro Thr Leu Cys Arg Ala Val Cys Gln Leu Ser Glu Ala 610 615 620 Leu Leu Glu Leu Gly Glu Asp Ala Lys Leu Pro Ser Thr Leu Thr Gly 625 630 635 640 Leu Tyr Val Gly Leu Leu Gly Arg Ala Ala Leu Asp Ser Pro Pro Gly 645 650 655 Ala Leu Ala Glu Leu Ala Lys Leu Ala Trp Glu Leu Gly Arg Arg His 660 665 670 Gln Ser Thr Leu Gln Glu Asp Gln Phe Pro Ser Ala Asp Val Arg Thr 675 680 685 Trp Ala Met Ala Lys Gly Leu Val Gln His Pro Pro Arg Ala Ala Glu 690 695 700 Ser Glu Leu Ala Phe Pro Ser Phe Leu Leu Gln Cys Phe Leu Gly Ala 705 710 715 720 Leu Trp Leu Ala Leu Ser Gly Glu Ile Lys Asp Lys Glu Leu Pro Gln 725 730 735 Tyr Leu Ala Leu Thr Pro Arg Lys Lys Arg Pro Tyr Asp Asn Trp Leu 740 745 750 Glu Gly Val Pro Arg Phe Leu Ala Gly Leu Ile Phe Gln Pro Ala 755 760 765 Arg Cys Leu Gly Ala Leu Leu Gly Pro Ser Ala Ala Ala Ser Val Asp 770 775 780 Arg Lys Gln Lys Val Leu Ala Arg Tyr Leu Lys Arg Leu Gln Pro Gly 785 790 795 800 Thr Leu Arg Ala Arg Gln Leu Leu Glu Leu Leu His Cys Ala His Glu 805 810 815 Ala Glu Glu Ala Gly Ile Trp Gln His Val Val Gln Glu Leu Pro Gly 820 825 830 Arg Leu Ser Phe Leu Gly Thr Arg Leu Thr Pro Pro Asp Ala His Val 835 840 845 Leu Gly Lys Ala Leu Glu Ala Ala Gly Gln Asp Phe Ser Leu Asp Leu 850 855 860 Arg Ser Thr Gly Ile Cys Pro Ser Gly Leu Gly Ser Leu Val Gly Leu 865 870 875 880 Ser Cys Val Thr Arg Phe Arg Ala Ala Leu Ser Asp Thr Val Ala Leu 885 890 895 Trp Glu Ser Leu Gln Gln His Gly Glu Thr Lys Leu Leu Gln Ala Ala 900 905 910 Glu Glu Lys Phe Thr Ile Glu Pro Phe Lys Ala Lys Ser Leu Lys Asp 915 920 925 Val Glu Asp Leu Gly Lys Leu Val Gln Thr Gln Arg Thr Arg Ser Ser 930 935 940 Ser Glu Asp Thr Ala Gly Glu Leu Pro Ala Val Arg Asp Leu Lys Lys 945 950 955 960 Leu Glu Phe Ala Leu Gly Pro Val Ser Gly Pro Gln Ala Phe Pro Lys 965 970 975 Leu Val Arg Ile Leu Thr Ala Phe Ser Ser Leu Gln His Leu Asp Leu 980 985 990 Asp Ala Leu Ser Glu Asn Lys Ile Gly Asp Glu Gly Val Ser Gln Leu 995 1000 1005 Ser Ala Thr Phe Pro Gln Leu Lys Ser Leu Glu Thr Leu Asn Leu Ser 1010 1015 1020 Gln Asn Asn Ile Thr Asp Leu Gly Ala Tyr Lys Leu Ala Glu Ala Leu 1025 1030 1035 1040 Pro Ser Leu Ala Ala Ser Leu Leu Arg Leu Ser Leu Tyr Asn Asn Cys 1045 1050 1055 Ile Cys Asp Val Gly Ala Glu Ser Leu Ala Arg Val Leu Pro Asp Met 1060 1065 1070 Val Ser Leu Arg Val Met Asp Val Gln Tyr Asn Lys Phe Thr Ala Ala 1075 1080 1085 Gly Ala Gln Gln Leu Ala Ala Ser Leu Arg Arg Cys Pro His Val Glu 1090 1095 1100 Thr Leu Ala Met Trp Thr Pro Thr Ile Pro Phe Ser Val Gln Glu His 1105 1110 1115 1120 Leu Gln Gln Gln Asp Ser Arg Ile Ser Leu Arg 1125 1130 <210> 10 <211> 1838 <212> PRT <213> Homo sapiens <400> 10 Met Asp Val His Thr Arg Trp Lys Ala Arg Ser Ala Leu Arg Pro Gly 1 5 10 15 Ala Pro Leu Leu Pro Pro Leu Leu Leu Leu Leu Leu Trp Ala Pro Pro 20 25 30 Pro Ser Arg Ala Ala Gln Pro Ala Asp Leu Leu Lys Val Leu Asp Phe 35 40 45 His Asn Leu Pro Asp Gly Ile Thr Lys Thr Thr Gly Phe Cys Ala Thr 50 55 60 Arg Arg Ser Ser Lys Gly Pro Asp Val Ala Tyr Arg Val Thr Lys Asp 65 70 75 80 Ala Gln Leu Ser Ala Pro Thr Lys Gln Leu Tyr Pro Ala Ser Ala Phe 85 90 95 Pro Glu Asp Phe Ser Ile Leu Thr Thr Val Lys Ala Lys Lys Gly Ser 100 105 110 Gln Ala Phe Leu Val Ser Ile Tyr Asn Glu Gln Gly Ile Gln Gln Ile 115 120 125 Gly Leu Glu Leu Gly Arg Ser Pro Val Phe Leu Tyr Glu Asp His Thr 130 135 140 Gly Lys Pro Gly Pro Glu Asp Tyr Pro Leu Phe Arg Gly Ile Asn Leu 145 150 155 160 Ser Asp Gly Lys Trp His Arg Ile Ala Leu Ser Val His Lys Lys Asn 165 170 175 Val Thr Leu Ile Leu Asp Cys Lys Lys Lys Thr Thr Lys Phe Leu Asp 180 185 190 Arg Ser Asp His Pro Met Ile Asp Ile Asn Gly Ile Ile Val Phe Gly 195 200 205 Thr Arg Ile Leu Asp Glu Glu Val Phe Glu Gly Asp Ile Gln Gln Leu 210 215 220 Leu Phe Val Ser Asp His Arg Ala Ala Tyr Asp Tyr Cys Glu His Tyr 225 230 235 240 Ser Pro Asp Cys Asp Thr Ala Val Pro Asp Thr Pro Gln Ser Gln Asp 245 250 255 Pro Asn Pro Asp Glu Tyr Tyr Thr Glu Gly Asp Gly Glu Gly Glu Thr 260 265 270 Tyr Tyr Tyr Glu Tyr Pro Tyr Tyr Glu Asp Pro Glu Asp Leu Gly Lys 275 280 285 Glu Pro Thr Pro Ser Lys Lys Pro Val Glu Ala Ala Lys Glu Thr Thr 290 295 300 Glu Val Pro Glu Glu Leu Thr Pro Thr Pro Thr Glu Ala Ala Pro Met 305 310 315 320 Pro Glu Thr Ser Glu Gly Ala Gly Lys Glu Glu Asp Val Gly Ile Gly 325 330 335 Asp Tyr Asp Tyr Val Pro Ser Glu Asp Tyr Tyr Thr Pro Ser Pro Tyr 340 345 350 Asp Asp Leu Thr Tyr Gly Glu Gly Glu Glu Asn Pro Asp Gln Pro Thr 355 360 365 Asp Pro Gly Ala Gly Ala Glu Ile Pro Thr Ser Thr Ala Asp Thr Ser 370 375 380 Asn Ser Ser Asn Pro Ala Pro Pro Pro Gly Glu Gly Ala Asp Asp Leu 385 390 395 400 Glu Gly Glu Phe Thr Glu Glu Thr Ile Arg Asn Leu Asp Glu Asn Tyr 405 410 415 Tyr Asp Pro Tyr Tyr Asp Pro Thr Ser Ser Pro Ser Glu Ile Gly Pro 420 425 430 Gly Met Pro Ala Asn Gln Asp Thr Ile Tyr Glu Gly Ile Gly Gly Pro 435 440 445 Arg Gly Glu Lys Gly Gln Lys Gly Glu Pro Ala Ile Ile Glu Pro Gly 450 455 460 Met Leu Ile Glu Gly Pro Pro Gly Pro Glu Gly Pro Ala Gly Leu Pro 465 470 475 480 Gly Pro Pro Gly Thr Met Gly Pro Thr Gly Gln Val Gly Asp Pro Gly 485 490 495 Glu Arg Gly Pro Pro Gly Arg Pro Gly Leu Pro Gly Ala Asp Gly Leu 500 505 510 Pro Gly Pro Pro Gly Thr Met Leu Met Leu Pro Phe Arg Phe Gly Gly 515 520 525 Gly Gly Asp Ala Gly Ser Lys Gly Pro Met Val Ser Ala Gln Glu Ser 530 535 540 Gln Ala Gln Ala Ile Leu Gln Gln Ala Arg Leu Ala Leu Arg Gly Pro 545 550 555 560 Ala Gly Pro Met Gly Leu Thr Gly Arg Pro Gly Pro Val Gly Pro Pro 565 570 575 Gly Ser Gly Gly Leu Lys Gly Glu Pro Gly Asp Val Gly Pro Gln Gly 580 585 590 Pro Arg Gly Val Gln Gly Pro Pro Gly Pro Ala Gly Lys Pro Gly Arg 595 600 605 Arg Gly Arg Ala Gly Ser Asp Gly Ala Arg Gly Met Pro Gly Gln Thr 610 615 620 Gly Pro Lys Gly Asp Arg Gly Phe Asp Gly Leu Ala Gly Leu Pro Gly 625 630 635 640 Glu Lys Gly His Arg Gly Asp Pro Gly Pro Ser Gly Pro Pro Gly Pro 645 650 655 Pro Gly Asp Asp Gly Glu Arg Gly Asp Asp Gly Glu Val Gly Pro Arg 660 665 670 Gly Leu Pro Gly Glu Pro Gly Pro Arg Gly Leu Leu Gly Pro Lys Gly 675 680 685 Pro Pro Gly Pro Pro Gly Pro Pro Gly Val Thr Gly Met Asp Gly Gln 690 695 700 Pro Gly Pro Lys Gly Asn Val Gly Pro Gln Gly Glu Pro Gly Pro Pro 705 710 715 720 Gly Gln Gln Gly Asn Pro Gly Ala Gln Gly Leu Pro Gly Pro Gln Gly 725 730 735 Ala Ile Gly Pro Pro Gly Glu Lys Gly Pro Leu Gly Lys Pro Gly Leu 740 745 750 Pro Gly Met Pro Gly Ala Asp Gly Pro Pro Gly His Pro Gly Lys Glu 755 760 765 Gly Pro Pro Gly Glu Lys Gly Gly Gln Gly Pro Gly Pro Gln Gly 770 775 780 Pro Ile Gly Tyr Pro Gly Pro Arg Gly Val Lys Gly Ala Asp Gly Ile 785 790 795 800 Arg Gly Leu Lys Gly Thr Lys Gly Glu Lys Gly Glu Asp Gly Phe Pro 805 810 815 Gly Phe Lys Gly Asp Met Gly Ile Lys Gly Asp Arg Gly Glu Ile Gly 820 825 830 Pro Pro Gly Pro Arg Gly Glu Asp Gly Pro Glu Gly Pro Lys Gly Arg 835 840 845 Gly Gly Pro Asn Gly Asp Pro Gly Pro Leu Gly Pro Pro Gly Glu Lys 850 855 860 Gly Lys Leu Gly Val Pro Gly Leu Pro Gly Tyr Pro Gly Arg Gln Gly 865 870 875 880 Pro Lys Gly Ser Ile Gly Phe Pro Gly Phe Pro Gly Ala Asn Gly Glu 885 890 895 Lys Gly Gly Arg Gly Thr Pro Gly Lys Pro Gly Pro Arg Gly Gln Arg 900 905 910 Gly Pro Thr Gly Pro Arg Gly Glu Arg Gly Pro Arg Gly Ile Thr Gly 915 920 925 Lys Pro Gly Pro Lys Gly Asn Ser Gly Gly Asp Gly Pro Ala Gly Pro 930 935 940 Pro Gly Glu Arg Gly Pro Asn Gly Pro Gln Gly Pro Thr Gly Phe Pro 945 950 955 960 Gly Pro Lys Gly Pro Pro Gly Pro Pro Gly Lys Asp Gly Leu Pro Gly 965 970 975 His Pro Gly Gln Arg Gly Glu Thr Gly Phe Gln Gly Lys Thr Gly Pro 980 985 990 Pro Gly Pro Pro Gly Val Val Gly Pro Gln Gly Pro Thr Gly Glu Thr 995 1000 1005 Gly Pro Met Gly Glu Arg Gly His Pro Gly Pro Pro Gly Pro Pro Gly 1010 1015 1020 Glu Gln Gly Leu Pro Gly Leu Ala Gly Lys Glu Gly Thr Lys Gly Asp 1025 1030 1035 1040 Pro Gly Pro Ala Gly Leu Pro Gly Lys Asp Gly Pro Pro Gly Leu Arg 1045 1050 1055 Gly Phe Pro Gly Asp Arg Gly Leu Pro Gly Pro Val Gly Ala Leu Gly 1060 1065 1070 Leu Lys Gly Asn Glu Gly Pro Pro Gly Pro Pro Gly Pro Ala Gly Ser 1075 1080 1085 Pro Gly Glu Arg Gly Pro Ala Gly Ala Ala Gly Pro Ile Gly Ile Pro 1090 1095 1100 Gly Arg Pro Gly Pro Gln Gly Pro Pro Gly Pro Ala Gly Glu Lys Gly 1105 1110 1115 1120 Ala Pro Gly Glu Lys Gly Pro Gln Gly Pro Ala Gly Arg Asp Gly Leu 1125 1130 1135 Gln Gly Pro Val Gly Leu Pro Gly Pro Ala Gly Pro Val Gly Pro Pro 1140 1145 1150 Gly Glu Asp Gly Asp Lys Gly Glu Ile Gly Glu Pro Gly Gln Lys Gly 1155 1160 1165 Ser Lys Gly Asp Lys Gly Glu Gln Gly Pro Pro Gly Pro Thr Gly Pro 1170 1175 1180 Gln Gly Pro Ile Gly Gln Pro Gly Pro Ser Gly Ala Asp Gly Glu Pro 1185 1190 1195 1200 Gly Pro Arg Gly Gln Gln Gly Leu Phe Gly Gln Lys Gly Asp Glu Gly 1205 1210 1215 Pro Arg Gly Phe Pro Gly Pro Pro Gly Pro Val Gly Leu Gln Gly Leu 1220 1225 1230 Pro Gly Pro Pro Gly Glu Lys Gly Glu Thr Gly Asp Val Gly Gln Met 1235 1240 1245 Gly Pro Pro Gly Pro Pro Gly Pro Arg Gly Pro Ser Gly Ala Pro Gly 1250 1255 1260 Ala Asp Gly Pro Gln Gly Pro Pro Gly Gly Ile Gly Asn Pro Gly Ala 1265 1270 1275 1280 Val Gly Glu Lys Gly Glu Pro Gly Glu Ala Gly Glu Pro Gly Leu Pro 1285 1290 1295 Gly Glu Gly Gly Pro Pro Gly Pro Lys Gly Glu Arg Gly Glu Lys Gly 1300 1305 1310 Glu Ser Gly Pro Ser Gly Ala Ala Gly Pro Pro Gly Pro Lys Gly Pro 1315 1320 1325 Pro Gly Asp Asp Gly Pro Lys Gly Ser Pro Gly Pro Val Gly Phe Pro 1330 1335 1340 Gly Asp Pro Gly Pro Pro Gly Glu Pro Gly Pro Ala Gly Gln Asp Gly 1345 1350 1355 1360 Pro Pro Gly Asp Lys Gly Asp Asp Gly Glu Pro Gly Gln Thr Gly Ser 1365 1370 1375 Pro Gly Pro Thr Gly Glu Pro Gly Pro Ser Gly Pro Pro Gly Lys Arg 1380 1385 1390 Gly Pro Pro Gly Pro Ala Gly Pro Glu Gly Arg Gln Gly Glu Lys Gly 1395 1400 1405 Ala Lys Gly Glu Ala Gly Leu Glu Gly Pro Pro Gly Lys Thr Gly Pro 1410 1415 1420 Ile Gly Pro Gln Gly Ala Pro Gly Lys Pro Gly Pro Asp Gly Leu Arg 1425 1430 1435 1440 Gly Ile Pro Gly Pro Val Gly Glu Gln Gly Leu Pro Gly Ser Pro Gly 1445 1450 1455 Pro Asp Gly Pro Pro Gly Pro Met Gly Pro Pro Gly Leu Pro Gly Leu 1460 1465 1470 Lys Gly Asp Ser Gly Pro Lys Gly Glu Lys Gly His Pro Gly Leu Ile 1475 1480 1485 Gly Leu Ile Gly Pro Gly Glu Gln Gly Glu Lys Gly Asp Arg Gly 1490 1495 1500 Leu Pro Gly Pro Gln Gly Ser Ser Gly Pro Lys Gly Glu Gln Gly Ile 1505 1510 1515 1520 Thr Gly Pro Ser Gly Pro Ile Gly Pro Pro Gly Pro Pro Gly Leu Pro 1525 1530 1535 Gly Pro Pro Gly Pro Lys Gly Ala Lys Gly Ser Ser Gly Pro Thr Gly 1540 1545 1550 Pro Lys Gly Glu Ala Gly His Pro Gly Pro Pro Gly Pro Pro Gly Pro 1555 1560 1565 Pro Gly Glu Val Ile Gln Pro Leu Pro Ile Gln Ala Ser Arg Thr Arg 1570 1575 1580 Arg Asn Ile Asp Ala Ser Gln Leu Leu Asp Asp Gly Asn Gly Glu Asn 1585 1590 1595 1600 Tyr Val Asp Tyr Ala Asp Gly Met Glu Glu Ile Phe Gly Ser Leu Asn 1605 1610 1615 Ser Leu Lys Leu Glu Ile Glu Gln Met Lys Arg Pro Leu Gly Thr Gln 1620 1625 1630 Gln Asn Pro Ala Arg Thr Cys Lys Asp Leu Gln Leu Cys His Pro Asp 1635 1640 1645 Phe Pro Asp Gly Glu Tyr Trp Val Asp Pro Asn Gin Gly Cys Ser Arg 1650 1655 1660 Asp Ser Phe Lys Val Tyr Cys Asn Phe Thr Ala Gly Gly Ser Thr Cys 1665 1670 1675 1680 Val Phe Pro Asp Lys Lys Ser Glu Gly Ala Arg Ile Thr Ser Trp Pro 1685 1690 1695 Lys Glu Asn Pro Gly Ser Trp Phe Ser Glu Phe Lys Arg Gly Lys Leu 1700 1705 1710 Leu Ser Tyr Val Asp Ala Glu Gly Asn Pro Val Gly Val Val Gln Met 1715 1720 1725 Thr Phe Leu Arg Leu Leu Ser Ala Ser Ala His Gln Asn Val Thr Tyr 1730 1735 1740 His Cys Tyr Gln Ser Val Ala Trp Gln Asp Ala Ala Thr Gly Ser Tyr 1745 1750 1755 1760 Asp Lys Ala Leu Arg Phe Leu Gly Ser Asn Asp Glu Glu Met Ser Tyr 1765 1770 1775 Asp Asn Asn Pro Tyr Ile Arg Ala Leu Val Asp Gly Cys Ala Thr Lys 1780 1785 1790 Lys Gly Tyr Gln Lys Thr Val Leu Glu Ile Asp Thr Pro Lys Val Glu 1795 1800 1805 Gln Val Pro Ile Val Asp Ile Met Phe Asn Asp Phe Gly Glu Ala Ser 1810 1815 1820 Gln Lys Phe Gly Phe Glu Val Gly Pro Ala Cys Phe Met Gly 1825 1830 1835 <210> 11 <211> 509 <212> PRT <213> Homo sapiens <400> 11 Met Ala Ala Ala Ala Gly Met Leu Leu Leu Gly Leu Leu Gln Ala Gly 1 5 10 15 Gly Ser Val Leu Gly Gln Ala Met Glu Lys Val Thr Gly Gly Asn Leu 20 25 30 Leu Ser Met Leu Leu Ile Ala Cys Ala Phe Thr Leu Ser Leu Val Tyr 35 40 45 Leu Ile Arg Leu Ala Ala Gly His Leu Val Gln Leu Pro Ala Gly Val 50 55 60 Lys Ser Pro Pro Tyr Ile Phe Ser Pro Ile Pro Phe Leu Gly His Ala 65 70 75 80 Ile Ala Phe Gly Lys Ser Pro Ile Glu Phe Leu Glu Asn Ala Tyr Glu 85 90 95 Lys Tyr Gly Pro Val Phe Ser Phe Thr Met Val Gly Lys Thr Phe Thr 100 105 110 Tyr Leu Leu Gly Ser Asp Ala Ala Ala Leu Leu Phe Asn Ser Lys Asn 115 120 125 Glu Asp Leu Asn Ala Glu Asp Val Tyr Ser Arg Leu Thr Thr Pro Val 130 135 140 Phe Gly Lys Gly Val Ala Tyr Asp Val Pro Asn Pro Val Phe Leu Glu 145 150 155 160 Gln Lys Lys Met Leu Lys Ser Gly Leu Asn Ile Ala His Phe Lys Gln 165 170 175 His Val Ser Ile Ile Glu Lys Glu Thr Lys Glu Tyr Phe Glu Ser Trp 180 185 190 Gly Glu Ser Gly Glu Lys Asn Val Phe Glu Ala Leu Ser Glu Leu Ile 195 200 205 Ile Leu Thr Ala Ser His Cys Leu His Gly Lys Glu Ile Arg Ser Gln 210 215 220 Leu Asn Glu Lys Val Ala Gln Leu Tyr Ala Asp Leu Asp Gly Gly Phe 225 230 235 240 Ser His Ala Ala Trp Leu Leu Pro Gly Trp Leu Pro Leu Pro Ser Phe 245 250 255 Arg Arg Arg Asp Arg Ala His Arg Glu Ile Lys Asp Ile Phe Tyr Lys 260 265 270 Ala Ile Gln Lys Arg Arg Gln Ser Gln Glu Lys Ile Asp Asp Ile Leu 275 280 285 Gln Thr Leu Leu Asp Ala Thr Tyr Lys Asp Gly Arg Pro Leu Thr Asp 290 295 300 Asp Glu Val Ala Gly Met Leu Ile Gly Leu Leu Leu Ala Gly Gln His 305 310 315 320 Thr Ser Ser Thr Thr Ser Ala Trp Met Gly Phe Phe Leu Ala Arg Asp 325 330 335 Lys Thr Leu Gln Lys Lys Cys Tyr Leu Glu Gln Lys Thr Val Cys Gly 340 345 350 Glu Asn Leu Pro Pro Leu Thr Tyr Asp Gln Leu Lys Asp Leu Asn Leu 355 360 365 Leu Asp Arg Cys Ile Lys Glu Thr Leu Arg Leu Arg Pro Pro Ile Met 370 375 380 Ile Met Met Arg Met Ala Arg Thr Pro Gln Thr Val Ala Gly Tyr Thr 385 390 395 400 Ile Pro Pro Gly His Gln Val Cys Val Ser Pro Thr Val Asn Gln Arg 405 410 415 Leu Lys Asp Ser Trp Val Glu Arg Leu Asp Phe Asn Pro Asp Arg Tyr 420 425 430 Leu Gln Asp Asn Pro Ala Ser Gly Glu Lys Phe Ala Tyr Val Pro Phe 435 440 445 Gly Ala Gly Arg His Arg Cys Ile Gly Glu Asn Phe Ala Tyr Val Gln 450 455 460 Ile Lys Thr Ile Trp Ser Thr Met Leu Arg Leu Tyr Glu Phe Asp Leu 465 470 475 480 Ile Asp Gly Tyr Phe Pro Thr Val Asn Tyr Thr Thr Met Ile His Thr 485 490 495 Pro Glu Asn Pro Val Ile Arg Tyr Lys Arg Arg Ser Lys 500 505 <210> 12 <211> 837 <212> PRT <213> Homo sapiens <400> 12 Met Ala Lys Ala Ala Ala Ser Ser Ser Leu Glu Asp Leu Asp Leu Ser 1 5 10 15 Gly Glu Glu Val Gln Arg Leu Thr Ser Ala Phe Gln Asp Pro Glu Phe 20 25 30 Arg Arg Met Phe Ser Gln Tyr Ala Glu Glu Leu Thr Asp Pro Glu Asn 35 40 45 Arg Arg Arg Tyr Glu Ala Glu Ile Thr Ala Leu Glu Arg Glu Arg Gly 50 55 60 Val Glu Val Arg Phe Val His Pro Glu Pro Gly His Val Leu Arg Thr 65 70 75 80 Ser Leu Asp Gly Ala Arg Arg Cys Phe Val Asn Val Cys Ser Asn Ala 85 90 95 Leu Val Gly Ala Pro Ser Ser Arg Pro Gly Ser Gly Gly Asp Arg Gly 100 105 110 Ala Ala Pro Gly Ser His Trp Ser Leu Pro Tyr Ser Leu Ala Pro Gly 115 120 125 Arg Glu Tyr Ala Gly Arg Ser Ser Ser Arg Tyr Met Val Tyr Asp Val 130 135 140 Val Phe His Pro Asp Ala Leu Ala Leu Ala Arg Arg His Glu Gly Phe 145 150 155 160 Arg Gln Met Leu Asp Ala Thr Ala Leu Glu Ala Val Glu Lys Gln Phe 165 170 175 Gly Val Lys Leu Asp Arg Arg Asn Ala Lys Thr Leu Lys Ala Lys Tyr 180 185 190 Lys Gly Thr Pro Glu Ala Ala Val Leu Arg Thr Pro Leu Pro Gly Val 195 200 205 Ile Pro Ala Arg Pro Asp Gly Glu Pro Lys Gly Pro Leu Pro Asp Phe 210 215 220 Pro Tyr Pro Tyr Gln Tyr Pro Ala Ala Pro Gly Pro Arg Ala Pro Ser 225 230 235 240 Pro Pro Glu Ala Ala Leu Gln Pro Ala Pro Thr Glu Pro Arg Tyr Ser 245 250 255 Val Val Gln Arg His His Val Asp Leu Gln Asp Tyr Arg Cys Ser Arg 260 265 270 Asp Ser Ala Pro Ser Pro Val Pro His Glu Leu Val Ile Thr Ile Glu 275 280 285 Leu Pro Leu Leu Arg Ser Ala Glu Gln Ala Ala Leu Glu Val Thr Arg 290 295 300 Lys Leu Leu Cys Leu Asp Ser Arg Lys Pro Asp Tyr Arg Leu Arg Leu 305 310 315 320 Ser Leu Pro Tyr Pro Val Asp Asp Gly Arg Gly Lys Ala Gln Phe Asn 325 330 335 Lys Ala Arg Arg Gln Leu Val Val Thr Leu Pro Val Val Leu Pro Ala 340 345 350 Ala Arg Arg Glu Pro Ala Val Ala Val Ala Ala Ala Ala Pro Glu Glu 355 360 365 Ser Ala Asp Arg Ser Gly Thr Asp Gly Gln Ala Cys Ala Ser Ala Arg 370 375 380 Glu Gly Glu Ala Gly Pro Ala Arg Ser Arg Ala Glu Asp Gly Gly His 385 390 395 400 Asp Thr Cys Val Ala Gly Ala Ala Gly Ser Gly Val Thr Thr Leu Gly 405 410 415 Asp Pro Glu Val Ala Pro Pro Pro Ala Ala Ala Gly Glu Glu Arg Val 420 425 430 Pro Lys Pro Gly Glu Gln Asp Leu Ser Arg His Ala Gly Ser Pro Pro 435 440 445 Gly Ser Val Glu Glu Pro Ser Pro Gly Gly Glu Asn Ser Pro Gly Gly 450 455 460 Gly Gly Ser Pro Cys Leu Ser Ser Arg Ser Leu Ala Trp Gly Ser Ser 465 470 475 480 Ala Gly Arg Glu Ser Ala Arg Gly Asp Ser Ser Val Glu Thr Arg Glu 485 490 495 Glu Ser Glu Gly Thr Gly Gly Gln Arg Ser Ala Cys Ala Met Gly Gly 500 505 510 Pro Gly Thr Lys Ser Gly Glu Pro Leu Cys Pro Pro Leu Leu Cys Asn 515 520 525 Gln Asp Lys Glu Thr Leu Thr Leu Leu Ile Gln Val Pro Arg Ile Gln 530 535 540 Pro Gln Ser Leu Gln Gly Asp Leu Asn Pro Leu Trp Tyr Lys Leu Arg 545 550 555 560 Phe Ser Ala Gln Asp Leu Val Tyr Ser Phe Phe Leu Gln Phe Ala Pro 565 570 575 Glu Asn Lys Leu Ser Thr Thr Glu Pro Val Ile Ser Ile Ser Ser Asn 580 585 590 Asn Ala Val Ile Glu Leu Ala Lys Ser Pro Glu Ser His Gly His Trp 595 600 605 Arg Glu Trp Tyr Tyr Gly Val Asn Asn Asp Ser Leu Glu Glu Arg Leu 610 615 620 Phe Val Asn Glu Glu Asn Val Asn Glu Phe Leu Glu Glu Val Leu Ser 625 630 635 640 Ser Pro Phe Lys Gln Ser Met Ser Leu Thr Pro Pro Leu Ile Glu Val 645 650 655 Leu Gln Val Thr Asp Asn Lys Ile Gln Ile Asn Ala Lys Leu Gln Glu 660 665 670 Cys Ser Asn Ser Asp Gln Leu Gln Gly Lys Glu Glu Arg Val Asn Glu 675 680 685 Glu Ser His Leu Thr Glu Lys Glu Tyr Ile Glu His Cys Asn Thr Pro 690 695 700 Thr Thr Asp Ser Asp Ser Ser Ile Ala Val Lys Ala Leu Gln Ile Asp 705 710 715 720 Ser Phe Gly Leu Val Thr Cys Phe Gln Gln Glu Ser Leu Asp Val Ser 725 730 735 Gln Met Ile Leu Gly Lys Ser Gln Gln Pro Glu Ser Lys Met Gln Ser 740 745 750 Glu Phe Ile Lys Glu Lys Ser Ala Thr Cys Ser Asn Glu Glu Lys Asp 755 760 765 Asn Leu Asn Glu Ser Val Ile Thr Glu Glu Lys Glu Thr Asp Gly Asp 770 775 780 His Leu Ser Ser Leu Leu Asn Lys Thr Thr Val His Asn Ile Pro Gly 785 790 795 800 Phe Asp Ser Ile Lys Glu Thr Asn Met Gln Asp Gly Ser Val Gln Val 805 810 815 Ile Lys Asp His Val Thr Asn Cys Ala Phe Ser Phe Gln Asn Ser Leu 820 825 830 Leu Tyr Asp Leu Asp 835 <210> 13 <211> 984 <212> PRT <213> Homo sapiens <400> 13 Met Ala Leu Asp Tyr Leu Leu Leu Leu Leu Leu Ala Ser Ala Val Ala 1 5 10 15 Ala Met Glu Glu Thr Leu Met Asp Thr Arg Thr Ala Thr Ala Glu Leu 20 25 30 Gly Trp Thr Ala Asn Pro Ala Ser Gly Trp Glu Glu Val Ser Gly Tyr 35 40 45 Asp Glu Asn Leu Asn Thr Ile Arg Thr Tyr Gln Val Cys Asn Val Phe 50 55 60 Glu Pro Asn Gln Asn Asn Trp Leu Leu Thr Thr Phe Ile Asn Arg Arg 65 70 75 80 Gly Ala His Arg Ile Tyr Thr Glu Met Arg Phe Thr Val Arg Asp Cys 85 90 95 Ser Ser Leu Pro Asn Val Pro Gly Ser Cys Lys Glu Thr Phe Asn Leu 100 105 110 Tyr Tyr Tyr Glu Thr Asp Ser Val Ile Ala Thr Lys Lys Ser Ala Phe 115 120 125 Trp Ser Glu Ala Pro Tyr Leu Lys Val Asp Thr Ile Ala Ala Asp Glu 130 135 140 Ser Phe Ser Gln Val Asp Phe Gly Gly Arg Leu Met Lys Val Asn Thr 145 150 155 160 Glu Val Arg Ser Phe Gly Pro Leu Thr Arg Asn Gly Phe Tyr Leu Ala 165 170 175 Phe Gln Asp Tyr Gly Ala Cys Met Ser Leu Leu Ser Val Arg Val Phe 180 185 190 Phe Lys Lys Cys Pro Ser Ile Val Gln Asn Phe Ala Val Phe Pro Glu 195 200 205 Thr Met Thr Gly Ala Glu Ser Thr Ser Leu Val Ile Ala Arg Gly Thr 210 215 220 Cys Ile Pro Asn Ala Glu Glu Val Asp Val Pro Ile Lys Leu Tyr Cys 225 230 235 240 Asn Gly Asp Gly Glu Trp Met Val Pro Ile Gly Arg Cys Thr Cys Lys 245 250 255 Pro Gly Tyr Glu Pro Glu Asn Ser Val Ala Cys Lys Ala Cys Pro Ala 260 265 270 Gly Thr Phe Lys Ala Ser Gln Glu Ala Glu Gly Cys Ser His Cys Pro 275 280 285 Ser Asn Ser Arg Ser Pro Ala Glu Ala Ser Pro Ile Cys Thr Cys Arg 290 295 300 Thr Gly Tyr Tyr Arg Ala Asp Phe Asp Pro Pro Glu Val Ala Cys Thr 305 310 315 320 Ser Val Pro Ser Gly Pro Arg Asn Val Ile Ser Ile Val Asn Glu Thr 325 330 335 Ser Ile Ile Leu Glu Trp His Pro Arg Glu Thr Gly Gly Arg Asp 340 345 350 Asp Val Thr Tyr Asn Ile Ile Cys Lys Lys Cys Arg Ala Asp Arg Arg 355 360 365 Ser Cys Ser Arg Cys Asp Asp Asn Val Glu Phe Val Pro Arg Gln Leu 370 375 380 Gly Leu Thr Glu Cys Arg Val Ser Ile Ser Ser Leu Trp Ala His Thr 385 390 395 400 Pro Tyr Thr Phe Asp Ile Gln Ala Ile Asn Gly Val Ser Ser Lys Ser 405 410 415 Pro Phe Pro Pro Gln His Val Ser Val Asn Ile Thr Thr Asn Gln Ala 420 425 430 Ala Pro Ser Thr Val Pro Ile Met His Gln Val Ser Ala Thr Met Arg 435 440 445 Ser Ile Thr Leu Ser Trp Pro Gln Pro Glu Gln Pro Asn Gly Ile Ile 450 455 460 Leu Asp Tyr Glu Ile Arg Tyr Tyr Glu Lys Glu His Asn Glu Phe Asn 465 470 475 480 Ser Ser Met Ala Arg Ser Gln Thr Asn Thr Ala Arg Ile Asp Gly Leu 485 490 495 Arg Pro Gly Met Val Tyr Val Val Gln Val Arg Ala Arg Thr Val Ala 500 505 510 Gly Tyr Gly Lys Phe Ser Gly Lys Met Cys Phe Gln Thr Leu Thr Asp 515 520 525 Asp Asp Tyr Lys Ser Glu Leu Arg Glu Gln Leu Pro Leu Ile Ala Gly 530 535 540 Ser Ala Ala Ala Gly Val Val Phe Val Val Ser Leu Val Ala Ile Ser 545 550 555 560 Ile Val Cys Ser Arg Lys Arg Ala Tyr Ser Lys Glu Ala Val Tyr Ser 565 570 575 Asp Lys Leu Gln His Tyr Ser Thr Gly Arg Gly Ser Pro Gly Met Lys 580 585 590 Ile Tyr Ile Asp Pro Phe Thr Tyr Glu Asp Pro Asn Glu Ala Val Arg 595 600 605 Glu Phe Ala Lys Glu Ile Asp Val Ser Phe Val Lys Ile Glu Glu Val 610 615 620 Ile Gly Ala Gly Glu Phe Gly Glu Val Tyr Lys Gly Arg Leu Lys Leu 625 630 635 640 Pro Gly Lys Arg Glu Ile Tyr Val Ala Ile Lys Thr Leu Lys Ala Gly 645 650 655 Tyr Ser Glu Lys Gln Arg Arg Asp Phe Leu Ser Glu Ala Ser Ile Met 660 665 670 Gly Gln Phe Asp His Pro Asn Ile Ile Arg Leu Glu Gly Val Val Thr 675 680 685 Lys Ser Arg Pro Val Met Ile Ile Thr Glu Phe Met Glu Asn Gly Ala 690 695 700 Leu Asp Ser Phe Leu Arg Gln Asn Asp Gly Gln Phe Thr Val Ile Gln 705 710 715 720 Leu Val Gly Met Leu Arg Gly Ile Ala Ala Gly Met Lys Tyr Leu Ala 725 730 735 Glu Met Asn Tyr Val His Arg Asp Leu Ala Ala Arg Asn Ile Leu Val 740 745 750 Asn Ser Asn Leu Val Cys Lys Val Ser Asp Phe Gly Leu Ser Arg Tyr 755 760 765 Leu Gln Asp Asp Thr Ser Asp Pro Thr Tyr Thr Ser Ser Leu Gly Gly 770 775 780 Lys Ile Pro Val Arg Trp Thr Ala Pro Glu Ala Ile Ala Tyr Arg Lys 785 790 795 800 Phe Thr Ser Ala Ser Asp Val Trp Ser Tyr Gly Ile Val Met Trp Glu 805 810 815 Val Met Ser Phe Gly Glu Arg Pro Tyr Trp Asp Met Ser Asn Gln Asp 820 825 830 Val Ile Asn Ala Ile Glu Gln Asp Tyr Arg Leu Pro Pro Met Asp 835 840 845 Cys Pro Ala Ala Leu His Gln Leu Met Leu Asp Cys Trp Gln Lys Asp 850 855 860 Arg Asn Ser Arg Pro Arg Phe Ala Glu Ile Val Asn Thr Leu Asp Lys 865 870 875 880 Met Ile Arg Asn Pro Ala Ser Leu Lys Thr Val Ala Thr Ile Thr Ala 885 890 895 Val Pro Ser Gln Pro Leu Leu Asp Arg Ser Ile Pro Asp Phe Thr Ala 900 905 910 Phe Thr Thr Val Asp Asp Trp Leu Ser Ala Ile Lys Met Val Gln Tyr 915 920 925 Arg Asp Ser Phe Leu Thr Ala Gly Phe Thr Ser Leu Gln Leu Val Thr 930 935 940 Gln Met Thr Ser Glu Asp Leu Leu Arg Ile Gly Ile Thr Leu Ala Gly 945 950 955 960 His Gln Lys Lys Ile Leu Asn Ser Ile His Ser Met Arg Val Gln Ile 965 970 975 Ser Gln Ser Pro Thr Ala Met Ala 980 <210> 14 <211> 717 <212> PRT <213> Homo sapiens <400> 14 Met Thr Pro Pro Pro Pro Pro Pro Pro Pro Gly Pro Asp Pro Ala 1 5 10 15 Ala Asp Pro Ala Ala Asp Pro Cys Pro Trp Pro Gly Ser Leu Val Val 20 25 30 Leu Phe Gly Ala Thr Ala Gly Ala Leu Gly Arg Asp Leu Gly Ser Asp 35 40 45 Glu Thr Asp Leu Ile Leu Leu Val Trp Gln Val Val Glu Pro Arg Ser 50 55 60 Arg Gln Val Gly Thr Leu His Lys Ser Leu Val Arg Ala Glu Ala Ala 65 70 75 80 Ala Leu Ser Thr Gln Cys Arg Glu Ala Ser Gly Leu Ser Ala Asp Ser 85 90 95 Leu Ala Arg Ala Glu Pro Leu Asp Lys Val Leu Gln Gln Phe Ser Gln 100 105 110 Leu Val Asn Gly Asp Val Ala Leu Leu Gly Gly Gly Pro Tyr Met Leu 115 120 125 Cys Thr Asp Gly Gln Gln Leu Leu Arg Gln Val Leu His Pro Glu Ala 130 135 140 Ser Arg Lys Asn Leu Val Leu Pro Asp Met Phe Phe Ser Phe Tyr Asp 145 150 155 160 Leu Arg Arg Glu Phe His Met Gln His Pro Ser Thr Cys Pro Ala Arg 165 170 175 Asp Leu Thr Val Ala Thr Met Ala Gln Gly Leu Gly Leu Glu Thr Asp 180 185 190 Ala Thr Glu Asp Asp Phe Gly Val Trp Glu Val Lys Thr Met Val Ala 195 200 205 Val Ile Leu His Leu Leu Lys Glu Pro Ser Ser Gln Leu Phe Ser Lys 210 215 220 Pro Glu Val Ile Lys Gln Lys Tyr Glu Thr Gly Pro Cys Ser Lys Ala 225 230 235 240 Asp Val Val Asp Ser Glu Thr Val Val Arg Ala Arg Gly Leu Pro Trp 245 250 255 Gln Ser Ser Asp Gln Asp Val Ala Arg Phe Phe Lys Gly Leu Asn Val 260 265 270 Ala Arg Gly Gly Val Ala Leu Cys Leu Asn Ala Gln Gly Arg Arg Asn 275 280 285 Gly Glu Ala Leu Ile Arg Phe Val Asp Ser Glu Gln Arg Asp Leu Ala 290 295 300 Leu Gln Arg His Lys His His Met Gly Val Arg Tyr Ile Glu Val Tyr 305 310 315 320 Lys Ala Thr Gly Glu Glu Phe Val Lys Ile Ala Gly Gly Thr Ser Leu 325 330 335 Glu Val Ala Arg Phe Leu Ser Arg Glu Asp Gln Val Ile Leu Arg Leu 340 345 350 Arg Gly Leu Pro Phe Ser Ala Gly Pro Thr Asp Val Leu Gly Phe Leu 355 360 365 Gly Pro Glu Cys Pro Val Thr Gly Gly Thr Glu Gly Leu Leu Phe Val 370 375 380 Arg His Pro Asp Gly Arg Pro Thr Gly Asp Ala Phe Ala Leu Phe Ala 385 390 395 400 Cys Glu Glu Leu Ala Gln Ala Ala Leu Arg Arg His Lys Gly Met Leu 405 410 415 Gly Lys Arg Tyr Ile Glu Leu Phe Arg Ser Thr Ala Ala Glu Val Gln 420 425 430 Gln Val Leu Asn Arg Tyr Ala Ser Gly Pro Leu Leu Pro Thr Leu Thr 435 440 445 Ala Pro Leu Leu Pro Ile Pro Phe Pro Leu Ala Pro Gly Thr Gly Arg 450 455 460 Asp Cys Val Arg Leu Arg Gly Leu Pro Tyr Thr Ala Thr Ile Glu Asp 465 470 475 480 Ile Leu Ser Phe Leu Gly Glu Ala Ala Ala Asp Ile Arg Pro His Gly 485 490 495 Val His Met Val Leu Asn Gln Gln Gly Arg Pro Ser Gly Asp Ala Phe 500 505 510 Ile Gln Met Thr Ser Ala Glu Arg Ala Leu Ala Ala Ala Gln Arg Cys 515 520 525 His Lys Lys Val Met Lys Glu Arg Tyr Val Glu Val Val Pro Cys Ser 530 535 540 Thr Glu Glu Met Ser Arg Val Leu Met Gly Gly Thr Leu Gly Arg Ser 545 550 555 560 Gly Met Ser Pro Pro Pro Cys Lys Leu Pro Cys Leu Ser Pro Pro Thr 565 570 575 Tyr Thr Thr Phe Gln Ala Thr Pro Thr Leu Ile Pro Thr Glu Thr Ala 580 585 590 Ala Leu Tyr Pro Ser Ser Ala Leu Leu Pro Ala Ala Arg Val Pro Ala 595 600 605 Ala Pro Thr Pro Val Ala Tyr Tyr Pro Gly Pro Ala Thr Gln Leu Tyr 610 615 620 Leu Asn Tyr Thr Ala Tyr Tyr Pro Ser Pro Pro Val Ser Pro Thr Thr 625 630 635 640 Val Gly Tyr Leu Thr Thr Pro Thr Ala Ala Leu Ala Ser Ala Pro Thr 645 650 655 Ser Val Leu Ser Gln Ser Gly Ala Leu Val Arg Met Gln Gly Val Pro 660 665 670 Tyr Thr Ala Gly Met Lys Asp Leu Leu Ser Val Phe Gln Ala Tyr Gln 675 680 685 Leu Pro Ala Asp Asp Tyr Thr Ser Leu Met Pro Val Gly Asp Pro Pro 690 695 700 Arg Thr Val Leu Gln Ala Pro Lys Glu Trp Val Cys Leu 705 710 715 <210> 15 <211> 458 <212> PRT <213> Homo sapiens <400> 15 Met Glu Leu Pro Leu Gly Arg Cys Asp Asp Ser Arg Thr Trp Asp Asp 1 5 10 15 Asp Ser Asp Pro Glu Ser Glu Thr Asp Pro Asp Ala Gln Ala Lys Ala 20 25 30 Tyr Val Ala Arg Val Leu Ser Pro Lys Ser Gly Leu Ala Phe Ser 35 40 45 Arg Pro Ser Gln Leu Ser Thr Pro Ala Ala Ser Pro Ser Ala Ser Glu 50 55 60 Pro Arg Ala Ala Ser Arg Val Ser Ala Val Ser Glu Pro Gly Leu Leu 65 70 75 80 Ser Leu Pro Pro Glu Leu Leu Leu Glu Ile Cys Ser Tyr Leu Asp Ala 85 90 95 Arg Leu Val Leu His Val Leu Ser Arg Val Cys His Ala Leu Arg Asp 100 105 110 Leu Val Ser Asp His Val Thr Trp Arg Leu Arg Ala Leu Arg Arg Val 115 120 125 Arg Ala Pro Tyr Pro Val Val Glu Glu Lys Asn Phe Asp Trp Pro Ala 130 135 140 Ala Cys Ile Ala Leu Glu Gln His Leu Ser Arg Trp Ala Glu Asp Gly 145 150 155 160 Arg Trp Val Glu Tyr Phe Cys Leu Ala Glu Gly His Val Ala Ser Val 165 170 175 Asp Ser Val Leu Leu Leu Gln Gly Gly Ser Leu Cys Leu Ser Gly Ser 180 185 190 Arg Asp Arg Asn Val Asn Leu Trp Asp Leu Arg Gln Leu Gly Thr Glu 195 200 205 Ser Asn Gln Val Leu Ile Lys Thr Leu Gly Thr Lys Arg Asn Ser Thr 210 215 220 His Glu Gly Trp Val Trp Ser Leu Ala Ala Gln Asp His Arg Val Cys 225 230 235 240 Ser Gly Ser Trp Asp Ser Thr Val Lys Leu Trp Asp Met Ala Ala Asp 245 250 255 Gly Gln Gln Phe Gly Glu Ile Lys Ala Ser Ser Ala Val Leu Cys Leu 260 265 270 Ser Tyr Leu Pro Asp Ile Leu Val Thr Gly Thr Tyr Asp Lys Lys Val 275 280 285 Thr Ile Tyr Asp Pro Arg Ala Gly Pro Ala Leu Leu Lys His Gln Gln 290 295 300 Leu His Ser Arg Pro Val Leu Thr Leu Leu Ala Asp Asp Arg His Ile 305 310 315 320 Ile Ser Gly Ser Glu Asp His Thr Leu Val Val Val Asp Arg Arg Ala 325 330 335 Asn Ser Val Leu Gln Arg Leu Gln Leu Asp Ser Tyr Leu Leu Cys Met 340 345 350 Ser Tyr Gln Glu Pro Gln Leu Trp Ala Gly Asp Asn Gln Gly Leu Leu 355 360 365 His Val Phe Ala Asn Arg Asn Gly Cys Phe Gln Leu Ile Arg Ser Phe 370 375 380 Asp Val Gly His Ser Phe Pro Ile Thr Gly Ile Gln Tyr Ser Val Gly 385 390 395 400 Ala Leu Tyr Thr Thr Ser Thr Asp Lys Thr Ile Arg Val His Val Pro 405 410 415 Thr Asp Pro Pro Arg Thr Ile Cys Thr Arg Arg His Asp Asn Gly Leu 420 425 430 Asn Arg Val Cys Ala Glu Gly Asn Leu Val Val Ala Gly Ser Gly Asp 435 440 445 Leu Ser Leu Glu Val Trp Arg Leu Gln Ala 450 455 <210> 16 <211> 1051 <212> PRT <213> Homo sapiens <400> 16 Met Gly Pro Gly Pro Ser Arg Ala Pro Arg Ala Pro Arg Leu Met Leu 1 5 10 15 Cys Ala Leu Ala Leu Met Val Ala Ala Gly Gly Cys Val Val Ser Ala 20 25 30 Phe Asn Leu Asp Thr Arg Phe Leu Val Val Lys Glu Ala Gly Asn Pro 35 40 45 Gly Ser Leu Phe Gly Tyr Ser Val Ala Leu His Arg Gln Thr Glu Arg 50 55 60 Gln Gln Arg Tyr Leu Leu Leu Ala Gly Ala Pro Arg Glu Leu Ala Val 65 70 75 80 Pro Asp Gly Tyr Thr Asn Arg Thr Gly Ala Val Tyr Leu Cys Pro Leu 85 90 95 Thr Ala His Lys Asp Asp Cys Glu Arg Met Asn Ile Thr Val Lys Asn 100 105 110 Asp Pro Gly His His Ile Ile Glu Asp Met Trp Leu Gly Val Thr Val 115 120 125 Ala Ser Gln Gly Pro Ala Gly Arg Val Leu Val Cys Ala His Arg Tyr 130 135 140 Thr Gln Val Leu Trp Ser Gly Ser Glu Asp Gln Arg Arg Met Val Gly 145 150 155 160 Lys Cys Tyr Val Arg Gly Asn Asp Leu Glu Leu Asp Ser Ser Asp Asp 165 170 175 Trp Gln Thr Tyr His Asn Glu Met Cys Asn Ser Asn Thr Asp Tyr Leu 180 185 190 Glu Thr Gly Met Cys Gln Leu Gly Thr Ser Gly Gly Phe Thr Gln Asn 195 200 205 Thr Val Tyr Phe Gly Ala Pro Gly Ala Tyr Asn Trp Lys Gly Asn Ser 210 215 220 Tyr Met Ile Gln Arg Lys Glu Trp Asp Leu Ser Glu Tyr Ser Tyr Lys 225 230 235 240 Asp Pro Glu Asp Gln Gly Asn Leu Tyr Ile Gly Tyr Thr Met Gln Val 245 250 255 Gly Ser Phe Ile Leu His Pro Lys Asn Ile Thr Ile Val Thr Gly Ala 260 265 270 Pro Arg His Arg His Met Gly Ala Val Phe Leu Leu Ser Gln Glu Ala 275 280 285 Gly Gly Asp Leu Arg Arg Arg Gln Val Leu Glu Gly Ser Gln Val Gly 290 295 300 Ala Tyr Phe Gly Ser Ala Ile Ala Leu Ala Asp Leu Asn Asn Asp Gly 305 310 315 320 Trp Gln Asp Leu Leu Val Gly Ala Pro Tyr Tyr Phe Glu Arg Lys Glu 325 330 335 Glu Val Gly Gly Ala Ile Tyr Val Phe Met Asn Gln Ala Gly Thr Ser 340 345 350 Phe Pro Ala His Pro Ser Leu Leu Leu His Gly Pro Ser Gly Ser Ala 355 360 365 Phe Gly Leu Ser Val Ala Ser Ile Gly Asp Ile Asn Gln Asp Gly Phe 370 375 380 Gln Asp Ile Ala Val Gly Ala Pro Phe Glu Gly Leu Gly Lys Val Tyr 385 390 395 400 Ile Tyr His Ser Ser Ser Lys Gly Leu Leu Arg Gln Pro Gln Gln Val 405 410 415 Ile His Gly Glu Lys Leu Gly Leu Pro Gly Leu Ala Thr Phe Gly Tyr 420 425 430 Ser Leu Ser Gly Gln Met Asp Val Asp Glu Asn Phe Tyr Pro Asp Leu 435 440 445 Leu Val Gly Ser Leu Ser Asp His Ile Val Leu Leu Arg Ala Arg Pro 450 455 460 Val Ile Asn Ile Val His Lys Thr Leu Val Pro Arg Pro Ala Val Leu 465 470 475 480 Asp Pro Ala Leu Cys Thr Ala Thr Ser Cys Val Gln Val Glu Leu Cys 485 490 495 Phe Ala Tyr Asn Gln Ser Ala Gly Asn Pro Asn Tyr Arg Arg Asn Ile 500 505 510 Thr Leu Ala Tyr Thr Leu Glu Ala Asp Arg Asp Arg Arg Pro Pro Arg 515 520 525 Leu Arg Phe Ala Gly Ser Glu Ser Ala Val Phe His Gly Phe Phe Ser 530 535 540 Met Pro Glu Met Arg Cys Gln Lys Leu Glu Leu Leu Leu Leu Met Asp Asn 545 550 555 560 Leu Arg Asp Lys Leu Arg Pro Ile Ile Ile Ser Met Asn Tyr Ser Leu 565 570 575 Pro Leu Arg Met Pro Asp Arg Pro Arg Leu Gly Leu Arg Ser Leu Asp 580 585 590 Ala Tyr Pro Ile Leu Asn Gln Ala Gln Ala Leu Glu Asn His Thr Glu 595 600 605 Val Gln Phe Gln Lys Glu Cys Gly Pro Asp Asn Lys Cys Glu Ser Asn 610 615 620 Leu Gln Met Arg Ala Ala Phe Val Ser Glu Gln Gln Gln Lys Leu Ser 625 630 635 640 Arg Leu Gln Tyr Ser Arg Asp Val Arg Lys Leu Leu Leu Ser Ile Asn 645 650 655 Val Thr Asn Thr Arg Thr Ser Glu Arg Ser Gly Glu Asp Ala His Glu 660 665 670 Ala Leu Leu Thr Leu Val Val Pro Ala Leu Leu Leu Ser Ser Val 675 680 685 Arg Pro Pro Gly Ala Cys Gln Ala Asn Glu Thr Ile Phe Cys Glu Leu 690 695 700 Gly Asn Pro Phe Lys Arg Asn Gln Arg Met Glu Leu Leu Ile Ala Phe 705 710 715 720 Glu Val Ile Gly Val Thr Leu His Thr Arg Asp Leu Gln Val Gln Leu 725 730 735 Gln Leu Ser Thr Ser Ser His Gln Asp Asn Leu Trp Pro Met Ile Leu 740 745 750 Thr Leu Leu Val Asp Tyr Thr Leu Gln Thr Ser Leu Ser Met Val Asn 755 760 765 His Arg Leu Gln Ser Phe Phe Gly Gly Thr Val Met Gly Glu Ser Gly 770 775 780 Met Lys Thr Val Glu Asp Val Gly Ser Pro Leu Lys Tyr Glu Phe Gln 785 790 795 800 Val Gly Pro Met Gly Glu Gly Leu Val Gly Leu Gly Thr Leu Val Leu 805 810 815 Gly Leu Glu Trp Pro Tyr Glu Val Ser Asn Gly Lys Trp Leu Leu Tyr 820 825 830 Pro Thr Glu Ile Thr Val His Gly Asn Gly Ser Trp Pro Cys Arg Pro 835 840 845 Pro Gly Asp Leu Ile Asn Pro Leu Asn Leu Thr Leu Ser Asp Pro Gly 850 855 860 Asp Arg Pro Ser Ser Pro Gln Arg Arg Arg Arg Gln Leu Asp Pro Gly 865 870 875 880 Gly Gly Gln Gly Pro Pro Pro Val Thr Leu Ala Ala Ala Lys Lys Ala 885 890 895 Lys Ser Glu Thr Val Leu Thr Cys Ala Thr Gly Arg Ala His Cys Val 900 905 910 Trp Leu Glu Cys Pro Ile Pro Asp Ala Pro Val Val Thr Asn Val Thr 915 920 925 Val Lys Ala Arg Val Trp Asn Ser Thr Phe Ile Glu Asp Tyr Arg Asp 930 935 940 Phe Asp Arg Val Arg Val Asn Gly Trp Ala Thr Leu Phe Leu Arg Thr 945 950 955 960 Ser Ile Pro Thr Ile Asn Met Glu Asn Lys Thr Thr Trp Phe Ser Val 965 970 975 Asp Ile Asp Ser Glu Leu Val Glu Glu Leu Pro Ala Glu Ile Glu Leu 980 985 990 Trp Leu Val Leu Val Ala Val Gly Ala Gly Leu Leu Leu Leu Gly Leu 995 1000 1005 Ile Ile Leu Leu Leu Trp Lys Cys Gly Phe Phe Lys Arg Ala Arg Thr 1010 1015 1020 Arg Ala Leu Tyr Glu Ala Lys Arg Gln Lys Ala Glu Met Lys Ser Gln 1025 1030 1035 1040 Pro Ser Glu Thr Glu Arg Leu Thr Asp Asp Tyr 1045 1050 <210> 17 <211> 1032 <212> PRT <213> Homo sapiens <400> 17 Met Ala Trp Glu Ala Arg Arg Glu Pro Gly Pro Arg Arg Ala Ala Val 1 5 10 15 Arg Glu Thr Val Met Leu Leu Leu Cys Leu Gly Val Pro Thr Gly Arg 20 25 30 Pro Tyr Asn Val Asp Thr Glu Ser Ala Leu Leu Tyr Gln Gly Pro His 35 40 45 Asn Thr Leu Phe Gly Tyr Ser Val Val Leu His Ser His Gly Ala Asn 50 55 60 Arg Trp Leu Leu Val Gly Ala Pro Thr Ala Asn Trp Leu Ala Asn Ala 65 70 75 80 Ser Val Ile Asn Pro Gly Ala Ile Tyr Arg Cys Arg Ile Gly Lys Asn 85 90 95 Pro Gly Gln Thr Cys Glu Gln Leu Gln Leu Gly Ser Pro Asn Gly Glu 100 105 110 Pro Cys Gly Lys Thr Cys Leu Glu Glu Arg Asp Asn Gln Trp Leu Gly 115 120 125 Val Thr Leu Ser Arg Gln Pro Gly Glu Asn Gly Ser Ile Val Thr Cys 130 135 140 Gly His Arg Trp Lys Asn Ile Phe Tyr Ile Lys Asn Glu Asn Lys Leu 145 150 155 160 Pro Thr Gly Gly Cys Tyr Gly Val Pro Pro Asp Leu Arg Thr Glu Leu 165 170 175 Ser Lys Arg Ile Ala Pro Cys Tyr Gln Asp Tyr Val Lys Lys Phe Gly 180 185 190 Glu Asn Phe Ala Ser Cys Gln Ala Gly Ile Ser Ser Phe Tyr Thr Lys 195 200 205 Asp Leu Ile Val Met Gly Ala Pro Gly Ser Ser Tyr Trp Thr Gly Ser 210 215 220 Leu Phe Val Tyr Asn Ile Thr Thr Asn Lys Tyr Lys Ala Phe Leu Asp 225 230 235 240 Lys Gln Asn Gln Val Lys Phe Gly Ser Tyr Leu Gly Tyr Ser Val Gly 245 250 255 Ala Gly His Phe Arg Ser Gln His Thr Thr Glu Val Val Gly Gly Ala 260 265 270 Pro Gln His Glu Gln Ile Gly Lys Ala Tyr Ile Phe Ser Ile Asp Glu 275 280 285 Lys Glu Leu Asn Ile Leu His Glu Met Lys Gly Lys Lys Leu Gly Ser 290 295 300 Tyr Phe Gly Ala Ser Val Cys Ala Val Asp Leu Asn Ala Asp Gly Phe 305 310 315 320 Ser Asp Leu Leu Val Gly Ala Pro Met Gln Ser Thr Ile Arg Glu Glu 325 330 335 Gly Arg Val Phe Val Tyr Ile Asn Ser Gly Ser Gly Ala Val Met Asn 340 345 350 Ala Met Glu Thr Asn Leu Val Gly Ser Asp Lys Tyr Ala Ala Arg Phe 355 360 365 Gly Glu Ser Ile Val Asn Leu Gly Asp Ile Asp Asn Asp Gly Phe Glu 370 375 380 Asp Val Ala Ile Gly Ala Pro Gln Glu Asp Asp Leu Gln Gly Ala Ile 385 390 395 400 Tyr Ile Tyr Asn Gly Arg Ala Asp Gly Ile Ser Ser Thr Phe Ser Gln 405 410 415 Arg Ile Glu Gly Leu Gln Ile Ser Lys Ser Leu Ser Met Phe Gly Gln 420 425 430 Ser Ile Ser Gly Gln Ile Asp Ala Asp Asn Asn Gly Tyr Val Asp Val 435 440 445 Ala Val Gly Ala Phe Arg Ser Asp Ser Ala Val Leu Leu Arg Thr Arg 450 455 460 Pro Val Val Ile Val Asp Ala Ser Leu Ser His Pro Glu Ser Val Asn 465 470 475 480 Arg Thr Lys Phe Asp Cys Val Glu Asn Gly Trp Pro Ser Val Cys Ile 485 490 495 Asp Leu Thr Leu Cys Phe Ser Tyr Lys Gly Lys Glu Val Pro Gly Tyr 500 505 510 Ile Val Leu Phe Tyr Asn Met Ser Leu Asp Val Asn Arg Lys Ala Glu 515 520 525 Ser Pro Pro Arg Phe Tyr Phe Ser Ser Asn Gly Thr Ser Asp Val Ile 530 535 540 Thr Gly Ser Ile Gln Val Ser Ser Arg Glu Ala Asn Cys Arg Thr His 545 550 555 560 Gln Ala Phe Met Arg Lys Asp Val Arg Asp Ile Leu Thr Pro Ile Gln 565 570 575 Ile Glu Ala Ala Tyr His Leu Gly Pro His Val Ile Ser Lys Arg Ser 580 585 590 Thr Glu Glu Phe Pro Leu Gln Pro Ile Leu Gln Gln Lys Lys Glu 595 600 605 Lys Asp Ile Met Lys Lys Thr Ile Asn Phe Ala Arg Phe Cys Ala His 610 615 620 Glu Asn Cys Ser Ala Asp Leu Gln Val Ser Ala Lys Ile Gly Phe Leu 625 630 635 640 Lys Pro His Glu Asn Lys Thr Tyr Leu Ala Val Gly Ser Met Lys Thr 645 650 655 Leu Met Leu Asn Val Ser Leu Phe Asn Ala Gly Asp Asp Ala Tyr Glu 660 665 670 Thr Thr Leu His Val Lys Leu Pro Val Gly Leu Tyr Phe Ile Lys Ile 675 680 685 Leu Glu Leu Glu Glu Lys Gln Ile Asn Cys Glu Val Thr Asp Asn Ser 690 695 700 Gly Val Val Gln Leu Asp Cys Ser Ile Gly Tyr Ile Tyr Val Asp His 705 710 715 720 Leu Ser Arg Ile Asp Ile Ser Phe Leu Leu Asp Val Ser Ser Leu Ser 725 730 735 Arg Ala Glu Glu Asp Leu Ser Ile Thr Val His Ala Thr Cys Glu Asn 740 745 750 Glu Glu Glu Met Asp Asn Leu Lys His Ser Arg Val Thr Val Ala Ile 755 760 765 Pro Leu Lys Tyr Glu Val Lys Leu Thr Val His Gly Phe Val Asn Pro 770 775 780 Thr Ser Phe Val Tyr Gly Ser Asn Asp Glu Asn Glu Pro Glu Thr Cys 785 790 795 800 Met Val Glu Lys Met Asn Leu Thr Phe His Val Ile Asn Thr Gly Asn 805 810 815 Ser Met Ala Pro Asn Val Ser Val Glu Ile Met Val Pro Asn Ser Phe 820 825 830 Ser Pro Gln Thr Asp Lys Leu Phe Asn Ile Leu Asp Val Gln Thr Thr 835 840 845 Thr Gly Glu Cys His Phe Glu Asn Tyr Gln Arg Val Cys Ala Leu Glu 850 855 860 Gln Gln Lys Ser Ala Met Gln Thr Leu Lys Gly Ile Val Arg Phe Leu 865 870 875 880 Ser Lys Thr Asp Lys Arg Leu Leu Tyr Cys Ile Lys Ala Asp Pro His 885 890 895 Cys Leu Asn Phe Leu Cys Asn Phe Gly Lys Met Glu Ser Gly Lys Glu 900 905 910 Ala Ser Val His Ile Gln Leu Glu Gly Arg Pro Ser Ile Leu Glu Met 915 920 925 Asp Glu Thr Ser Ala Leu Lys Phe Glu Ile Arg Ala Thr Gly Phe Pro 930 935 940 Glu Pro Asn Pro Arg Val Ile Glu Leu Asn Lys Asp Glu Asn Val Ala 945 950 955 960 His Val Leu Leu Glu Gly Leu His His Gln Arg Pro Lys Arg Tyr Phe 965 970 975 Thr Ile Val Ile Ile Ser Ser Ser Leu Leu Leu Gly Leu Ile Val Leu 980 985 990 Leu Leu Ile Ser Tyr Val Met Trp Lys Ala Gly Phe Phe Lys Arg Gln 995 1000 1005 Tyr Lys Ser Ile Leu Gln Glu Glu Asn Arg Arg Asp Ser Trp Ser Tyr 1010 1015 1020 Ile Asn Ser Lys Ser Asn Asp Asp 1025 1030 <210> 18 <211> 1063 <212> PRT <213> Homo sapiens <400> 18 Met Ser Pro Gly Ala Ser Arg Gly Pro Arg Gly Ser Gln Ala Pro Leu 1 5 10 15 Ile Ala Pro Leu Cys Cys Ala Ala Ala Ala Leu Gly Met Leu Leu Trp 20 25 30 Ser Pro Ala Cys Gln Ala Phe Asn Leu Asp Val Glu Lys Leu Thr Val 35 40 45 Tyr Ser Gly Pro Lys Gly Ser Tyr Phe Gly Tyr Ala Val Asp Phe His 50 55 60 Ile Pro Asp Ala Arg Thr Ala Ser Val Leu Val Gly Ala Pro Lys Ala 65 70 75 80 Asn Thr Ser Gln Pro Asp Ile Val Glu Gly Gly Ala Val Tyr Tyr Cys 85 90 95 Pro Trp Pro Ala Glu Gly Ser Ala Gln Cys Arg Gln Ile Pro Phe Asp 100 105 110 Thr Thr Asn Asn Arg Lys Ile Arg Val Asn Gly Thr Lys Glu Pro Ile 115 120 125 Glu Phe Lys Ser Asn Gln Trp Phe Gly Ala Thr Val Lys Ala His Lys 130 135 140 Gly Lys Val Val Ala Cys Ala Pro Leu Tyr His Trp Arg Thr Leu Lys 145 150 155 160 Pro Thr Pro Glu Lys Asp Pro Val Gly Thr Cys Tyr Val Ala Ile Gln 165 170 175 Asn Phe Ser Ala Tyr Ala Glu Phe Ser Pro Cys Arg Asn Ser Asn Ala 180 185 190 Asp Pro Glu Gly Gln Gly Tyr Cys Gln Ala Gly Phe Ser Leu Asp Phe 195 200 205 Tyr Lys Asn Gly Asp Leu Ile Val Gly Gly Pro Gly Ser Phe Tyr Trp 210 215 220 Gln Gly Gln Val Ile Thr Ala Ser Val Ala Asp Ile Ile Ala Asn Tyr 225 230 235 240 Ser Phe Lys Asp Ile Leu Arg Lys Leu Ala Gly Glu Lys Gln Thr Glu 245 250 255 Val Ala Pro Ala Ser Tyr Asp Asp Ser Tyr Leu Gly Tyr Ser Val Ala 260 265 270 Ala Gly Glu Phe Thr Gly Asp Ser Gln Gln Glu Leu Val Ala Gly Ile 275 280 285 Pro Arg Gly Ala Gln Asn Phe Gly Tyr Val Ser Ile Ile Asn Ser Thr 290 295 300 Asp Met Thr Phe Ile Gln Asn Phe Thr Gly Glu Gln Met Ala Ser Tyr 305 310 315 320 Phe Gly Tyr Thr Val Val Val Ser Asp Val Asn Ser Asp Gly Leu Asp 325 330 335 Asp Val Leu Val Gly Ala Pro Leu Phe Met Glu Arg Glu Phe Glu Ser 340 345 350 Asn Pro Arg Glu Val Gly Gln Ile Tyr Leu Tyr Leu Gln Val Ser Ser 355 360 365 Leu Leu Phe Arg Asp Pro Gln Ile Leu Thr Gly Thr Glu Thr Phe Gly 370 375 380 Arg Phe Gly Ser Ala Met Ala His Leu Gly Asp Leu Asn Gln Asp Gly 385 390 395 400 Tyr Asn Asp Ile Ala Ile Gly Val Pro Phe Ala Gly Lys Asp Gln Arg 405 410 415 Gly Lys Val Leu Ile Tyr Asn Gly Asn Lys Asp Gly Leu Asn Thr Lys 420 425 430 Pro Ser Gln Val Leu Gln Gly Val Trp Ala Ser His Ala Val Pro Ser 435 440 445 Gly Phe Gly Phe Thr Leu Arg Gly Asp Ser Asp Ile Asp Lys Asn Asp 450 455 460 Tyr Pro Asp Leu Ile Val Gly Ala Phe Gly Thr Gly Lys Val Ala Val 465 470 475 480 Tyr Arg Ala Arg Pro Val Val Thr Val Asp Ala Gln Leu Leu Leu His 485 490 495 Pro Met Ile Ile Asn Leu Glu Asn Lys Thr Cys Gln Val Pro Asp Ser 500 505 510 Met Thr Ser Ala Ala Cys Phe Ser Leu Arg Val Cys Ala Ser Val Thr 515 520 525 Gly Gln Ser Ile Ala Asn Thr Ile Val Leu Met Ala Glu Val Gln Leu 530 535 540 Asp Ser Leu Lys Gln Lys Gly Ala Ile Lys Arg Thr Leu Phe Leu Asp 545 550 555 560 Asn His Gln Ala His Arg Val Phe Pro Leu Val Ile Lys Arg Gln Lys 565 570 575 Ser His Gln Cys Gln Asp Phe Ile Val Tyr Leu Arg Asp Glu Thr Glu 580 585 590 Phe Arg Asp Lys Leu Ser Pro Ile Asn Ile Ser Leu Asn Tyr Ser Leu 595 600 605 Asp Glu Ser Thr Phe Lys Glu Gly Leu Glu Val Lys Pro Ile Leu Asn 610 615 620 Tyr Tyr Arg Glu Asn Ile Val Ser Glu Gln Ala His Ile Leu Val Asp 625 630 635 640 Cys Gly Glu Asp Asn Leu Cys Val Pro Asp Leu Lys Leu Ser Ala Arg 645 650 655 Pro Asp Lys His Gln Val Ile Ile Gly Asp Glu Asn His Leu Met Leu 660 665 670 Ile Ile Asn Ala Arg Asn Glu Gly Glu Gly Ala Tyr Glu Ala Glu Leu 675 680 685 Phe Val Met Ile Pro Glu Glu Ala Asp Tyr Val Gly Ile Glu Arg Asn 690 695 700 Asn Lys Gly Phe Arg Pro Leu Ser Cys Glu Tyr Lys Met Glu Asn Val 705 710 715 720 Thr Arg Met Val Val Cys Asp Leu Gly Asn Pro Met Val Ser Gly Thr 725 730 735 Asn Tyr Ser Leu Gly Leu Arg Phe Ala Val Pro Arg Leu Glu Lys Thr 740 745 750 Asn Met Ser Ile Asn Phe Asp Leu Gln Ile Arg Ser Ser Asn Lys Asp 755 760 765 Asn Pro Asp Ser Asn Phe Val Ser Leu Gln Ile Asn Ile Thr Ala Val 770 775 780 Ala Gln Val Glu Ile Arg Gly Val Ser His Pro Gln Ile Val Leu 785 790 795 800 Pro Ile His Asn Trp Glu Pro Glu Glu Glu Pro His Lys Glu Glu Glu 805 810 815 Val Gly Pro Leu Val Glu His Ile Tyr Glu Leu His Asn Ile Gly Pro 820 825 830 Ser Thr Ile Ser Asp Thr Ile Leu Glu Val Gly Trp Pro Phe Ser Ala 835 840 845 Arg Asp Glu Phe Leu Leu Tyr Ile Phe His Ile Gln Thr Leu Gly Pro 850 855 860 Leu Gln Cys Gln Pro Asn Pro Asn Ile Asn Pro Gln Asp Ile Lys Pro 865 870 875 880 Ala Ala Ser Pro Glu Asp Thr Pro Glu Leu Ser Ala Phe Leu Arg Asn 885 890 895 Ser Thr Ile Pro His Leu Val Arg Lys Arg Asp Val His Val Val Glu 900 905 910 Phe His Arg Gln Ser Pro Ala Lys Ile Leu Asn Cys Thr Asn Ile Glu 915 920 925 Cys Leu Gln Ile Ser Cys Ala Val Gly Arg Leu Glu Gly Gly Glu Ser 930 935 940 Ala Val Leu Lys Val Arg Ser Arg Leu Trp Ala His Thr Phe Leu Gln 945 950 955 960 Arg Lys Asn Asp Pro Tyr Ala Leu Ala Ser Leu Val Ser Phe Glu Val 965 970 975 Lys Lys Met Pro Tyr Thr Asp Gln Pro Ala Lys Leu Pro Glu Gly Ser 980 985 990 Ile Val Ile Lys Thr Ser Val Ile Trp Ala Thr Pro Asn Val Ser Phe 995 1000 1005 Ser Ile Pro Leu Trp Val Ile Ile Leu Ala Ile Leu Leu Gly Leu Leu 1010 1015 1020 Val Leu Ala Ile Leu Thr Leu Ala Leu Trp Lys Cys Gly Phe Phe Asp 1025 1030 1035 1040 Arg Ala Arg Pro Pro Gln Glu Asp Met Thr Asp Arg Glu Gln Leu Thr 1045 1050 1055 Asn Asp Lys Thr Pro Glu Ala 1060 <210> 19 <211> 957 <212> PRT <213> Homo sapiens <400> 19 Met Ala Asp Pro Ala Glu Cys Ser Ile Lys Val Met Cys Arg Phe Arg 1 5 10 15 Pro Leu Asn Glu Ala Glu Ile Leu Arg Gly Asp Lys Phe Ile Pro Lys 20 25 30 Phe Lys Gly Asp Glu Thr Val Val Ile Gly Gln Gly Lys Pro Tyr Val 35 40 45 Phe Asp Arg Val Leu Pro Pro Asn Thr Thr Gln Glu Gln Val Tyr Asn 50 55 60 Ala Cys Ala Lys Gln Ile Val Lys Asp Val Leu Glu Gly Tyr Asn Gly 65 70 75 80 Thr Ile Phe Ala Tyr Gly Gln Thr Ser Ser Gly Lys Thr His Thr Met 85 90 95 Glu Gly Lys Leu His Asp Pro Gln Leu Met Gly Ile Ile Pro Arg Ile 100 105 110 Ala His Asp Ile Phe Asp His Ile Tyr Ser Met Asp Glu Asn Leu Glu 115 120 125 Phe His Ile Lys Val Ser Tyr Phe Glu Ile Tyr Leu Asp Lys Ile Arg 130 135 140 Asp Leu Leu Asp Val Ser Lys Thr Asn Leu Ala Val His Glu Asp Lys 145 150 155 160 Asn Arg Val Pro Tyr Val Lys Gly Cys Thr Glu Arg Phe Val Ser Ser 165 170 175 Pro Glu Glu Val Met Asp Val Ile Asp Glu Gly Lys Ala Asn Arg His 180 185 190 Val Ala Val Thr Asn Met Asn Glu His Ser Ser Arg Ser His Ser Ile 195 200 205 Phe Leu Ile Asn Ile Lys Gln Glu Asn Val Glu Thr Glu Lys Lys Leu 210 215 220 Ser Gly Lys Leu Tyr Leu Val Asp Leu Ala Gly Ser Glu Lys Val Ser 225 230 235 240 Lys Thr Gly Ala Glu Gly Ala Val Leu Asp Glu Ala Lys Asn Ile Asn 245 250 255 Lys Ser Leu Ser Ala Leu Gly Asn Val Ile Ser Ala Leu Ala Glu Gly 260 265 270 Thr Lys Thr His Val Pro Tyr Arg Asp Ser Lys Met Thr Arg Ile Leu 275 280 285 Gln Asp Ser Leu Gly Gly Asn Cys Arg Thr Thr Ile Val Ile Cys Cys 290 295 300 Ser Pro Ser Val Phe Asn Glu Ala Glu Thr Lys Ser Thr Leu Met Phe 305 310 315 320 Gly Gln Arg Ala Lys Thr Ile Lys Asn Thr Val Ser Val Asn Leu Glu 325 330 335 Leu Thr Ala Glu Glu Trp Lys Lys Lys Tyr Glu Lys Glu Lys Glu Lys 340 345 350 Asn Lys Thr Leu Lys Asn Val Ile Gln His Leu Glu Met Glu Leu Asn 355 360 365 Arg Trp Arg Asn Gly Glu Ala Val Pro Glu Asp Glu Gln Ile Ser Ala 370 375 380 Lys Asp Gln Lys Asn Leu Glu Pro Cys Asp Asn Thr Pro Ile Ile Asp 385 390 395 400 Asn Ile Ala Pro Val Val Ala Gly Ile Ser Thr Glu Glu Lys Glu Lys 405 410 415 Tyr Asp Glu Glu Ile Ser Ser Leu Tyr Arg Gln Leu Asp Asp Lys Asp 420 425 430 Asp Glu Ile Asn Gln Gln Ser Gln Leu Ala Glu Lys Leu Lys Gln Gln 435 440 445 Met Leu Asp Gln Asp Glu Leu Leu Ala Ser Thr Arg Arg Asp Tyr Glu 450 455 460 Lys Ile Gln Glu Glu Leu Thr Arg Leu Gln Ile Glu Asn Glu Ala Ala 465 470 475 480 Lys Asp Glu Val Lys Glu Val Leu Gln Ala Leu Glu Glu Leu Ala Val 485 490 495 Asn Tyr Asp Gln Lys Ser Gln Glu Val Glu Asp Lys Thr Arg Ala Asn 500 505 510 Glu Gln Leu Thr Asp Glu Leu Ala Gln Lys Thr Thr Thr Leu Thr Thr 515 520 525 Thr Gln Arg Glu Leu Ser Gln Leu Gln Glu Leu Ser Asn His Gln Lys 530 535 540 Lys Arg Ala Thr Glu Ile Leu Asn Leu Leu Leu Lys Asp Leu Gly Glu 545 550 555 560 Ile Gly Gly Ile Ile Gly Thr Asn Asp Val Lys Thr Leu Ala Asp Val 565 570 575 Asn Gly Val Ile Glu Glu Glu Phe Thr Met Ala Arg Leu Tyr Ile Ser 580 585 590 Lys Met Lys Ser Glu Val Lys Ser Leu Val Asn Arg Ser Lys Gln Leu 595 600 605 Glu Ser Ala Gln Met Asp Ser Asn Arg Lys Met Asn Ala Ser Glu Arg 610 615 620 Glu Leu Ala Ala Cys Gln Leu Leu Ile Ser Gln His Glu Ala Lys Ile 625 630 635 640 Lys Ser Leu Thr Asp Tyr Met Gln Asn Met Glu Gln Lys Arg Arg Gln 645 650 655 Leu Glu Glu Ser Gln Asp Ser Leu Ser Glu Glu Leu Ala Lys Leu Arg 660 665 670 Ala Gln Glu Lys Met His Glu Val Ser Phe Gln Asp Lys Glu Lys Glu 675 680 685 His Leu Thr Arg Leu Gln Asp Ala Glu Glu Met Lys Lys Ala Leu Glu 690 695 700 Gln Gln Met Glu Ser His Arg Glu Ala His Gln Lys Gln Leu Ser Arg 705 710 715 720 Leu Arg Asp Glu Ile Glu Glu Lys Gln Lys Ile Ile Asp Glu Ile Arg 725 730 735 Asp Leu Asn Gln Lys Leu Gln Leu Glu Gln Glu Lys Leu Ser Ser Asp 740 745 750 Tyr Asn Lys Leu Lys Ile Glu Asp Gln Glu Arg Glu Met Lys Leu Glu 755 760 765 Lys Leu Leu Leu Leu Asn Asp Lys Arg Glu Gln Ala Arg Glu Asp Leu 770 775 780 Lys Gly Leu Glu Glu Thr Val Ser Arg Glu Leu Gln Thr Leu His Asn 785 790 795 800 Leu Arg Lys Leu Phe Val Gln Asp Leu Thr Thr Arg Val Lys Lys Ser 805 810 815 Val Glu Leu Asp Asn Asp Asp Gly Gly Gly Ser Ala Ala Gln Lys Gln 820 825 830 Lys Ile Ser Phe Leu Glu Asn Asn Leu Glu Gln Leu Thr Lys Val His 835 840 845 Lys Gln Leu Val Arg Asp Asn Ala Asp Leu Arg Cys Glu Leu Pro Lys 850 855 860 Leu Glu Lys Arg Leu Arg Ala Thr Ala Glu Arg Val Lys Ala Leu Glu 865 870 875 880 Ser Ala Leu Lys Glu Ala Lys Glu Asn Ala Met Arg Asp Arg Lys Arg 885 890 895 Tyr Gln Gln Glu Val Asp Arg Ile Lys Glu Ala Val Arg Ala Lys Asn 900 905 910 Met Ala Arg Arg Ala His Ser Ala Gln Ile Ala Lys Pro Ile Arg Pro 915 920 925 Gly His Tyr Pro Ala Ser Ser Pro Thr Ala Val His Ala Ile Arg Gly 930 935 940 Gly Gly Gly Ser Ser Ser Asn Ser Thr His Tyr Gln Lys 945 950 955 <210> 20 <211> 579 <212> PRT <213> Homo sapiens <400> 20 Met Cys Asp Gln Gln Gln Ile Gln Cys Arg Leu Pro Leu Gln Gln Cys 1 5 10 15 Cys Val Lys Gly Pro Ser Phe Cys Ser Ser Gln Ser Pro Phe Ala Gln 20 25 30 Ser Gln Val Val Val Gln Ala Pro Cys Glu Met Gln Ile Val Asp Cys 35 40 45 Pro Ala Ser Cys Pro Val Gln Val Cys Gln Val Ser Asp Gln Ala Pro 50 55 60 Cys Gln Ser Gln Thr Thr Gln Val Lys Cys Gln Ser Lys Thr Lys Gln 65 70 75 80 Val Lys Gly Gln Ala Gln Cys Gln Ser Lys Thr Thr Gln Val Lys Gly 85 90 95 Gln Ala Ala Ser Gln Ser Gln Thr Ser Ser Val Gln Ser Gln Ala Pro 100 105 110 Cys Gln Ser Glu Val Ser Tyr Val Gln Cys Glu Ala Ser Gln Pro Val 115 120 125 Gln Thr Cys Phe Val Glu Cys Ala Pro Val Cys Tyr Thr Glu Thr Cys 130 135 140 Tyr Val Glu Cys Pro Val Gln Asn Tyr Val Pro Cys Pro Ala Pro Gln 145 150 155 160 Pro Val Gln Met Tyr Arg Gly Arg Pro Ala Val Cys Gln Pro Gln Gly 165 170 175 Arg Phe Ser Thr Gln Cys Gln Tyr Gln Gly Ser Tyr Ser Ser Ser Cys Gly 180 185 190 Pro Gln Phe Gln Ser Arg Ala Thr Cys Asn Asn Tyr Thr Pro Gln Phe 195 200 205 Gln Leu Arg Pro Ser Tyr Ser Ser Cys Phe Pro Gln Tyr Arg Ser Arg 210 215 220 Thr Ser Phe Ser Pro Cys Val Pro Gln Cys Gln Thr Gln Gly Ser Tyr 225 230 235 240 Gly Ser Phe Thr Glu Gln His Arg Ser Arg Ser Thr Ser Arg Cys Leu 245 250 255 Pro Pro Pro Arg Arg Leu Gln Leu Phe Pro Arg Ser Cys Ser Pro Pro 260 265 270 Arg Arg Phe Glu Pro Cys Ser Ser Ser Tyr Leu Pro Leu Arg Pro Ser 275 280 285 Glu Gly Phe Pro Asn Tyr Cys Thr Pro Pro Arg Arg Ser Glu Pro Ile 290 295 300 Tyr Asn Ser Arg Cys Pro Arg Arg Pro Ile Ser Ser Cys Ser Gln Arg 305 310 315 320 Arg Gly Pro Lys Cys Arg Ile Glu Ile Ser Ser Pro Cys Cys Pro Arg 325 330 335 Gln Val Pro Pro Gln Arg Cys Pro Val Glu Ile Pro Pro Ile Arg Arg 340 345 350 Arg Ser Gln Ser Cys Gly Pro Gln Pro Ser Trp Gly Ala Ser Cys Pro 355 360 365 Glu Leu Arg Pro His Val Glu Pro Arg Pro Leu Pro Ser Phe Cys Pro 370 375 380 Pro Arg Arg Leu Asp Gln Cys Pro Glu Ser Pro Leu Gln Arg Cys Pro 385 390 395 400 Pro Pro Ala Pro Arg Pro Arg Leu Arg Pro Glu Pro Cys Ile Ser Leu 405 410 415 Glu Pro Arg Pro Arg Pro Leu Pro Arg Gln Leu Ser Glu Pro Cys Leu 420 425 430 Tyr Pro Glu Pro Leu Pro Ala Leu Arg Pro Thr Pro Arg Pro Val Pro 435 440 445 Leu Pro Arg Pro Gly Gln Cys Glu Ile Pro Glu Pro Arg Pro Cys Leu 450 455 460 Gln Pro Cys Glu His Pro Glu Pro Cys Pro Arg Pro Glu Pro Ile Pro 465 470 475 480 Leu Pro Ala Pro Cys Pro Ser Pro Glu Pro Cys Arg Glu Thr Trp Arg 485 490 495 Ser Pro Ser Pro Cys Trp Gly Pro Asn Pro Val Pro Tyr Pro Gly Asp 500 505 510 Leu Gly Cys His Glu Ser Ser Pro His Arg Leu Asp Thr Glu Ala Pro 515 520 525 Tyr Cys Gly Pro Ser Ser Tyr Asn Gln Gly Gln Glu Ser Gly Ala Gly 530 535 540 Cys Gly Pro Gly Asp Val Phe Pro Glu Arg Arg Gly Gln Asp Gly His 545 550 555 560 Gly Asp Gln Gly Asn Ala Phe Ala Gly Val Lys Gly Glu Ala Lys Ser 565 570 575 Ala Tyr Phe <210> 21 <211> 520 <212> PRT <213> Homo sapiens <400> 21 Met Ser Asn Lys Cys Asp Val Val Val Val Gly Gly Gly Ile Ser Gly 1 5 10 15 Met Ala Ala Ala Lys Leu Leu His Asp Ser Gly Leu Asn Val Val Val 20 25 30 Leu Glu Ala Arg Asp Arg Val Gly Gly Arg Thr Tyr Thr Leu Arg Asn 35 40 45 Gln Lys Val Lys Tyr Val Asp Leu Gly Gly Ser Tyr Val Gly Pro Thr 50 55 60 Gln Asn Arg Ile Leu Arg Leu Ala Lys Glu Leu Gly Leu Glu Thr Tyr 65 70 75 80 Lys Val Asn Glu Val Glu Arg Leu Ile His His Val Lys Gly Lys Ser 85 90 95 Tyr Pro Phe Arg Gly Pro Phe Pro Pro Val Trp Asn Pro Ile Thr Tyr 100 105 110 Leu Asp His Asn Asn Phe Trp Arg Thr Met Asp Asp Met Gly Arg Glu 115 120 125 Ile Pro Ser Asp Ala Pro Trp Lys Ala Pro Leu Ala Glu Glu Trp Asp 130 135 140 Asn Met Thr Met Lys Glu Leu Leu Asp Lys Leu Cys Trp Thr Glu Ser 145 150 155 160 Ala Lys Gln Leu Ala Thr Leu Phe Val Asn Leu Cys Val Thr Ala Glu 165 170 175 Thr His Glu Val Ser Ala Leu Trp Phe Leu Trp Tyr Val Lys Gln Cys 180 185 190 Gly Gly Thr Thr Arg Ile Ile Ser Thr Thr Asn Gly Gly Gln Glu Arg 195 200 205 Lys Phe Val Gly Gly Ser Gly Gly Gln Val Ser Glu Arg Ile Met Asp Leu 210 215 220 Leu Gly Asp Arg Val Lys Leu Glu Arg Pro Val Ile Tyr Ile Asp Gln 225 230 235 240 Thr Arg Glu Asn Val Leu Val Glu Thr Leu Asn His Glu Met Tyr Glu 245 250 255 Ala Lys Tyr Val Ile Ser Ala Ile Pro Pro Thr Leu Gly Met Lys Ile 260 265 270 His Phe Asn Pro Pro Leu Pro Met Met Arg Asn Gln Met Ile Thr Arg 275 280 285 Val Pro Leu Gly Ser Val Ile Lys Cys Ile Val Tyr Tyr Lys Glu Pro 290 295 300 Phe Trp Arg Lys Lys Asp Tyr Cys Gly Thr Met Ile Ile Asp Gly Glu 305 310 315 320 Glu Ala Pro Val Ala Tyr Thr Leu Asp Asp Thr Lys Pro Glu Gly Asn 325 330 335 Tyr Ala Ala Ile Met Gly Phe Ile Leu Ala His Lys Ala Arg Lys Leu 340 345 350 Ala Arg Leu Thr Lys Glu Glu Arg Leu Lys Lys Leu Cys Glu Leu Tyr 355 360 365 Ala Lys Val Leu Gly Ser Leu Glu Ala Leu Glu Pro Val His Tyr Glu 370 375 380 Glu Lys Asn Trp Cys Glu Glu Gln Tyr Ser Gly Gly Cys Tyr Thr Thr 385 390 395 400 Tyr Phe Pro Pro Gly Ile Leu Thr Gln Tyr Gly Arg Val Leu Arg Gln 405 410 415 Pro Val Asp Arg Ile Tyr Phe Ala Gly Thr Glu Thr Ala Thr His Trp 420 425 430 Ser Gly Tyr Met Glu Gly Ala Val Glu Ala Gly Glu Arg Ala Ala Arg 435 440 445 Glu Ile Leu His Ala Met Gly Lys Ile Pro Glu Asp Glu Ile Trp Gln 450 455 460 Ser Glu Pro Glu Ser Val Asp Val Pro Ala Gln Pro Ile Thr Thr Thr 465 470 475 480 Phe Leu Glu Arg His Leu Pro Ser Val Pro Gly Leu Leu Arg Leu Ile 485 490 495 Gly Leu Thr Thr Ile Phe Ser Ala Thr Ala Leu Gly Phe Leu Ala His 500 505 510 Lys Arg Gly Leu Leu Val Arg Val 515 520 <210> 22 <211> 4493 <212> PRT <213> Homo sapiens <400> 22 Met Pro Arg Pro Gly Thr Met Ala Leu Cys Leu Leu Thr Leu Val Leu 1 5 10 15 Ser Leu Leu Pro Pro Gln Ala Ala Ala Glu Gln Asp Leu Ser Val Asn 20 25 30 Arg Ala Val Trp Asp Gly Gly Gly Cys Ile Ser Gln Gly Asp Val Leu 35 40 45 Asn Arg Gln Cys Gln Gln Leu Ser Gln His Val Arg Thr Gly Ser Ala 50 55 60 Ala Asn Thr Ala Thr Gly Thr Thr Ser Thr Asn Val Val Glu Pro Arg 65 70 75 80 Met Tyr Leu Ser Cys Ser Thr Asn Pro Glu Met Thr Ser Ile Glu Ser 85 90 95 Ser Val Thr Ser Asp Thr Pro Gly Val Ser Ser Thr Arg Met Thr Pro 100 105 110 Thr Glu Ser Arg Thr Thr Ser Glu Ser Thr Ser Asp Ser Thr Thr Leu 115 120 125 Phe Pro Ser Ser Thr Glu Asp Thr Ser Ser Pro Thr Thr Pro Glu Gly 130 135 140 Thr Asp Val Pro Met Ser Thr Pro Ser Glu Glu Ser Ile Ser Ser Thr 145 150 155 160 Met Ala Phe Val Ser Thr Ala Pro Leu Pro Ser Phe Glu Ala Tyr Thr 165 170 175 Ser Leu Thr Tyr Lys Val Asp Met Ser Thr Pro Leu Thr Thr Ser Thr 180 185 190 Gln Ala Ser Ser Ser Pro Thr Thr Pro Glu Ser Thr Thr Ile Pro Lys 195 200 205 Ser Thr Asn Ser Glu Gly Ser Thr Pro Leu Thr Ser Met Pro Ala Ser 210 215 220 Thr Met Lys Val Ala Ser Ser Glu Ala Ile Thr Leu Leu Thr Thr Pro 225 230 235 240 Val Glu Ile Ser Thr Pro Val Thr Ile Ser Ala Gln Ala Ser Ser Ser 245 250 255 Pro Thr Thr Ala Glu Gly Pro Ser Leu Ser Asn Ser Ala Pro Ser Gly 260 265 270 Gly Ser Thr Pro Leu Thr Arg Met Pro Leu Ser Val Met Leu Val Val 275 280 285 Ser Ser Glu Ala Ser Thr Leu Ser Thr Thr Pro Ala Ala Thr Asn Ile 290 295 300 Pro Val Ile Thr Ser Thr Glu Ala Ser Ser Ser Pro Thr Thr Ala Glu 305 310 315 320 Gly Thr Ser Ile Pro Thr Ser Thr Tyr Thr Glu Gly Ser Thr Pro Leu 325 330 335 Thr Ser Thr Pro Ala Ser Thr Met Pro Val Ala Thr Ser Glu Met Ser 340 345 350 Thr Leu Ser Ile Thr Pro Val Asp Thr Ser Thr Leu Val Thr Thr Ser 355 360 365 Thr Glu Pro Ser Ser Leu Pro Thr Thr Ala Glu Ala Thr Ser Met Leu 370 375 380 Thr Ser Thr Leu Ser Glu Gly Ser Thr Pro Leu Thr Asn Met Pro Val 385 390 395 400 Ser Thr Ile Leu Val Ala Ser Ser Glu Ala Ser Thr Thr Ser Thr Ile 405 410 415 Pro Val Asp Ser Lys Thr Phe Val Thr Thr Ala Ser Glu Ala Ser Ser 420 425 430 Ser Pro Thr Thr Ala Glu Asp Thr Ser Ile Ala Thr Ser Thr Pro Ser 435 440 445 Glu Gly Ser Thr Pro Leu Thr Ser Met Pro Val Ser Thr Thr Pro Val 450 455 460 Ala Ser Ser Glu Ala Ser Asn Leu Ser Thr Thr Pro Val Asp Ser Lys 465 470 475 480 Thr Gln Val Thr Thr Ser Thr Glu Ala Ser Ser Ser Pro Pro Thr Ala 485 490 495 Glu Val Asn Ser Met Pro Thr Ser Thr Pro Ser Glu Gly Ser Thr Pro 500 505 510 Leu Thr Ser Met Ser Val Ser Thr Met Pro Val Ala Ser Ser Glu Ala 515 520 525 Ser Thr Leu Ser Thr Thr Pro Val Asp Thr Ser Thr Pro Val Thr Thr 530 535 540 Ser Ser Glu Ala Ser Ser Ser Ser Thr Thr Pro Glu Gly Thr Ser Ile 545 550 555 560 Pro Thr Ser Thr Pro Ser Glu Gly Ser Thr Pro Leu Thr Asn Met Pro 565 570 575 Val Ser Thr Arg Leu Val Val Ser Ser Glu Ala Ser Thr Thr Ser Thr 580 585 590 Thr Pro Ala Asp Ser Asn Thr Phe Val Thr Thr Ser Ser Glu Ala Ser 595 600 605 Ser Ser Ser Thr Thr Ala Glu Gly Thr Ser Met Pro Thr Ser Thr Tyr 610 615 620 Ser Glu Arg Gly Thr Thr Ile Thr Ser Met Ser Val Ser Thr Thr Leu 625 630 635 640 Val Ala Ser Ser Glu Ala Ser Thr Leu Ser Thr Thr Pro Val Asp Ser 645 650 655 Asn Thr Pro Val Thr Thr Ser Thr Glu Ala Thr Ser Ser Ser Thr Thr 660 665 670 Ala Glu Gly Thr Ser Met Pro Thr Ser Thr Tyr Thr Glu Gly Ser Thr 675 680 685 Pro Leu Thr Ser Met Pro Val Asn Thr Thr Leu Val Ala Ser Ser Glu 690 695 700 Ala Ser Thr Leu Ser Thr Thr Pro Val Asp Thr Ser Thr Pro Val Thr 705 710 715 720 Thr Ser Thr Glu Ala Ser Ser Ser Pro Thr Thr Ala Asp Gly Ala Ser 725 730 735 Met Pro Thr Ser Thr Pro Ser Glu Gly Ser Thr Pro Leu Thr Ser Met 740 745 750 Pro Val Ser Lys Thr Leu Leu Thr Ser Ser Glu Ala Ser Thr Leu Ser 755 760 765 Thr Thr Pro Leu Asp Thr Ser Thr His Ile Thr Thr Ser Thr Glu Ala 770 775 780 Ser Cys Ser Pro Thr Thr Thr Glu Gly Thr Ser Met Pro Ile Ser Thr 785 790 795 800 Pro Ser Glu Gly Ser Pro Leu Leu Thr Ser Ile Pro Val Ser Ile Thr 805 810 815 Pro Val Thr Ser Pro Glu Ala Ser Thr Leu Ser Thr Thr Pro Val Asp 820 825 830 Ser Asn Ser Pro Val Thr Thr Ser Thr Glu Val Ser Ser Ser Pro Thr 835 840 845 Pro Ala Glu Gly Thr Ser Met Pro Thr Ser Thr Tyr Ser Glu Gly Arg 850 855 860 Thr Pro Leu Thr Ser Met Pro Val Ser Thr Thr Leu Val Ala Thr Ser 865 870 875 880 Ala Ile Ser Thr Leu Ser Thr Thr Pro Val Asp Thr Ser Thr Pro Val 885 890 895 Thr Asn Ser Thr Glu Ala Arg Ser Ser Pro Thr Thr Ser Glu Gly Thr 900 905 910 Ser Met Pro Thr Ser Thr Pro Gly Glu Gly Ser Thr Pro Leu Thr Ser 915 920 925 Met Pro Asp Ser Thr Thr Pro Val Val Ser Ser Glu Ala Arg Thr Leu 930 935 940 Ser Ala Thr Pro Val Asp Thr Ser Thr Pro Val Thr Thr Ser Thr Glu 945 950 955 960 Ala Thr Ser Ser Pro Thr Thr Ala Glu Gly Thr Ser Ile Pro Thr Ser 965 970 975 Thr Pro Ser Glu Gly Thr Thr Pro Leu Thr Ser Thr Pro Val Ser His 980 985 990 Thr Leu Val Ala Asn Ser Glu Ala Ser Thr Leu Ser Thr Thr Pro Val 995 1000 1005 Asp Ser Asn Thr Pro Leu Thr Thr Ser Thr Glu Ala Ser Ser Pro Pro 1010 1015 1020 Pro Thr Ala Glu Gly Thr Ser Met Pro Thr Ser Thr Pro Ser Glu Gly 1025 1030 1035 1040 Ser Thr Pro Leu Thr Arg Met Pro Val Ser Thr Thr Met Val Ala Ser 1045 1050 1055 Ser Glu Thr Ser Thr Leu Ser Thr Thr Pro Ala Asp Thr Ser Thr Pro 1060 1065 1070 Val Thr Thr Tyr Ser Gln Ala Ser Ser Ser Ser Thr Thr Ala Asp Gly 1075 1080 1085 Thr Ser Met Pro Thr Ser Thr Tyr Ser Glu Gly Ser Thr Pro Leu Thr 1090 1095 1100 Ser Val Pro Val Ser Thr Arg Leu Val Val Ser Ser Glu Ala Ser Thr 1105 1110 1115 1120 Leu Ser Thr Thr Pro Val Asp Thr Ser Ile Pro Val Thr Thr Ser Thr 1125 1130 1135 Glu Ala Ser Ser Ser Pro Thr Thr Ala Glu Gly Thr Ser Ile Pro Thr 1140 1145 1150 Ser Pro Pro Ser Glu Gly Thr Thr Pro Leu Ala Ser Met Pro Val Ser 1155 1160 1165 Thr Thr Leu Val Val Ser Ser Glu Ala Asn Thr Leu Ser Thr Thr Pro 1170 1175 1180 Val Asp Ser Lys Thr Gln Val Ala Thr Ser Thr Glu Ala Ser Ser Pro 1185 1190 1195 1200 Pro Pro Thr Ala Glu Val Thr Ser Met Pro Thr Ser Thr Pro Gly Glu 1205 1210 1215 Arg Ser Thr Pro Leu Thr Ser Met Pro Val Arg His Thr Pro Val Ala 1220 1225 1230 Ser Ser Glu Ala Ser Thr Leu Ser Thr Ser Pro Val Asp Thr Ser Thr 1235 1240 1245 Pro Val Thr Thr Ser Ala Glu Thr Ser Ser Ser Pro Thr Thr Ala Glu 1250 1255 1260 Gly Thr Ser Leu Pro Thr Ser Thr Thr Ser Glu Gly Ser Thr Leu Leu 1265 1270 1275 1280 Thr Ser Ile Pro Val Ser Thr Thr Leu Val Thr Ser Pro Glu Ala Ser 1285 1290 1295 Thr Leu Leu Thr Thr Pro Val Asp Thr Lys Gly Pro Val Val Thr Ser 1300 1305 1310 Asn Glu Val Ser Ser Ser Pro Thr Pro Ala Glu Gly Thr Ser Met Pro 1315 1320 1325 Thr Ser Thr Tyr Ser Glu Gly Arg Thr Pro Leu Thr Ser Ile Pro Val 1330 1335 1340 Asn Thr Thr Leu Val Ala Ser Ser Ala Ile Ser Ile Leu Ser Thr Thr 1345 1350 1355 1360 Pro Val Asp Asn Ser Thr Pro Val Thr Thr Ser Thr Glu Ala Cys Ser 1365 1370 1375 Ser Pro Thr Thr Ser Glu Gly Thr Ser Met Pro Asn Ser Asn Pro Ser 1380 1385 1390 Glu Gly Thr Thr Pro Leu Thr Ser Ile Pro Val Ser Thr Thr Pro Val 1395 1400 1405 Val Ser Ser Glu Ala Ser Thr Leu Ser Ala Thr Pro Val Asp Thr Ser 1410 1415 1420 Thr Pro Gly Thr Thr Ser Ala Glu Ala Thr Ser Ser Pro Thr Thr Ala 1425 1430 1435 1440 Glu Gly Ile Ser Ile Pro Thr Ser Thr Pro Ser Glu Gly Lys Thr Pro 1445 1450 1455 Leu Lys Ser Ile Pro Val Ser Asn Thr Pro Val Ala Asn Ser Glu Ala 1460 1465 1470 Ser Thr Leu Ser Thr Thr Pro Val Asp Ser Asn Ser Pro Val Val Thr 1475 1480 1485 Ser Thr Ala Val Ser Ser Ser Ser Pro Thr Pro Ala Glu Gly Thr Ser Ile 1490 1495 1500 Ala Ile Ser Thr Pro Ser Glu Gly Ser Thr Ala Leu Thr Ser Ile Pro 1505 1510 1515 1520 Val Ser Thr Thr Thr Val Ala Ser Ser Glu Ile Asn Ser Leu Ser Thr 1525 1530 1535 Thr Pro Ala Val Thr Ser Thr Pro Val Thr Thr Tyr Ser Gln Ala Ser 1540 1545 1550 Ser Ser Pro Thr Thr Ala Asp Gly Thr Ser Met Gln Thr Ser Thr Tyr 1555 1560 1565 Ser Glu Gly Ser Thr Pro Leu Thr Ser Leu Pro Val Ser Thr Met Leu 1570 1575 1580 Val Val Ser Ser Glu Ala Asn Thr Leu Ser Thr Thr Pro Ile Asp Ser 1585 1590 1595 1600 Lys Thr Gln Val Thr Ala Ser Thr Glu Ala Ser Ser Ser Thr Thr Ala 1605 1610 1615 Glu Gly Ser Ser Met Thr Ile Ser Thr Pro Ser Glu Gly Ser Pro Leu 1620 1625 1630 Leu Thr Ser Ile Pro Val Ser Thr Thr Pro Val Ala Ser Pro Glu Ala 1635 1640 1645 Ser Thr Leu Ser Thr Thr Pro Val Asp Ser Asn Ser Pro Val Ile Thr 1650 1655 1660 Ser Thr Glu Val Ser Ser Ser Pro Thr Pro Ala Glu Gly Thr Ser Met 1665 1670 1675 1680 Pro Thr Ser Thr Tyr Thr Glu Gly Arg Thr Pro Leu Thr Ser Ile Thr 1685 1690 1695 Val Arg Thr Thr Pro Val Ala Ser Ser Ala Ile Ser Thr Leu Ser Thr 1700 1705 1710 Thr Pro Val Asp Asn Ser Thr Pro Val Thr Thr Ser Thr Glu Ala Arg 1715 1720 1725 Ser Ser Pro Thr Thr Ser Glu Gly Thr Ser Met Pro Asn Ser Thr Pro 1730 1735 1740 Ser Glu Gly Thr Thr Pro Leu Thr Ser Ile Pro Val Ser Thr Thr Pro 1745 1750 1755 1760 Val Leu Ser Ser Glu Ala Ser Thr Leu Ser Ala Thr Pro Ile Asp Thr 1765 1770 1775 Ser Thr Pro Val Thr Thr Ser Thr Glu Ala Thr Ser Ser Pro Thr Thr 1780 1785 1790 Ala Glu Gly Thr Ser Ile Pro Thr Ser Thr Leu Ser Glu Gly Met Thr 1795 1800 1805 Pro Leu Thr Ser Thr Pro Val Ser His Thr Leu Val Ala Asn Ser Glu 1810 1815 1820 Ala Ser Thr Leu Ser Thr Thr Pro Val Asp Ser Asn Ser Pro Val Val 1825 1830 1835 1840 Thr Ser Thr Ala Val Ser Ser Ser Pro Thr Pro Ala Glu Gly Thr Ser 1845 1850 1855 Ile Ala Thr Ser Thr Pro Ser Glu Gly Ser Thr Ala Leu Thr Ser Ile 1860 1865 1870 Pro Val Ser Thr Thr Thr Val Ala Ser Ser Glu Thr Asn Thr Leu Ser 1875 1880 1885 Thr Thr Pro Ala Val Thr Ser Thr Pro Val Thr Thr Tyr Ala Gln Val 1890 1895 1900 Ser Ser Ser Pro Thr Thr Ala Asp Gly Ser Ser Met Pro Thr Ser Thr 1905 1910 1915 1920 Pro Arg Glu Gly Arg Pro Pro Leu Thr Ser Ile Pro Val Ser Thr Thr 1925 1930 1935 Thr Val Ala Ser Ser Glu Ile Asn Thr Leu Ser Thr Thr Leu Ala Asp 1940 1945 1950 Thr Arg Thr Pro Val Thr Thr Tyr Ser Gln Ala Ser Ser Ser Pro Thr 1955 1960 1965 Thr Ala Asp Gly Thr Ser Met Pro Thr Pro Ala Tyr Ser Glu Gly Ser 1970 1975 1980 Thr Pro Leu Thr Ser Met Pro Leu Ser Thr Thr Leu Val Val Ser Ser 1985 1990 1995 2000 Glu Ala Ser Thr Leu Ser Thr Thr Pro Val Asp Thr Ser Thr Pro Ala 2005 2010 2015 Thr Thr Ser Thr Glu Gly Ser Ser Ser Pro Thr Thr Ala Gly Gly Thr 2020 2025 2030 Ser Ile Gln Thr Ser Thr Pro Ser Glu Arg Thr Thr Pro Leu Ala Gly 2035 2040 2045 Met Pro Val Ser Thr Thr Leu Val Val Ser Ser Glu Gly Asn Thr Leu 2050 2055 2060 Ser Thr Thr Pro Val Asp Ser Lys Thr Gln Val Thr Asn Ser Thr Glu 2065 2070 2075 2080 Ala Ser Ser Ser Ala Thr Ala Glu Gly Ser Ser Met Thr Ile Ser Ala 2085 2090 2095 Pro Ser Glu Gly Ser Pro Leu Leu Thr Ser Ile Pro Leu Ser Thr Thr 2100 2105 2110 Pro Val Ala Ser Pro Glu Ala Ser Thr Leu Ser Thr Thr Pro Val Asp 2115 2120 2125 Ser Asn Ser Pro Val Ile Thr Ser Thr Glu Val Ser Ser Ser Pro Ile 2130 2135 2140 Pro Thr Glu Gly Thr Ser Met Gln Thr Ser Thr Tyr Ser Asp Arg Arg 2145 2150 2155 2160 Thr Pro Leu Thr Ser Met Pro Val Ser Thr Thr Val Val Ala Ser Ser 2165 2170 2175 Ala Ile Ser Thr Leu Ser Thr Thr Pro Val Asp Thr Ser Thr Pro Val 2180 2185 2190 Thr Asn Ser Thr Glu Ala Arg Ser Ser Pro Thr Thr Ser Glu Gly Thr 2195 2200 2205 Ser Met Pro Thr Ser Thr Pro Ser Glu Gly Ser Thr Pro Phe Thr Ser 2210 2215 2220 Met Pro Val Ser Thr Met Pro Val Val Thr Ser Glu Ala Ser Thr Leu 2225 2230 2235 2240 Ser Ala Thr Pro Val Asp Thr Ser Thr Pro Val Thr Thr Ser Thr Glu 2245 2250 2255 Ala Thr Ser Ser Pro Thr Thr Ala Glu Gly Thr Ser Ile Pro Thr Ser 2260 2265 2270 Thr Leu Ser Glu Gly Thr Thr Pro Leu Thr Ser Ile Pro Val Ser His 2275 2280 2285 Thr Leu Val Ala Asn Ser Glu Val Ser Thr Leu Ser Thr Thr Pro Val 2290 2295 2300 Asp Ser Asn Thr Pro Phe Thr Thr Ser Thr Glu Ala Ser Ser Pro Pro 2305 2310 2315 2320 Pro Thr Ala Glu Gly Thr Ser Met Pro Thr Ser Thr Ser Ser Glu Gly 2325 2330 2335 Asn Thr Pro Leu Thr Arg Met Pro Val Ser Thr Thr Met Val Ala Ser 2340 2345 2350 Phe Glu Thr Ser Thr Leu Ser Thr Thr Pro Ala Asp Thr Ser Thr Pro 2355 2360 2365 Val Thr Thr Tyr Ser Gln Ala Gly Ser Ser Pro Thr Thr Ala Asp Asp 2370 2375 2380 Thr Ser Met Pro Thr Ser Thr Tyr Ser Glu Gly Ser Thr Pro Leu Thr 2385 2390 2395 2400 Ser Val Pro Val Ser Thr Met Pro Val Val Ser Ser Glu Ala Ser Thr 2405 2410 2415 His Ser Thr Thr Pro Val Asp Thr Ser Thr Pro Val Thr Thr Ser Thr 2420 2425 2430 Glu Ala Ser Ser Ser Pro Thr Thr Ala Glu Gly Thr Ser Ile Pro Thr 2435 2440 2445 Ser Pro Pro Ser Glu Gly Thr Thr Pro Leu Ala Ser Met Pro Val Ser 2450 2455 2460 Thr Thr Pro Val Val Ser Ser Glu Ala Gly Thr Leu Ser Thr Thr Pro 2465 2470 2475 2480 Val Asp Thr Ser Thr Pro Met Thr Thr Ser Thr Glu Ala Ser Ser Ser 2485 2490 2495 Pro Thr Thr Ala Glu Asp Ile Val Val Pro Ile Ser Thr Ala Ser Glu 2500 2505 2510 Gly Ser Thr Leu Leu Thr Ser Ile Pro Val Ser Thr Thr Pro Val Ala 2515 2520 2525 Ser Pro Glu Ala Ser Thr Leu Ser Thr Thr Pro Val Asp Ser Asn Ser 2530 2535 2540 Pro Val Val Thr Ser Thr Glu Ile Ser Ser Ser Ala Thr Ser Ala Glu 2545 2550 2555 2560 Gly Thr Ser Met Pro Thr Ser Thr Tyr Ser Glu Gly Ser Thr Pro Leu 2565 2570 2575 Arg Ser Met Pro Val Ser Thr Lys Pro Leu Ala Ser Ser Glu Ala Ser 2580 2585 2590 Thr Leu Ser Thr Thr Pro Val Asp Thr Ser Ile Pro Val Thr Thr Ser 2595 2600 2605 Thr Glu Thr Ser Ser Ser Pro Thr Thr Ala Lys Asp Thr Ser Met Pro 2610 2615 2620 Ile Ser Thr Pro Ser Glu Val Ser Thr Ser Leu Thr Ser Ile Leu Val 2625 2630 2635 2640 Ser Thr Met Pro Val Ala Ser Ser Glu Ala Ser Thr Leu Ser Thr Thr 2645 2650 2655 Pro Val Asp Thr Arg Thr Leu Val Thr Thr Ser Thr Gly Thr Ser Ser 2660 2665 2670 Ser Pro Thr Thr Ala Glu Gly Ser Ser Met Pro Thr Ser Thr Pro Gly 2675 2680 2685 Glu Arg Ser Thr Pro Leu Thr Asn Ile Leu Val Ser Thr Thr Leu Leu 2690 2695 2700 Ala Asn Ser Glu Ala Ser Thr Leu Ser Thr Thr Pro Val Asp Thr Ser 2705 2710 2715 2720 Thr Pro Val Thr Thr Ser Ala Glu Ala Ser Ser Ser Pro Thr Thr Ala 2725 2730 2735 Glu Gly Thr Ser Met Arg Ile Ser Thr Pro Ser Asp Gly Ser Thr Pro 2740 2745 2750 Leu Thr Ser Ile Leu Val Ser Thr Leu Pro Val Ala Ser Ser Glu Ala 2755 2760 2765 Ser Thr Val Ser Thr Thr Ala Val Asp Thr Ser Ile Pro Val Thr Thr 2770 2775 2780 Ser Thr Glu Ala Ser Ser Ser Pro Thr Thr Ala Glu Val Thr Ser Met 2785 2790 2795 2800 Pro Thr Ser Thr Pro Ser Glu Thr Ser Thr Pro Leu Thr Ser Met Pro 2805 2810 2815 Val Asn His Thr Pro Val Ala Ser Ser Glu Ala Gly Thr Leu Ser Thr 2820 2825 2830 Thr Pro Val Asp Thr Ser Thr Pro Val Thr Thr Ser Thr Lys Ala Ser 2835 2840 2845 Ser Ser Pro Thr Thr Ala Glu Gly Ile Val Val Pro Ile Ser Thr Ala 2850 2855 2860 Ser Glu Gly Ser Thr Leu Leu Thr Ser Ile Pro Val Ser Thr Thr Pro 2865 2870 2875 2880 Val Ala Ser Ser Glu Ala Ser Thr Leu Ser Thr Thr Pro Val Asp Thr 2885 2890 2895 Ser Ile Pro Val Thr Thr Ser Thr Glu Gly Ser Ser Ser Pro Thr Thr 2900 2905 2910 Ala Glu Gly Thr Ser Met Pro Ile Ser Thr Pro Ser Glu Val Ser Thr 2915 2920 2925 Pro Leu Thr Ser Ile Leu Val Ser Thr Val Pro Val Ala Gly Ser Glu 2930 2935 2940 Ala Ser Thr Leu Ser Thr Thr Pro Val Asp Thr Arg Thr Pro Val Thr 2945 2950 2955 2960 Thr Ser Ala Glu Ala Ser Ser Ser Pro Thr Thr Ala Glu Gly Thr Ser 2965 2970 2975 Met Pro Ile Ser Thr Pro Gly Glu Arg Arg Thr Pro Leu Thr Ser Met 2980 2985 2990 Ser Val Ser Thr Met Pro Val Ala Ser Ser Glu Ala Ser Thr Leu Ser 2995 3000 3005 Arg Thr Pro Ala Asp Thr Ser Thr Pro Val Thr Thr Ser Thr Glu Ala 3010 3015 3020 Ser Ser Ser Pro Thr Thr Ala Glu Gly Thr Gly Ile Pro Ile Ser Thr 3025 3030 3035 3040 Pro Ser Glu Gly Ser Thr Pro Leu Thr Ser Ile Pro Val Ser Thr Thr 3045 3050 3055 Pro Val Ala Ile Pro Glu Ala Ser Thr Leu Ser Thr Thr Pro Val Asp 3060 3065 3070 Ser Asn Ser Pro Val Val Thr Ser Thr Glu Val Ser Ser Ser Pro Thr 3075 3080 3085 Pro Ala Glu Gly Thr Ser Met Pro Ile Ser Thr Tyr Ser Glu Gly Ser 3090 3095 3100 Thr Pro Leu Thr Gly Val Pro Val Ser Thr Thr Pro Val Thr Ser Ser 3105 3110 3115 3120 Ala Ile Ser Thr Leu Ser Thr Thr Pro Val Asp Thr Ser Thr Pro Val 3125 3130 3135 Thr Thr Ser Thr Glu Ala His Ser Ser Pro Thr Thr Ser Glu Gly Thr 3140 3145 3150 Ser Met Pro Thr Ser Thr Pro Ser Glu Gly Ser Thr Pro Leu Thr Tyr 3155 3160 3165 Met Pro Val Ser Thr Met Leu Val Val Ser Ser Glu Asp Ser Thr Leu 3170 3175 3180 Ser Ala Thr Pro Val Asp Thr Ser Thr Pro Val Thr Thr Ser Thr Glu 3185 3190 3195 3200 Ala Thr Ser Ser Thr Thr Ala Glu Gly Thr Ser Ile Pro Thr Ser Thr 3205 3210 3215 Pro Ser Glu Gly Met Thr Pro Leu Thr Ser Val Pro Val Ser Asn Thr 3220 3225 3230 Pro Val Ala Ser Ser Glu Ala Ser Ile Leu Ser Thr Thr Pro Val Asp 3235 3240 3245 Ser Asn Thr Pro Leu Thr Thr Ser Thr Glu Ala Ser Ser Ser Pro Pro 3250 3255 3260 Thr Ala Glu Gly Thr Ser Met Pro Thr Ser Thr Pro Ser Glu Gly Ser 3265 3270 3275 3280 Thr Pro Leu Thr Ser Met Pro Val Ser Thr Thr Thr Val Ala Ser Ser 3285 3290 3295 Glu Thr Ser Thr Leu Ser Thr Thr Pro Ala Asp Thr Ser Thr Pro Val 3300 3305 3310 Thr Thr Tyr Ser Gln Ala Ser Ser Ser Pro Pro Ile Ala Asp Gly Thr 3315 3320 3325 Ser Met Pro Thr Ser Thr Tyr Ser Glu Gly Ser Thr Pro Leu Thr Asn 3330 3335 3340 Met Ser Phe Ser Thr Thr Pro Val Val Ser Ser Glu Ala Ser Thr Leu 3345 3350 3355 3360 Ser Thr Thr Pro Val Asp Thr Ser Thr Pro Val Thr Thr Ser Thr Glu 3365 3370 3375 Ala Ser Leu Ser Pro Thr Thr Ala Glu Gly Thr Ser Ile Pro Thr Ser 3380 3385 3390 Ser Pro Ser Glu Gly Thr Thr Pro Leu Ala Ser Met Pro Val Ser Thr 3395 3400 3405 Thr Pro Val Val Ser Ser Glu Val Asn Thr Leu Ser Thr Thr Pro Val 3410 3415 3420 Asp Ser Asn Thr Leu Val Thr Thr Ser Thr Glu Ala Ser Ser Ser Pro 3425 3430 3435 3440 Thr Ile Ala Glu Gly Thr Ser Leu Pro Thr Ser Thr Thr Ser Glu Gly 3445 3450 3455 Ser Thr Pro Leu Ser Ile Met Pro Leu Ser Thr Thr Pro Val Ala Ser 3460 3465 3470 Ser Glu Ala Ser Thr Leu Ser Thr Thr Pro Val Asp Thr Ser Thr Pro 3475 3480 3485 Val Thr Thr Ser Ser Pro Thr Asn Ser Ser Pro Thr Thr Ala Glu Val 3490 3495 3500 Thr Ser Met Pro Thr Ser Thr Ala Gly Glu Gly Ser Thr Pro Leu Thr 3505 3510 3515 3520 Asn Met Pro Val Ser Thr Thr Pro Val Ala Ser Ser Glu Ala Ser Thr 3525 3530 3535 Leu Ser Thr Thr Pro Val Asp Ser Asn Thr Phe Val Thr Ser Ser Ser Ser 3540 3545 3550 Gln Ala Ser Ser Ser Pro Ala Thr Leu Gln Val Thr Thr Met Arg Met 3555 3560 3565 Ser Thr Pro Ser Glu Gly Ser Ser Ser Leu Thr Thr Met Leu Leu Ser 3570 3575 3580 Ser Thr Tyr Val Thr Ser Ser Glu Ala Ser Thr Pro Ser Thr Pro Ser 3585 3590 3595 3600 Val Asp Arg Ser Thr Pro Val Thr Thr Ser Thr Gln Ser Asn Ser Thr 3605 3610 3615 Pro Thr Pro Pro Glu Val Ile Thr Leu Pro Met Ser Thr Pro Ser Glu 3620 3625 3630 Val Ser Thr Pro Leu Thr Ile Met Pro Val Ser Thr Thr Ser Val Thr 3635 3640 3645 Ile Ser Glu Ala Gly Thr Ala Ser Thr Leu Pro Val Asp Thr Ser Thr 3650 3655 3660 Pro Val Ile Thr Ser Thr Gln Val Ser Ser Ser Pro Val Thr Pro Glu 3665 3670 3675 3680 Gly Thr Thr Met Pro Ile Trp Thr Pro Ser Glu Gly Ser Thr Pro Leu 3685 3690 3695 Thr Thr Met Pro Val Ser Thr Thr Arg Val Thr Ser Ser Glu Gly Ser 3700 3705 3710 Thr Leu Ser Thr Pro Ser Val Val Thr Ser Thr Pro Val Thr Thr Ser 3715 3720 3725 Thr Glu Ala Ile Ser Ser Ser Ala Thr Leu Asp Ser Thr Thr Met Ser 3730 3735 3740 Val Ser Met Pro Met Glu Ile Ser Thr Leu Gly Thr Thr Ile Leu Val 3745 3750 3755 3760 Ser Thr Thr Pro Val Thr Arg Phe Pro Glu Ser Ser Thr Pro Ser Ile 3765 3770 3775 Pro Ser Val Tyr Thr Ser Met Ser Met Thr Thr Ala Ser Glu Gly Ser 3780 3785 3790 Ser Ser Pro Thr Thr Leu Glu Gly Thr Thr Thr Met Pro Met Ser Thr 3795 3800 3805 Thr Ser Glu Arg Ser Thr Leu Leu Thr Thr Val Leu Ile Ser Pro Ile 3810 3815 3820 Ser Val Met Ser Pro Ser Glu Ala Ser Thr Leu Ser Thr Pro Pro Gly 3825 3830 3835 3840 Asp Thr Ser Thr Pro Leu Leu Thr Ser Thr Lys Ala Gly Ser Phe Ser 3845 3850 3855 Ile Pro Ala Glu Val Thr Thr Ile Arg Ile Ser Ile Thr Ser Glu Arg 3860 3865 3870 Ser Thr Pro Leu Thr Thr Leu Leu Val Ser Thr Thr Leu Pro Thr Ser 3875 3880 3885 Phe Pro Gly Ala Ser Ile Ala Ser Thr Pro Leu Asp Thr Ser Thr 3890 3895 3900 Thr Phe Thr Pro Ser Thr Asp Thr Ala Ser Thr Pro Thr Ile Pro Val 3905 3910 3915 3920 Ala Thr Thr Ile Ser Val Ser Val Ile Thr Glu Gly Ser Thr Pro Gly 3925 3930 3935 Thr Thr Ile Phe Ile Pro Ser Thr Pro Val Thr Ser Ser Thr Ala Asp 3940 3945 3950 Val Phe Pro Ala Thr Thr Gly Ala Val Ser Thr Pro Val Ile Thr Ser 3955 3960 3965 Thr Glu Leu Asn Thr Pro Ser Thr Ser Ser Ser Ser Thr Thr Thr Ser 3970 3975 3980 Phe Ser Thr Thr Lys Glu Phe Thr Thr Pro Ala Met Thr Thr Ala Ala 3985 3990 3995 4000 Pro Leu Thr Tyr Val Thr Met Ser Thr Ala Pro Ser Thr Pro Arg Thr 4005 4010 4015 Thr Ser Arg Gly Cys Thr Thr Ser Ala Ser Thr Leu Ser Ala Thr Ser 4020 4025 4030 Thr Pro His Thr Ser Thr Ser Val Thr Thr Arg Pro Val Thr Pro Ser 4035 4040 4045 Ser Glu Ser Ser Arg Pro Ser Thr Ile Thr Ser His Thr Ile Pro Pro 4050 4055 4060 Thr Phe Pro Pro Ala His Ser Ser Thr Pro Pro Thr Thr Ser Ala Ser 4065 4070 4075 4080 Ser Thr Thr Val Asn Pro Glu Ala Val Thr Thr Met Thr Thr Arg Thr 4085 4090 4095 Lys Pro Ser Thr Arg Thr Thr Ser Phe Pro Thr Val Thr Thr Thr Ala 4100 4105 4110 Val Pro Thr Asn Thr Thr Ile Lys Ser Asn Pro Thr Ser Thr Pro Thr 4115 4120 4125 Val Pro Arg Thr Thr Thr Cys Phe Gly Asp Gly Cys Gln Asn Thr Ala 4130 4135 4140 Ser Arg Cys Lys Asn Gly Gly Thr Trp Asp Gly Leu Lys Cys Gln Cys 4145 4150 4155 4160 Pro Asn Leu Tyr Tyr Gly Glu Leu Cys Glu Glu Val Val Ser Ser Ile 4165 4170 4175 Asp Ile Gly Pro Glu Thr Ile Ser Ala Gln Met Glu Leu Thr Val 4180 4185 4190 Thr Val Thr Ser Val Lys Phe Thr Glu Glu Leu Lys Asn His Ser Ser 4195 4200 4205 Gln Glu Phe Gln Glu Phe Lys Gln Thr Phe Thr Glu Gln Met Asn Ile 4210 4215 4220 Val Tyr Ser Gly Ile Pro Glu Tyr Val Gly Val Asn Ile Thr Lys Leu 4225 4230 4235 4240 Arg Leu Gly Ser Val Val Val Glu His Asp Val Leu Leu Arg Thr Lys 4245 4250 4255 Tyr Thr Pro Glu Tyr Lys Thr Val Leu Asp Asn Ala Thr Glu Val Val 4260 4265 4270 Lys Glu Lys Ile Thr Lys Val Thr Thr Gln Gln Ile Met Ile Asn Asp 4275 4280 4285 Ile Cys Ser Asp Met Met Cys Phe Asn Thr Thr Gly Thr Gln Val Gln 4290 4295 4300 Asn Ile Thr Val Thr Gln Tyr Asp Pro Glu Glu Asp Cys Arg Lys Met 4305 4310 4315 4320 Ala Lys Glu Tyr Gly Asp Tyr Phe Val Val Glu Tyr Arg Asp Gln Lys 4325 4330 4335 Pro Tyr Cys Ile Ser Pro Cys Glu Pro Gly Phe Ser Val Ser Lys Asn 4340 4345 4350 Cys Asn Leu Gly Lys Cys Gln Met Ser Leu Ser Gly Pro Gln Cys Leu 4355 4360 4365 Cys Val Thr Thr Glu Thr His Trp Tyr Ser Gly Glu Thr Cys Asn Gln 4370 4375 4380 Gly Thr Gln Lys Ser Leu Val Tyr Gly Leu Val Gly Ala Gly Val Val 4385 4390 4395 4400 Leu Met Leu Ile Ile Leu Val Ala Leu Leu Met Leu Val Phe Arg Ser 4405 4410 4415 Lys Arg Glu Val Lys Arg Gln Lys Tyr Arg Leu Ser Gln Leu Tyr Lys 4420 4425 4430 Trp Gln Glu Glu Asp Ser Gly Pro Ala Pro Gly Thr Phe Gln Asn Ile 4435 4440 4445 Gly Phe Asp Ile Cys Gln Asp Asp Asp Ser Ile His Leu Glu Ser Ile 4450 4455 4460 Tyr Ser Asn Phe Gln Pro Ser Leu Arg His Ile Asp Pro Glu Thr Lys 4465 4470 4475 4480 Ile Arg Ile Gln Arg Pro Gln Val Met Thr Thr Ser Phe 4485 4490 <210> 23 <211> 1976 <212> PRT <213> Homo sapiens <400> 23 Met Ala Gln Arg Thr Gly Leu Glu Asp Pro Glu Arg Tyr Leu Phe Val 1 5 10 15 Asp Arg Ala Val Ile Tyr Asn Pro Ala Thr Gln Ala Asp Trp Thr Ala 20 25 30 Lys Lys Leu Val Trp Ile Pro Ser Glu Arg His Gly Phe Glu Ala Ala 35 40 45 Ser Ile Lys Glu Glu Arg Gly Asp Glu Val Met Val Glu Leu Ala Glu 50 55 60 Asn Gly Lys Lys Ala Met Val Asn Lys Asp Asp Ile Gln Lys Met Asn 65 70 75 80 Pro Pro Lys Phe Ser Lys Val Glu Asp Met Ala Glu Leu Thr Cys Leu 85 90 95 Asn Glu Ala Ser Val Leu His Asn Leu Lys Asp Arg Tyr Tyr Ser Gly 100 105 110 Leu Ile Tyr Thr Tyr Ser Gly Leu Phe Cys Val Val Ile Asn Pro Tyr 115 120 125 Lys Asn Leu Pro Ile Tyr Ser Glu Asn Ile Ile Glu Met Tyr Arg Gly 130 135 140 Lys Lys Arg His Glu Met Pro His Ile Tyr Ala Ile Ser Glu Ser 145 150 155 160 Ala Tyr Arg Cys Met Leu Gln Asp Arg Glu Asp Gln Ser Ile Leu Cys 165 170 175 Thr Gly Glu Ser Gly Ala Gly Lys Thr Glu Asn Thr Lys Lys Val Ile 180 185 190 Gln Tyr Leu Ala His Val Ala Ser Ser His Lys Gly Arg Lys Asp His 195 200 205 Asn Ile Pro Gly Glu Leu Glu Arg Gln Leu Leu Gln Ala Asn Pro Ile 210 215 220 Leu Glu Ser Phe Gly Asn Ala Lys Thr Val Lys Asn Asp Asn Ser Ser 225 230 235 240 Arg Phe Gly Lys Phe Ile Arg Ile Asn Phe Asp Val Thr Gly Tyr Ile 245 250 255 Val Gly Ala Asn Ile Glu Thr Tyr Leu Leu Glu Lys Ser Arg Ala Val 260 265 270 Arg Gln Ala Lys Asp Glu Arg Thr Phe His Ile Phe Tyr Gln Leu Leu 275 280 285 Ser Gly Ala Gly Glu His Leu Lys Ser Asp Leu Leu Leu Glu Gly Phe 290 295 300 Asn Asn Tyr Arg Phe Leu Ser Asn Gly Tyr Ile Pro Ile Pro Gly Gln 305 310 315 320 Gln Asp Lys Asp Asn Phe Gln Glu Thr Met Glu Ala Met His Ile Met 325 330 335 Gly Phe Ser His Glu Glu Ile Leu Ser Met Leu Lys Val Val Ser Ser 340 345 350 Val Leu Gln Phe Gly Asn Ile Ser Phe Lys Lys Glu Arg Asn Thr Asp 355 360 365 Gln Ala Ser Met Pro Glu Asn Thr Val Ala Gln Lys Leu Cys His Leu 370 375 380 Leu Gly Met Asn Val Met Glu Phe Thr Arg Ala Ile Leu Thr Pro Arg 385 390 395 400 Ile Lys Val Gly Arg Asp Tyr Val Gln Lys Ala Gln Thr Lys Glu Gln 405 410 415 Ala Asp Phe Ala Val Glu Ala Leu Ala Lys Ala Thr Tyr Glu Arg Leu 420 425 430 Phe Arg Trp Leu Val His Arg Ile Asn Lys Ala Leu Asp Arg Thr Lys 435 440 445 Arg Gln Gly Ala Ser Phe Ile Gly Ile Leu Asp Ile Ala Gly Phe Glu 450 455 460 Ile Phe Glu Leu Asn Ser Phe Glu Gln Leu Cys Ile Asn Tyr Thr Asn 465 470 475 480 Glu Lys Leu Gln Gln Leu Phe Asn His Thr Met Phe Ile Leu Glu Gln 485 490 495 Glu Glu Tyr Gln Arg Glu Gly Ile Glu Trp Asn Phe Ile Asp Phe Gly 500 505 510 Leu Asp Leu Gln Pro Cys Ile Asp Leu Ile Glu Arg Pro Ala Asn Pro 515 520 525 Pro Gly Val Leu Ala Leu Leu Asp Glu Glu Cys Trp Phe Pro Lys Ala 530 535 540 Thr Asp Lys Thr Phe Val Glu Lys Leu Val Gln Glu Gln Gly Ser His 545 550 555 560 Ser Lys Phe Gln Lys Pro Arg Gln Leu Lys Asp Lys Ala Asp Phe Cys 565 570 575 Ile Ile His Tyr Ala Gly Lys Val Asp Tyr Lys Ala Asp Glu Trp Leu 580 585 590 Met Lys Asn Met Asp Pro Leu Asn Asp Asn Val Ala Thr Leu Leu His 595 600 605 Gln Ser Ser Asp Arg Phe Val Ala Glu Leu Trp Lys Asp Val Asp Arg 610 615 620 Ile Val Gly Leu Asp Gln Val Thr Gly Met Thr Glu Thr Ala Phe Gly 625 630 635 640 Ser Ala Tyr Lys Thr Lys Lys Gly Met Phe Arg Thr Val Gly Gln Leu 645 650 655 Tyr Lys Glu Ser Leu Thr Lys Leu Met Ala Thr Leu Arg Asn Thr Asn 660 665 670 Pro Asn Phe Val Arg Cys Ile Ile Pro Asn His Glu Lys Arg Ala Gly 675 680 685 Lys Leu Asp Pro His Leu Val Leu Asp Gln Leu Arg Cys Asn Gly Val 690 695 700 Leu Glu Gly Ile Arg Ile Cys Arg Gln Gly Phe Pro Asn Arg Ile Val 705 710 715 720 Phe Gln Glu Phe Arg Gln Arg Tyr Glu Ile Leu Thr Pro Asn Ala Ile 725 730 735 Pro Lys Gly Phe Met Asp Gly Lys Gln Ala Cys Glu Arg Met Ile Arg 740 745 750 Ala Leu Glu Leu Asp Pro Asn Leu Tyr Arg Ile Gly Gln Ser Lys Ile 755 760 765 Phe Phe Arg Ala Gly Val Leu Ala His Leu Glu Glu Glu Arg Asp Leu 770 775 780 Lys Ile Thr Asp Ile Ile Ile Ile Phe Phe Gln Ala Val Cys Arg Gly Tyr 785 790 795 800 Leu Ala Arg Lys Ala Phe Ala Lys Lys Gln Gln Gln Leu Ser Ala Leu 805 810 815 Lys Val Leu Gln Arg Asn Cys Ala Ala Tyr Leu Lys Leu Arg His Trp 820 825 830 Gln Trp Trp Arg Val Phe Thr Lys Val Lys Pro Leu Leu Gln Val Thr 835 840 845 Arg Gln Glu Glu Glu Leu Gln Ala Lys Asp Glu Glu Leu Leu Lys Val 850 855 860 Lys Glu Lys Gln Thr Lys Val Glu Gly Glu Leu Glu Glu Met Glu Arg 865 870 875 880 Lys His Gln Gln Leu Leu Glu Glu Lys Asn Ile Leu Ala Glu Gln Leu 885 890 895 Gln Ala Glu Thr Glu Leu Phe Ala Glu Ala Glu Glu Met Arg Ala Arg 900 905 910 Leu Ala Ala Lys Lys Gln Glu Leu Glu Glu Ile Leu His Asp Leu Glu 915 920 925 Ser Arg Val Glu Glu Glu Glu Glu Arg Asn Gln Ile Leu Gln Asn Glu 930 935 940 Lys Lys Lys Met Gln Ala His Ile Gln Asp Leu Glu Glu Gln Leu Asp 945 950 955 960 Glu Glu Glu Gly Ala Arg Gln Lys Leu Gln Leu Glu Lys Val Thr Ala 965 970 975 Glu Ala Lys Ile Lys Lys Met Glu Glu Glu Ile Leu Leu Leu Glu Asp 980 985 990 Gln Asn Ser Lys Phe Ile Lys Glu Lys Lys Leu Met Glu Asp Arg Ile 995 1000 1005 Ala Glu Cys Ser Ser Gln Leu Ala Glu Glu Glu Glu Lys Ala Lys Asn 1010 1015 1020 Leu Ala Lys Ile Arg Asn Lys Gln Glu Val Met Ile Ser Asp Leu Glu 1025 1030 1035 1040 Glu Arg Leu Lys Lys Glu Glu Lys Thr Arg Gln Glu Leu Glu Lys Ala 1045 1050 1055 Lys Arg Lys Leu Asp Gly Glu Thr Thr Asp Leu Gln Asp Gln Ile Ala 1060 1065 1070 Glu Leu Gln Ala Gln Ile Asp Glu Leu Lys Leu Gln Leu Ala Lys Lys 1075 1080 1085 Glu Glu Glu Leu Gln Gly Ala Leu Ala Arg Gly Asp Asp Glu Thr Leu 1090 1095 1100 His Lys Asn Asn Ala Leu Lys Val Val Arg Glu Leu Gln Ala Gln Ile 1105 1110 1115 1120 Ala Glu Leu Gln Glu Asp Phe Glu Ser Glu Lys Ala Ser Arg Asn Lys 1125 1130 1135 Ala Glu Lys Gln Lys Arg Asp Leu Ser Glu Glu Leu Glu Ala Leu Lys 1140 1145 1150 Thr Glu Leu Glu Asp Thr Leu Asp Thr Thr Ala Ala Gln Gln Glu Leu 1155 1160 1165 Arg Thr Lys Arg Glu Gln Glu Val Ala Glu Leu Lys Lys Ala Leu Glu 1170 1175 1180 Glu Glu Thr Lys Asn His Glu Ala Gln Ile Gln Asp Met Arg Gln Arg 1185 1190 1195 1200 His Ala Thr Ala Leu Glu Glu Leu Ser Glu Gln Leu Glu Gln Ala Lys 1205 1210 1215 Arg Phe Lys Ala Asn Leu Glu Lys Asn Lys Gln Gly Leu Glu Thr Asp 1220 1225 1230 Asn Lys Glu Leu Ala Cys Glu Val Lys Val Leu Gln Gln Val Lys Ala 1235 1240 1245 Glu Ser Glu His Lys Arg Lys Lys Leu Asp Ala Gln Val Gln Glu Leu 1250 1255 1260 His Ala Lys Val Ser Glu Gly Asp Arg Leu Arg Val Glu Leu Ala Glu 1265 1270 1275 1280 Lys Ala Ser Lys Leu Gln Asn Glu Leu Asp Asn Val Ser Thr Leu Leu 1285 1290 1295 Glu Glu Ala Glu Lys Lys Gly Ile Lys Phe Ala Lys Asp Ala Ala Ser 1300 1305 1310 Leu Glu Ser Gln Leu Gln Asp Thr Gln Glu Leu Leu Gln Glu Glu Thr 1315 1320 1325 Arg Gln Lys Leu Asn Leu Ser Ser Arg Ile Arg Gln Leu Glu Glu Glu 1330 1335 1340 Lys Asn Ser Leu Gln Glu Gln Gln Glu Glu Glu Glu Glu Ala Arg Lys 1345 1350 1355 1360 Asn Leu Glu Lys Gln Val Leu Ala Leu Gln Ser Gln Leu Ala Asp Thr 1365 1370 1375 Lys Lys Lys Val Asp Asp Asp Leu Gly Thr Ile Glu Ser Leu Glu Glu 1380 1385 1390 Ala Lys Lys Lys Leu Leu Lys Asp Ala Glu Ala Leu Ser Gln Arg Leu 1395 1400 1405 Glu Glu Lys Ala Leu Ala Tyr Asp Lys Leu Glu Lys Thr Lys Asn Arg 1410 1415 1420 Leu Gln Gln Glu Leu Asp Asp Leu Thr Val Asp Leu Asp His Gln Arg 1425 1430 1435 1440 Gln Val Ala Ser Asn Leu Glu Lys Lys Gln Lys Lys Phe Asp Gln Leu 1445 1450 1455 Leu Ala Glu Glu Lys Ser Ile Ser Ala Arg Tyr Ala Glu Glu Arg Asp 1460 1465 1470 Arg Ala Glu Ala Glu Ala Arg Glu Lys Glu Thr Lys Ala Leu Ser Leu 1475 1480 1485 Ala Arg Ala Leu Glu Glu Ala Leu Glu Ala Lys Glu Glu Phe Glu Arg 1490 1495 1500 Gln Asn Lys Gln Leu Arg Ala Asp Met Glu Asp Leu Met Ser Ser Lys 1505 1510 1515 1520 Asp Asp Val Gly Lys Asn Val His Glu Leu Glu Lys Ser Lys Arg Ala 1525 1530 1535 Leu Glu Gln Gln Val Glu Glu Met Arg Thr Gln Leu Glu Glu Leu Glu 1540 1545 1550 Asp Glu Leu Gln Ala Thr Glu Asp Ala Lys Leu Arg Leu Glu Val Asn 1555 1560 1565 Met Gln Ala Met Lys Ala Gln Phe Glu Arg Asp Leu Gln Thr Arg Asp 1570 1575 1580 Glu Gln Asn Glu Glu Lys Lys Arg Leu Leu Ile Lys Gln Val Arg Glu 1585 1590 1595 1600 Leu Glu Ala Glu Leu Glu Asp Glu Arg Lys Gln Arg Ala Leu Ala Val 1605 1610 1615 Ala Ser Lys Lys Lys Met Glu Ile Asp Leu Lys Asp Leu Glu Ala Gln 1620 1625 1630 Ile Glu Ala Ala Asn Lys Ala Arg Asp Glu Val Ile Lys Gln Leu Arg 1635 1640 1645 Lys Leu Gln Ala Gln Met Lys Asp Tyr Gln Arg Glu Leu Glu Glu Ala 1650 1655 1660 Arg Ala Ser Arg Asp Glu Ile Phe Ala Gln Ser Lys Glu Ser Glu Lys 1665 1670 1675 1680 Lys Leu Lys Ser Leu Glu Ala Glu Ile Leu Gln Leu Gln Glu Glu Leu 1685 1690 1695 Ala Ser Ser Glu Arg Ala Arg Arg His Ala Glu Gln Glu Arg Asp Glu 1700 1705 1710 Leu Ala Asp Glu Ile Thr Asn Ser Ala Ser Gly Lys Ser Ala Leu Leu 1715 1720 1725 Asp Glu Lys Arg Arg Leu Glu Ala Arg Ile Ala Gln Leu Glu Glu Glu 1730 1735 1740 Leu Glu Glu Glu Gln Ser Asn Met Glu Leu Leu Asn Asp Arg Phe Arg 1745 1750 1755 1760 Lys Thr Thr Leu Gln Val Asp Thr Leu Asn Ala Glu Leu Ala Ala Glu 1765 1770 1775 Arg Ser Ala Ala Gln Lys Ser Asp Asn Ala Arg Gln Gln Leu Glu Arg 1780 1785 1790 Gln Asn Lys Glu Leu Lys Ala Lys Leu Gln Glu Leu Glu Gly Ala Val 1795 1800 1805 Lys Ser Lys Phe Lys Ala Thr Ile Ser Ala Leu Glu Ala Lys Ile Gly 1810 1815 1820 Gln Leu Glu Glu Gln Leu Glu Gln Glu Ala Lys Glu Arg Ala Ala Ala 1825 1830 1835 1840 Asn Lys Leu Val Arg Arg Thr Glu Lys Lys Leu Lys Glu Ile Phe Met 1845 1850 1855 Gln Val Glu Asp Glu Arg Arg His Ala Asp Gln Tyr Lys Glu Gln Met 1860 1865 1870 Glu Lys Ala Asn Ala Arg Met Lys Gln Leu Lys Arg Gln Leu Glu Glu 1875 1880 1885 Ala Glu Glu Glu Ala Thr Arg Ala Asn Ala Ser Arg Arg Lys Leu Gln 1890 1895 1900 Arg Glu Leu Asp Asp Ala Thr Glu Ala Asn Glu Gly Leu Ser Arg Glu 1905 1910 1915 1920 Val Ser Thr Leu Lys Asn Arg Leu Arg Arg Gly Gly Pro Ile Ser Phe 1925 1930 1935 Ser Ser Ser Arg Ser Gly Arg Arg Gln Leu His Leu Glu Gly Ala Ser 1940 1945 1950 Leu Glu Leu Ser Asp Asp Asp Thr Glu Ser Lys Thr Ser Asp Val Asn 1955 1960 1965 Glu Thr Gln Pro Gln Ser Glu 1970 1975 <210> 24 <211> 677 <212> PRT <213> Homo sapiens <400> 24 Met Asp Asp Pro Asp Cys Asp Ser Thr Trp Glu Glu Asp Glu Glu Asp 1 5 10 15 Ala Glu Asp Ala Glu Asp Glu Asp Cys Glu Asp Gly Glu Ala Ala Gly 20 25 30 Ala Arg Asp Ala Asp Ala Gly Asp Glu Asp Glu Glu Ser Glu Glu Pro 35 40 45 Arg Ala Ala Arg Pro Ser Ser Phe Gln Ser Arg Met Thr Gly Ser Arg 50 55 60 Asn Trp Arg Ala Thr Arg Asp Met Cys Arg Tyr Arg His Asn Tyr Pro 65 70 75 80 Asp Leu Val Glu Arg Asp Cys Asn Gly Asp Thr Pro Asn Leu Ser Phe 85 90 95 Tyr Arg Asn Glu Ile Arg Phe Leu Pro Asn Gly Cys Phe Ile Glu Asp 100 105 110 Ile Leu Gln Asn Trp Thr Asp Asn Tyr Asp Leu Leu Glu Asp Asn His 115 120 125 Ser Tyr Ile Gln Trp Leu Phe Pro Leu Arg Glu Pro Gly Val Asn Trp 130 135 140 His Ala Lys Pro Leu Thr Leu Arg Glu Val Glu Val Phe Lys Ser Ser 145 150 155 160 Gln Glu Ile Gln Glu Arg Leu Val Arg Ala Tyr Glu Leu Met Leu Gly 165 170 175 Phe Tyr Gly Ile Arg Leu Glu Asp Arg Gly Thr Gly Thr Val Gly Arg 180 185 190 Ala Gln Asn Tyr Gln Lys Arg Phe Gln Asn Leu Asn Trp Arg Ser His 195 200 205 Asn Asn Leu Arg Ile Thr Arg Ile Leu Lys Ser Leu Gly Glu Leu Gly 210 215 220 Leu Glu His Phe Gln Ala Pro Leu Val Arg Phe Phe Leu Glu Glu Thr 225 230 235 240 Leu Val Arg Arg Glu Leu Pro Gly Val Arg Gln Ser Ala Leu Asp Tyr 245 250 255 Phe Met Phe Ala Val Arg Cys Arg His Gln Arg Arg Gln Leu Val His 260 265 270 Phe Ala Trp Glu His Phe Arg Pro Arg Cys Lys Phe Val Trp Gly Pro 275 280 285 Gln Asp Lys Leu Arg Arg Phe Lys Pro Ser Ser Leu Pro His Pro Leu 290 295 300 Glu Gly Ser Arg Lys Val Glu Glu Glu Gly Ser Pro Gly Asp Pro Asp 305 310 315 320 His Glu Ala Ser Thr Gln Gly Arg Thr Cys Gly Pro Glu His Ser Lys 325 330 335 Gly Gly Gly Arg Val Asp Glu Gly Pro Gln Pro Arg Ser Val Glu Pro 340 345 350 Gln Asp Ala Gly Pro Leu Glu Arg Ser Gln Gly Asp Glu Ala Gly Gly 355 360 365 His Gly Glu Asp Arg Pro Glu Pro Leu Ser Pro Lys Glu Ser Lys Lys 370 375 380 Arg Lys Leu Glu Leu Ser Arg Arg Glu Gln Pro Pro Thr Glu Pro Gly 385 390 395 400 Pro Gln Ser Ala Ser Glu Val Glu Lys Ile Ala Leu Asn Leu Glu Gly 405 410 415 Cys Ala Leu Ser Gln Gly Ser Leu Arg Thr Gly Thr Gln Glu Val Gly 420 425 430 Gly Gln Asp Pro Gly Glu Ala Val Gln Pro Cys Arg Gln Pro Leu Gly 435 440 445 Ala Arg Val Ala Asp Lys Val Arg Lys Arg Arg Lys Val Asp Glu Gly 450 455 460 Ala Gly Asp Ser Ala Ala Val Ala Ser Gly Gly Ala Gln Thr Leu Ala 465 470 475 480 Leu Ala Gly Ser Pro Ala Pro Ser Gly His Pro Lys Ala Gly His Ser 485 490 495 Glu Asn Gly Val Glu Glu Asp Thr Glu Gly Arg Thr Gly Pro Lys Glu 500 505 510 Gly Thr Pro Gly Ser Pro Ser Glu Thr Pro Gly Pro Ser Pro Ala Gly 515 520 525 Pro Ala Gly Asp Glu Pro Ala Glu Ser Pro Ser Glu Thr Pro Gly Pro 530 535 540 Arg Pro Ala Gly Pro Ala Gly Asp Glu Pro Ala Glu Ser Pro Ser Glu 545 550 555 560 Thr Pro Gly Pro Arg Pro Ala Gly Pro Ala Gly Asp Glu Pro Ala Glu 565 570 575 Ser Pro Ser Glu Thr Pro Gly Pro Ser Pro Ala Gly Pro Thr Arg Asp 580 585 590 Glu Pro Ala Glu Ser Pro Ser Glu Thr Pro Gly Pro Arg Pro Ala Gly 595 600 605 Pro Ala Gly Asp Glu Pro Ala Glu Ser Pro Ser Glu Thr Pro Gly Pro 610 615 620 Arg Pro Ala Gly Pro Ala Gly Asp Glu Pro Ala Glu Ser Pro Ser Glu 625 630 635 640 Thr Pro Gly Pro Ser Pro Ala Gly Pro Thr Arg Asp Glu Pro Ala Lys 645 650 655 Ala Gly Glu Ala Ala Glu Leu Gln Asp Ala Glu Val Glu Ser Ser Ala 660 665 670 Lys Ser Gly Lys Pro 675 <210> 25 <211> 325 <212> PRT <213> Homo sapiens <400> 25 Met Lys Thr Phe Ser Ser Phe Leu Gln Ile Gly Arg Asn Met His Gln 1 5 10 15 Gly Asn Gln Thr Thr Ile Thr Glu Phe Ile Leu Leu Gly Phe Phe Lys 20 25 30 Gln Asp Glu His Gln Asn Leu Leu Phe Val Leu Phe Leu Gly Met Tyr 35 40 45 Leu Val Thr Val Ile Gly Asn Gly Leu Ile Ile Val Ala Ile Ser Leu 50 55 60 Asp Thr Tyr Leu His Thr Pro Met Tyr Leu Phe Leu Ala Asn Leu Ser 65 70 75 80 Phe Ala Asp Ile Ser Ser Ile Ser Asn Ser Val Pro Lys Met Leu Val 85 90 95 Asn Ile Gln Thr Lys Ser Gln Ser Ile Ser Tyr Glu Ser Cys Ile Thr 100 105 110 Gln Met Tyr Phe Ser Ile Val Phe Val Val Ile Asp Asn Leu Leu Leu 115 120 125 Gly Thr Met Ala Tyr Asp His Phe Val Ala Ile Cys His Pro Leu Asn 130 135 140 Tyr Thr Ile Leu Met Arg Pro Arg Phe Gly Ile Leu Leu Thr Val Ile 145 150 155 160 Ser Trp Phe Leu Ser Asn Ile Ile Ala Leu Thr His Thr Leu Leu Leu 165 170 175 Ile Gln Leu Leu Phe Cys Asn His Asn Thr Leu Pro His Phe Phe Cys 180 185 190 Asp Leu Ala Pro Leu Leu Lys Leu Ser Cys Ser Asp Thr Leu Ile Asn 195 200 205 Glu Leu Val Leu Phe Ile Val Gly Leu Ser Val Ile Ile Phe Pro Phe 210 215 220 Thr Leu Ser Phe Phe Ser Tyr Val Cys Ile Ile Arg Ala Val Leu Arg 225 230 235 240 Val Ser Ser Thr Gln Gly Lys Trp Lys Ala Phe Ser Thr Cys Gly Ser 245 250 255 His Leu Thr Val Val Leu Leu Phe Tyr Gly Thr Ile Val Gly Val Tyr 260 265 270 Phe Phe Pro Ser Ser Thr His Pro Glu Asp Thr Asp Lys Ile Gly Ala 275 280 285 Val Leu Phe Thr Val Val Thr Pro Met Ile Asn Pro Phe Ile Tyr Ser 290 295 300 Leu Arg Asn Lys Asp Met Lys Gly Ala Leu Arg Lys Leu Ile Asn Arg 305 310 315 320 Lys Ile Ser Ser Leu 325 <210> 26 <211> 403 <212> PRT <213> Homo sapiens <400> 26 Met Ser Gly Ser Asp Gly Gly Leu Glu Glu Glu Pro Glu Leu Ser Ile 1 5 10 15 Thr Leu Thr Leu Arg Met Leu Met His Gly Lys Glu Val Gly Ser Ile 20 25 30 Ile Gly Lys Lys Gly Glu Thr Val Lys Arg Ile Arg Glu Gln Ser Ser 35 40 45 Ala Arg Ile Thr Ile Ser Glu Gly Ser Cys Pro Glu Arg Ile Thr Thr 50 55 60 Ile Thr Gly Ser Thr Ala Ala Val Phe His Ala Val Ser Met Ile Ala 65 70 75 80 Phe Lys Leu Asp Glu Asp Leu Cys Ala Ala Pro Ala Asn Gly Gly Asn 85 90 95 Val Ser Arg Pro Val Thr Leu Arg Leu Val Ile Pro Ala Ser Gln 100 105 110 Cys Gly Ser Leu Ile Gly Lys Ala Gly Thr Lys Ile Lys Glu Ile Arg 115 120 125 Glu Thr Thr Gly Ala Gln Val Gln Val Ala Gly Asp Leu Leu Pro Asn 130 135 140 Ser Thr Glu Arg Ala Val Thr Val Ser Gly Val Pro Asp Ala Ile Ile 145 150 155 160 Leu Cys Val Arg Gln Ile Cys Ala Val Ile Leu Glu Ser Pro Pro Lys 165 170 175 Gly Ala Thr Ile Pro Tyr His Pro Ser Leu Ser Leu Gly Thr Val Leu 180 185 190 Leu Ser Ala Asn Gln Gly Phe Ser Val Gln Gly Gln Tyr Gly Ala Val 195 200 205 Thr Pro Ala Glu Val Thr Lys Leu Gln Gln Leu Ser Ser His Ala Val 210 215 220 Pro Phe Ala Thr Pro Ser Val Val Pro Gly Leu Asp Pro Gly Thr Gln 225 230 235 240 Thr Ser Ser Gln Glu Phe Leu Val Pro Asn Asp Leu Ile Gly Cys Val 245 250 255 Ile Gly Arg Gln Gly Ser Lys Ile Ser Glu Ile Arg Gln Met Ser Gly 260 265 270 Ala His Ile Lys Ile Gly Asn Gln Ala Glu Gly Ala Gly Glu Arg His 275 280 285 Val Thr Ile Thr Gly Ser Pro Val Ser Ile Ala Leu Ala Gln Tyr Leu 290 295 300 Ile Thr Ala Cys Leu Glu Thr Ala Lys Ser Thr Ser Gly Gly Thr Pro 305 310 315 320 Ser Ser Ala Pro Ala Asp Leu Pro Ala Pro Phe Ser Pro Pro Leu Thr 325 330 335 Ala Leu Pro Thr Ala Pro Pro Gly Leu Leu Gly Thr Pro Tyr Ala Ile 340 345 350 Ser Leu Ser Asn Phe Ile Gly Leu Lys Pro Met Pro Phe Leu Ala Leu 355 360 365 Pro Pro Ala Ser Pro Gly Pro Pro Pro Gly Leu Ala Ala Tyr Thr Ala 370 375 380 Lys Met Ala Ala Ala Asn Gly Ser Lys Lys Ala Glu Arg Gln Lys Phe 385 390 395 400 Ser Pro Tyr <210> 27 <211> 344 <212> PRT <213> Homo sapiens <400> 27 Met His Arg Thr Thr Arg Ile Lys Ile Thr Glu Leu Asn Pro His Leu 1 5 10 15 Met Cys Ala Leu Cys Gly Gly Tyr Phe Ile Asp Ala Thr Thr Ile Val 20 25 30 Glu Cys Leu His Ser Phe Cys Lys Thr Cys Ile Val Arg Tyr Leu Glu 35 40 45 Thr Asn Lys Tyr Cys Pro Met Cys Asp Val Gln Val His Lys Thr Arg 50 55 60 Pro Leu Leu Ser Ile Arg Ser Asp Lys Thr Leu Gln Asp Ile Val Tyr 65 70 75 80 Lys Leu Val Pro Gly Leu Phe Lys Asp Glu Met Lys Arg Arg Arg Asp 85 90 95 Phe Tyr Ala Ala Tyr Pro Leu Thr Glu Val Pro Asn Gly Ser Asn Glu 100 105 110 Asp Arg Gly Glu Val Leu Glu Gln Glu Lys Gly Ala Leu Ser Asp Asp 115 120 125 Glu Ile Val Ser Leu Ser Ile Glu Phe Tyr Glu Gly Ala Arg Asp Arg 130 135 140 Asp Glu Lys Lys Gly Pro Leu Glu Asn Gly Asp Gly Asp Lys Glu Lys 145 150 155 160 Thr Gly Val Arg Phe Leu Arg Cys Pro Ala Ala Met Thr Val Met His 165 170 175 Leu Ala Lys Phe Leu Arg Asn Lys Met Asp Val Pro Ser Lys Tyr Lys 180 185 190 Val Glu Val Leu Tyr Glu Asp Glu Pro Leu Lys Glu Tyr Tyr Thr Leu 195 200 205 Met Asp Ile Ala Tyr Ile Tyr Pro Trp Arg Arg Asn Gly Pro Leu Pro 210 215 220 Leu Lys Tyr Arg Val Gln Pro Ala Cys Lys Arg Leu Thr Leu Ala Thr 225 230 235 240 Val Pro Thr Pro Ser Glu Gly Thr Asn Thr Ser Gly Ala Ser Glu Cys 245 250 255 Glu Ser Val Ser Asp Lys Ala Pro Ser Pro Ala Thr Leu Pro Ala Thr 260 265 270 Ser Ser Ser Leu Pro Ser Pro Ala Thr Pro Ser His Gly Ser Pro Ser 275 280 285 Ser His Gly Pro Pro Ala Thr His Pro Thr Ser Pro Thr Pro Pro Ser 290 295 300 Thr Ala Ser Gly Ala Thr Thr Ala Ala Asn Gly Gly Ser Leu Asn Cys 305 310 315 320 Leu Gln Thr Pro Ser Ser Thr Ser Arg Gly Arg Lys Met Thr Val Asn 325 330 335 Gly Ala Pro Val Pro Leu Thr 340 <210> 28 <211> 638 <212> PRT <213> Homo sapiens <400> 28 Met Lys Gly Gly Cys Val Ser Gln Trp Lys Ala Ala Ala Gly Phe Leu 1 5 10 15 Phe Cys Val Met Val Phe Ala Ser Ala Glu Arg Pro Val Phe Thr Asn 20 25 30 His Phe Leu Val Glu Leu His Lys Gly Gly Glu Asp Lys Ala Arg Gln 35 40 45 Val Ala Ala Glu His Gly Phe Gly Val Arg Lys Leu Pro Phe Ala Glu 50 55 60 Gly Leu Tyr His Phe Tyr His Asn Gly Leu Ala Lys Ala Lys Arg Arg 65 70 75 80 Arg Ser Leu His His Lys Gln Gln Leu Glu Arg Asp Pro Arg Val Lys 85 90 95 Met Ala Leu Gln Gln Glu Gly Phe Asp Arg Lys Lys Arg Gly Tyr Arg 100 105 110 Asp Ile Asn Glu Ile Asp Ile Asn Met Asn Asp Pro Leu Phe Thr Lys 115 120 125 Gln Trp Tyr Leu Ile Asn Thr Gly Gln Ala Asp Gly Thr Pro Gly Leu 130 135 140 Asp Leu Asn Val Ala Glu Ala Trp Glu Leu Gly Tyr Thr Gly Lys Gly 145 150 155 160 Val Thr Ile Gly Ile Met Asp Asp Gly Ile Asp Tyr Leu His Pro Asp 165 170 175 Leu Ala Ser Asn Tyr Asn Ala Glu Ala Ser Tyr Asp Phe Ser Ser Asn 180 185 190 Asp Pro Tyr Pro Tyr Pro Arg Tyr Thr Asp Asp Trp Phe Asn Ser His 195 200 205 Gly Thr Arg Cys Ala Gly Glu Val Ser Ala Ala Ala Asn Asn Asn Ile 210 215 220 Cys Gly Val Gly Val Ala Tyr Asn Ser Lys Val Ala Gly Ile Arg Met 225 230 235 240 Leu Asp Gln Pro Phe Met Thr Asp Ile Ile Glu Ala Ser Ser Ile Ser 245 250 255 His Met Pro Gln Leu Ile Asp Ile Tyr Ser Ala Ser Trp Gly Pro Thr 260 265 270 Asp Asn Gly Lys Thr Val Asp Gly Pro Arg Glu Leu Thr Leu Gln Ala 275 280 285 Met Ala Asp Gly Val Asn Lys Gly Arg Gly Gly Lys Gly Ser Ile Tyr 290 295 300 Val Trp Ala Ser Gly Asp Gly Gly Ser Tyr Asp Asp Cys Asn Cys Asp 305 310 315 320 Gly Tyr Ala Ser Ser Met Trp Thr Ile Ser Ile Asn Ser Ala Ile Asn 325 330 335 Asp Gly Arg Thr Ala Leu Tyr Asp Glu Ser Cys Ser Ser Thr Leu Ala 340 345 350 Ser Thr Phe Ser Asn Gly Arg Lys Arg Asn Pro Glu Ala Gly Val Ala 355 360 365 Thr Thr Asp Leu Tyr Gly Asn Cys Thr Leu Arg His Ser Gly Thr Ser 370 375 380 Ala Ala Ala Pro Glu Ala Ala Gly Val Phe Ala Leu Ala Leu Glu Ala 385 390 395 400 Asn Leu Gly Leu Thr Trp Arg Asp Met Gln His Leu Thr Val Leu Thr 405 410 415 Ser Lys Arg Asn Gln Leu His Asp Glu Val His Gln Trp Arg Arg Asn 420 425 430 Gly Val Gly Leu Glu Phe Asn His Leu Phe Gly Tyr Gly Val Leu Asp 435 440 445 Ala Gly Ala Met Val Lys Met Ala Lys Asp Trp Lys Thr Val Pro Glu 450 455 460 Arg Phe His Cys Val Gly Gly Ser Val Gln Asp Pro Glu Lys Ile Pro 465 470 475 480 Ser Thr Gly Lys Leu Val Leu Thr Leu Thr Thr Asp Ala Cys Glu Gly 485 490 495 Lys Glu Asn Phe Val Arg Tyr Leu Glu His Val Gln Ala Val Ile Thr 500 505 510 Val Asn Ala Thr Arg Arg Gly Asp Leu Asn Ile Asn Met Thr Ser Pro 515 520 525 Met Gly Thr Lys Ser Ile Leu Leu Ser Arg Arg Pro Arg Asp Asp Asp 530 535 540 Ser Lys Val Gly Phe Asp Lys Trp Pro Phe Met Thr Thr His Thr Trp 545 550 555 560 Gly Glu Asp Ala Arg Gly Thr Trp Thr Leu Glu Leu Gly Phe Val Gly 565 570 575 Ser Ala Pro Gln Lys Gly Val Leu Lys Glu Trp Thr Leu Met Leu His 580 585 590 Gly Thr Gln Ser Ala Pro Tyr Ile Asp Gln Val Val Arg Asp Tyr Gln 595 600 605 Ser Lys Leu Ala Met Ser Lys Lys Glu Glu Leu Glu Glu Glu Leu Asp 610 615 620 Glu Ala Val Glu Arg Ser Leu Lys Ser Ile Leu Asn Lys Asn 625 630 635 <210> 29 <211> 222 <212> PRT <213> Homo sapiens <400> 29 Met Ala Phe Val Lys Ser Gly Trp Leu Leu Arg Gln Ser Thr Ile Leu 1 5 10 15 Lys Arg Trp Lys Lys Asn Trp Phe Asp Leu Trp Ser Asp Gly His Leu 20 25 30 Ile Tyr Tyr Asp Asp Gln Thr Arg Gln Asn Ile Glu Asp Lys Val His 35 40 45 Met Pro Met Asp Cys Ile Asn Ile Arg Thr Gly Gln Glu Cys Arg Asp 50 55 60 Thr Gln Pro Pro Asp Gly Lys Ser Lys Asp Cys Met Leu Gln Ile Val 65 70 75 80 Cys Arg Asp Gly Lys Thr Ile Ser Leu Cys Ala Glu Ser Thr Asp Asp 85 90 95 Cys Leu Ala Trp Lys Phe Thr Leu Gln Asp Ser Arg Thr Asn Thr Ala 100 105 110 Tyr Val Gly Ser Ala Val Met Thr Asp Glu Thr Ser Val Val Ser Ser 115 120 125 Pro Pro Pro Tyr Thr Ala Tyr Ala Ala Pro Ala Pro Glu Gln Ala Tyr 130 135 140 Gly Tyr Gly Pro Tyr Gly Gly Ala Tyr Pro Pro Gly Thr Gln Val Val 145 150 155 160 Tyr Ala Ala Asn Gly Gln Ala Tyr Ala Val Pro Tyr Gln Tyr Pro Tyr 165 170 175 Ala Gly Leu Tyr Gly Gln Gln Pro Ala Asn Gln Val Ile Ile Arg Glu 180 185 190 Arg Tyr Arg Asp Asn Asp Ser Asp Leu Ala Leu Gly Met Leu Ala Gly 195 200 205 Ala Ala Thr Gly Met Ala Leu Gly Ser Leu Phe Trp Val Phe 210 215 220 <210> 30 <211> 454 <212> PRT <213> Homo sapiens <400> 30 Met Ser Ser Gly Ala Pro Gln Lys Ser Ser Pro Met Ala Ser Gly Ala 1 5 10 15 Glu Glu Thr Pro Gly Phe Leu Asp Thr Leu Leu Gln Asp Phe Pro Ala 20 25 30 Leu Leu Asn Pro Glu Asp Pro Leu Pro Trp Lys Ala Pro Gly Thr Val 35 40 45 Leu Ser Gln Glu Glu Val Glu Gly Glu Leu Ala Glu Leu Ala Met Gly 50 55 60 Phe Leu Gly Ser Arg Lys Ala Pro Pro Leu Ala Ala Ala Leu Ala 65 70 75 80 His Glu Ala Val Ser Gln Leu Leu Gln Thr Asp Leu Ser Glu Phe Arg 85 90 95 Lys Leu Pro Arg Glu Glu Glu Glu Glu Glu Glu Asp Asp Asp Glu Glu 100 105 110 Glu Lys Ala Pro Val Thr Leu Leu Asp Ala Gln Ser Leu Ala Gln Ser 115 120 125 Phe Phe Asn Arg Leu Trp Glu Val Ala Gly Gln Trp Gln Lys Gln Val 130 135 140 Pro Leu Ala Ala Arg Ala Ser Gln Arg Gln Trp Leu Val Ser Ile His 145 150 155 160 Ala Ile Arg Asn Thr Arg Arg Lys Met Glu Asp Arg His Val Ser Leu 165 170 175 Pro Ser Phe Asn Gln Leu Phe Gly Leu Ser Asp Pro Val Asn Arg Ala 180 185 190 Tyr Phe Ala Val Phe Asp Gly His Gly Gly Val Asp Ala Ala Arg Tyr 195 200 205 Ala Ala Val His Val His Thr Asn Ala Ala Arg Gln Pro Glu Leu Pro 210 215 220 Thr Asp Pro Glu Gly Ala Leu Arg Glu Ala Phe Arg Arg Thr Asp Gln 225 230 235 240 Met Phe Leu Arg Lys Ala Lys Arg Glu Arg Leu Gln Ser Gly Thr Thr 245 250 255 Gly Val Cys Ala Leu Ile Ala Gly Ala Thr Leu His Val Ala Trp Leu 260 265 270 Gly Asp Ser Gln Val Ile Leu Val Gln Gln Gly Gln Val Val Lys Leu 275 280 285 Met Glu Pro His Arg Pro Glu Arg Gln Asp Glu Lys Ala Arg Ile Glu 290 295 300 Ala Leu Gly Gly Phe Val Ser His Met Asp Cys Trp Arg Val Asn Gly 305 310 315 320 Thr Leu Ala Val Ser Arg Ala Ile Gly Asp Val Phe Gln Lys Pro Tyr 325 330 335 Val Ser Gly Glu Ala Asp Ala Ala Ser Arg Ala Leu Thr Gly Ser Glu 340 345 350 Asp Tyr Leu Leu Leu Ala Cys Asp Gly Phe Phe Asp Val Val Pro His 355 360 365 Gln Glu Val Val Gly Leu Val Gln Ser His Leu Thr Arg Gln Gln Gly 370 375 380 Ser Gly Leu Arg Val Ala Glu Glu Leu Val Ala Ala Ala Arg Glu Arg 385 390 395 400 Gly Ser His Asp Asn Ile Thr Val Met Val Val Phe Leu Arg Asp Pro 405 410 415 Gln Glu Leu Leu Glu Gly Gly Asn Gln Gly Glu Gly Asp Pro Gln Ala 420 425 430 Glu Gly Arg Arg Gln Asp Leu Pro Ser Ser Leu Pro Glu Pro Glu Thr 435 440 445 Gln Ala Pro Pro Arg Ser 450 <210> 31 <211> 278 <212> PRT <213> Homo sapiens <400> 31 Met Ser Ala Leu Gly Ser Pro Val Arg Ala Tyr Asp Phe Leu Leu Lys 1 5 10 15 Phe Leu Leu Val Gly Asp Ser Asp Val Gly Lys Gly Glu Ile Leu Ala 20 25 30 Ser Leu Gln Asp Gly Ala Ala Glu Ser Pro Tyr Gly His Pro Ala Gly 35 40 45 Ile Asp Tyr Lys Thr Thr Thr Ile Leu Leu Asp Gly Arg Arg Val Lys 50 55 60 Leu Gln Leu Trp Asp Thr Ser Gly Gln Gly Arg Phe Cys Thr Ile Phe 65 70 75 80 Arg Ser Tyr Ser Arg Gly Ala Gln Gly Val Ile Leu Val Tyr Asp Ile 85 90 95 Ala Asn Arg Trp Ser Phe Asp Gly Ile Asp Arg Trp Ile Lys Glu Ile 100 105 110 Asp Glu His Ala Pro Gly Val Pro Lys Ile Leu Val Gly Asn Arg Leu 115 120 125 His Leu Ala Phe Lys Arg Gln Val Pro Thr Glu Gln Ala Gln Ala Tyr 130 135 140 Ala Glu Arg Leu Gly Val Thr Phe Phe Glu Val Ser Pro Leu Cys Asn 145 150 155 160 Phe Asn Ile Thr Glu Ser Phe Thr Glu Leu Ala Arg Ile Val Leu Leu 165 170 175 Arg His Gly Met Asp Arg Leu Trp Arg Pro Ser Lys Val Leu Ser Leu 180 185 190 Gln Asp Leu Cys Cys Arg Ala Val Val Ser Cys Thr Pro Val His Leu 195 200 205 Val Asp Lys Leu Pro Leu Pro Ile Ala Leu Arg Ser His Leu Lys Ser 210 215 220 Phe Ser Met Ala Asn Gly Leu Asn Ala Arg Met Met His Gly Gly Ser 225 230 235 240 Tyr Ser Leu Thr Thr Ser Ser Thr His Lys Arg Ser Ser Leu Arg Lys 245 250 255 Val Lys Leu Val Arg Pro Pro Gln Ser Pro Pro Lys Asn Cys Thr Arg 260 265 270 Asn Ser Cys Lys Ile Ser 275 <210> 32 <211> 259 <212> PRT <213> Homo sapiens <400> 32 Met Pro Gly Ala Asn Tyr Arg Ala Gly Ala Gly Ala Gly Ala Gly Ala 1 5 10 15 Arg Arg Pro Arg Gly Ala Arg Asp Arg Glu Glu Asp Gly Gly Gly Leu 20 25 30 Glu Pro Ala Ala Val Ala Arg Asp Leu Leu Arg Gly Thr Ser Asn Met 35 40 45 Ser Phe Glu Glu Leu Leu Glu Leu Gln Ser Gln Val Gly Thr Lys Thr 50 55 60 Tyr Lys Gln Leu Val Ala Gly Asn Ser Pro Lys Lys Gln Ala Ser Arg 65 70 75 80 Pro Pro Ile Gln Asn Ala Cys Val Ala Asp Lys His Arg Pro Leu Glu 85 90 95 Met Ser Ala Lys Ile Arg Val Pro Phe Leu Arg Gln Val Val Pro Ile 100 105 110 Ser Lys Lys Val Ala Arg Asp Pro Arg Phe Asp Asp Leu Ser Gly Glu 115 120 125 Tyr Asn Pro Glu Val Phe Asp Lys Thr Tyr Gln Phe Leu Asn Asp Ile 130 135 140 Arg Ala Lys Glu Lys Glu Leu Val Lys Lys Gln Leu Lys Lys His Leu 145 150 155 160 Ser Gly Glu Glu His Glu Lys Leu Gln Gln Leu Leu Gln Arg Met Glu 165 170 175 Gln Gln Glu Met Ala Gln Gln Glu Arg Lys Gln Gln Gln Glu Leu His 180 185 190 Leu Ala Leu Lys Gln Glu Arg Arg Ala Gln Ala Gln Gln Gly His Arg 195 200 205 Pro Tyr Phe Leu Lys Lys Ser Glu Gln Arg Gln Leu Ala Leu Ala Glu 210 215 220 Lys Phe Lys Glu Leu Lys Arg Ser Lys Lys Leu Glu Asn Phe Leu Ser 225 230 235 240 Arg Lys Arg Arg Arg Asn Ala Gly Lys Asp Arg Arg His Leu Pro Leu 245 250 255 Ser Lys Glu <210> 33 <211> 1358 <212> PRT <213> Homo sapiens <400> 33 Met Ile Glu Pro Ser Glu Asp Ser Phe Glu Thr Met Met Glu His Lys 1 5 10 15 Asn Pro Ser Ser Lys Gln Met Glu Ser Ser Glu Gly Ser Ser Asn Thr 20 25 30 Thr Glu Ala Thr Ser Gly Ser Gly Val Arg Gly Glu Ala Gly Pro Ala 35 40 45 Ser Gly Pro Ala Gln Glu Lys Lys Glu Pro Pro Ser Gly Pro Leu Gln 50 55 60 Glu Met Glu Glu Leu Pro Thr Asp Leu Leu Gln Asp Met Glu Glu Pro 65 70 75 80 Ser Ser Gly Pro Arg Lys Glu Ile Glu Asp Pro Pro Asn Asp Leu Leu 85 90 95 Gln Asp Leu Glu Glu Ser Cys Asn Gly Ser His Gln Ala Arg Gly Asp 100 105 110 Pro Leu Ser Gly Ala Ser Asp Arg Met Lys Glu Ala Ser Val Asn Pro 115 120 125 Ser Gly Ala Arg Glu Glu Gln Glu Ala His Thr Asp Leu Lys Glu Ser 130 135 140 Gly Arg Glu Glu Thr Pro Gln Glu Gln Asn Gln Thr Glu His Ser Thr 145 150 155 160 Ala Glu Leu Met Ala Met Val Arg Ser Ile Ile Ser Leu Tyr Phe Arg 165 170 175 Met Gln Asp Leu Lys Glu Gln Gln Arg Val Ala Glu Glu Ile Leu Ile 180 185 190 Lys Gly Ile Asn Ala Gly Gln Leu Pro Ala Pro Lys His Phe Ser Gly 195 200 205 Asp Arg Arg Glu Phe His Glu Phe Ile Val Leu Cys Gln Leu Thr Leu 210 215 220 Gln Ser Tyr Pro Arg Met Phe Tyr Asn Asp Arg Leu Arg Val Gly Tyr 225 230 235 240 Val Ile Asn His Leu Ser Gly Leu Ala Leu Glu Trp Ala Lys Ala Leu 245 250 255 Leu Gln Glu Asn Ser Pro Leu Ile Gly Asp Phe Pro Ala Phe Leu Glu 260 265 270 Ala Met Ser Glu Val Phe Glu Tyr Arg Gln Ala Leu Arg Val Ala Glu 275 280 285 Glu Ala Met Phe Thr Ile Arg Gln Gly Gly Arg Ser Ala Thr Glu Tyr 290 295 300 Ile Asp Glu Phe Gln Ser Leu Val Pro Ile Leu Gly Trp Pro Asp Glu 305 310 315 320 Val Leu Gln Ala His Leu Cys Gln Gly Leu Asn Glu Glu Ile Arg His 325 330 335 Tyr Leu Phe Arg Val Pro Gln Pro Asp Ser Leu Asp Ser Leu Ile Val 340 345 350 Leu Ile Leu Gln Ile Glu Glu Lys Leu Ala Glu Arg Arg Ala Met Leu 355 360 365 Arg Leu Pro Pro Glu Ala Arg Pro Arg Asn Leu Thr Trp Ile Asp Ser 370 375 380 Pro Ala Pro Glu Arg Trp Met Val Ser Ser Trp Leu Pro Ser Glu Val 385 390 395 400 His Pro Asp Ile Asn Arg Ala His Leu Phe Leu Leu Leu Met Val Arg 405 410 415 Val Asn Pro Tyr His Ser Val Ala Val Gln Ala Leu Val Asp Ser Gly 420 425 430 Ala Asp Gly Asn Phe Met Asp Glu Lys Phe Ala Gln Glu His Tyr Val 435 440 445 Glu Leu Tyr Glu Lys Pro Tyr Pro Gln Pro Val Gln Ser Val Asp Gly 450 455 460 Ser Leu Ile Gly Asn Glu Pro Val Trp Leu Tyr Thr Glu Pro Leu Val 465 470 475 480 Cys Ile His Gln Asn His Gln Glu Ser Ile Glu Phe Asp Ile Val Pro 485 490 495 Ser Pro Asn Phe Ser Val Val Leu Gly Ile Arg Trp Leu Arg Val His 500 505 510 Ala Pro Glu Val Asp Trp Ile Lys Gly Arg Cys Thr Phe His Ser Pro 515 520 525 Tyr Cys Leu Lys Asn Cys Phe Arg Pro Pro Pro Pro Cys Ile Ala Leu 530 535 540 Glu Arg His Gly Met Ser Leu Leu Pro Gly Leu Pro His Pro Tyr Ser 545 550 555 560 Asp Leu Ala Asp Val Phe Asn Pro Lys Glu Ala Asp Asp Glu Thr Ser 565 570 575 Asp Gln Pro Ser Ser Asp Gly Ser Asp Asp Leu Ser Glu Ser Glu Pro 580 585 590 Ser Glu Leu Gln Gln Ala Gly Asp Ser Asp His Ser Glu Thr Phe Tyr 595 600 605 Glu Cys Pro Ser Thr Ala Pro Trp Glu Pro Val Gly Ala Arg Met Gln 610 615 620 Glu Arg Ala Arg Leu Gln Glu Glu Tyr Trp Asp Leu Gln Asp Met Leu 625 630 635 640 Thr Asn Arg Gln Asp Tyr Ile Gln Met Ile Pro Glu Leu Phe Asp Gln 645 650 655 Leu His Gly Ala Glu Trp Phe Thr Lys Leu Glu Leu Arg Gly Thr Ile 660 665 670 Val Glu Glu Ser Val Asn Gly His Arg Thr Glu Asp Val Trp Lys Ala 675 680 685 Ala Phe Gly Leu Glu Leu Glu Glu Met Lys Ser Tyr Gln Pro Phe Ala 690 695 700 Leu Ser Pro Asp Pro Ile Ile Pro Gln Asn Val Ile His Phe Ile Leu 705 710 715 720 Lys Asp Met Leu Gly Phe Phe Val Leu Ser Tyr Gly Gln Glu Val Leu 725 730 735 Ile Tyr Ser Met Ser Gln Glu Glu His Leu His His Val Arg Gln Val 740 745 750 Leu Val Arg Phe Arg His His Asn Val Tyr Cys Ser Leu Asp Lys Ser 755 760 765 Gln Phe His Arg Gln Thr Val Glu Phe Leu Gly Phe Val Val Thr Pro 770 775 780 Lys Gly Val Lys Leu Asn Lys Asn Val Met Thr Ile Ile Thr Gly Tyr 785 790 795 800 Pro Thr Pro Gly Ser Lys Leu Ser Leu Arg Asn Phe Ile Glu Phe Val 805 810 815 Phe Pro Tyr Arg His Phe Val Glu Arg Phe Ser Ile Ile Ala Glu Pro 820 825 830 Leu Val Arg Gln Leu Leu Ser Ser Tyr Gln Phe Tyr Trp Gly Val Glu 835 840 845 Glu Gln Glu Ala Phe Glu Cys Leu Lys Arg Ala Phe Arg Lys Ala Pro 850 855 860 Leu Leu His His Pro Lys Pro Gln Asn Pro Phe Tyr Leu Glu Thr Gly 865 870 875 880 Val Thr Gly Thr Ala Leu His Ala Ser Leu Ile Gln Ile Asp Asp Gln 885 890 895 Thr Gly Lys Arg Ala Cys Cys Ala Phe Tyr Ser Arg Asn Ile Ser Pro 900 905 910 Ile Glu Val Glu Tyr Ser Gln Ala Glu Met Lys Ile Leu Pro Ile Arg 915 920 925 Ala Ala Phe Met Val Trp Cys Arg Tyr Leu Glu Asn Thr Glu Glu Pro 930 935 940 Ile Met Ile Leu Leu Asn Thr Glu Asp Leu Ala Ser Leu Asn Asn Asp 945 950 955 960 Arg Leu Thr Val Leu Leu Pro Gly His Trp Val Phe Phe Phe Ser His 965 970 975 Phe Asn Phe Asp Val Met Glu Leu Pro Glu Gln Asp Gly Gly Arg Ala 980 985 990 Leu Pro Pro Val Arg Asn Leu Arg Trp Arg Arg Ala Phe Gln Arg Asn 995 1000 1005 Thr Ala Ala Arg Gln Thr Leu Leu Leu Ala Ser Arg Gly Phe Pro Arg 1010 1015 1020 Asp Pro Ser Thr Glu Ser Gly Glu Glu Glu Asn Glu Glu Gln Asp Glu 1025 1030 1035 1040 Leu Asn Glu Gln Ile Leu Arg Gln Glu Leu Leu Ala Met Ile Pro Ile 1045 1050 1055 Asp Gln Ile Leu Asn Ser Phe Leu Ala His Phe Ser Met Ala Gln Ile 1060 1065 1070 Arg Ala Val Ile Leu His Phe Phe Arg Gly Leu Leu Tyr Trp Lys Asn 1075 1080 1085 Thr Leu Ala Leu Ala Ala Ile Leu Val Leu Leu Arg Val Arg Gln Cys 1090 1095 1100 Leu Ser Leu Arg Pro Ala Pro Ala Met Arg Val Ala Arg Pro Gln Pro 1105 1110 1115 1120 Gln Arg Ser Leu Arg Leu Ile Leu Asp Ser Ser Leu Ile Ala Gly Ser 1125 1130 1135 Ser Ile Thr Thr Ala Ile Thr Gln Leu Leu Thr Gln Met Pro Ala Leu 1140 1145 1150 Val Gly Ala Asn Thr Ile Pro Ala Gln Glu Leu Ala Glu Leu Phe Leu 1155 1160 1165 Gly Pro Gly Arg Trp Gln Arg Asn Ala Leu His Ser Gln Ala His Arg 1170 1175 1180 Gly Leu Gln Phe Thr Pro Gly Phe Trp Leu Thr Leu Cys Glu Phe Phe 1185 1190 1195 1200 Gly Val Arg Val Thr Pro Gln Glu Gly His Leu Pro Ala Leu Arg Gln 1205 1210 1215 Asn Arg Tyr Leu Glu Leu His Val Val Gly Asp Glu Asp Val Val Leu 1220 1225 1230 Arg Glu Ala Leu Gln Asp Asp Leu Gln Arg Tyr Arg Gln Cys Gly Leu 1235 1240 1245 His Asp Gly Leu Gln Asp Thr Ser Gln Asp Lys Gln Asp Asn Asp Val 1250 1255 1260 Gln Glu Ala Pro Pro Ser His Thr Ala Ala Thr His Pro Pro Arg Pro 1265 1270 1275 1280 Arg His Leu Met Asp Pro Gln Val Leu Glu Phe Leu Gly Ser Arg Leu 1285 1290 1295 Leu His Ile His Ser Ala Asp Gly Gln Leu His Leu Leu Ser Arg Glu 1300 1305 1310 Gln Ala Ala Arg Ala Leu Ser Gln Phe Leu Thr Leu Ile Tyr Arg Arg 1315 1320 1325 Ala Leu Pro Ile Pro Ala Trp Glu Ser Gln Pro Arg Glu Gln Ala Arg 1330 1335 1340 Leu Glu Glu Leu Pro Asp Glu Asp Glu Asp Ala Asn Leu Asp 1345 1350 1355 <210> 34 <211> 5038 <212> PRT <213> Homo sapiens <400> 34 Met Gly Asp Ala Glu Gly Glu Asp Glu Val Gln Phe Leu Arg Thr Asp 1 5 10 15 Asp Glu Val Val Leu Gln Cys Ser Ala Thr Val Leu Lys Glu Gln Leu 20 25 30 Lys Leu Cys Leu Ala Ala Glu Gly Phe Gly Asn Arg Leu Cys Phe Leu 35 40 45 Glu Pro Thr Ser Asn Ala Gln Asn Val Pro Asp Leu Ala Ile Cys 50 55 60 Cys Phe Val Leu Glu Gln Ser Leu Ser Val Arg Ala Leu Gln Glu Met 65 70 75 80 Leu Ala Asn Thr Val Glu Ala Gly Val Glu Ser Ser Gln Gly Gly Gly 85 90 95 His Arg Thr Leu Leu Tyr Gly His Ala Ile Leu Leu Arg His Ala His 100 105 110 Ser Arg Met Tyr Leu Ser Cys Leu Thr Thr Ser Arg Ser Met Thr Asp 115 120 125 Lys Leu Ala Phe Asp Val Gly Leu Gln Glu Asp Ala Thr Gly Glu Ala 130 135 140 Cys Trp Trp Thr Met His Pro Ala Ser Lys Gln Arg Ser Glu Gly Glu 145 150 155 160 Lys Val Arg Val Gly Asp Asp Ile Ile Leu Val Ser Val Ser Ser Glu 165 170 175 Arg Tyr Leu His Leu Ser Thr Ala Ser Gly Glu Leu Gln Val Asp Ala 180 185 190 Ser Phe Met Gln Thr Leu Trp Asn Met Asn Pro Ile Cys Ser Arg Cys 195 200 205 Glu Glu Gly Phe Val Thr Gly Gly His Val Leu Arg Leu Phe His Gly 210 215 220 His Met Asp Glu Cys Leu Thr Ile Ser Pro Ala Asp Ser Asp Asp Gln 225 230 235 240 Arg Arg Leu Val Tyr Tyr Glu Gly Gly Ala Val Cys Thr His Ala Arg 245 250 255 Ser Leu Trp Arg Leu Glu Pro Leu Arg Ile Ser Trp Ser Gly Ser His 260 265 270 Leu Arg Trp Gly Gln Pro Leu Arg Val Arg His Val Thr Thr Gly Gln 275 280 285 Tyr Leu Ala Leu Thr Glu Asp Gln Gly Leu Val Val Val Asp Ala Ser 290 295 300 Lys Ala His Thr Lys Ala Thr Ser Phe Cys Phe Arg Ile Ser Lys Glu 305 310 315 320 Lys Leu Asp Val Ala Pro Lys Arg Asp Val Glu Gly Met Gly Pro Pro 325 330 335 Glu Ile Lys Tyr Gly Glu Ser Leu Cys Phe Val Gln His Val Ala Ser 340 345 350 Gly Leu Trp Leu Thr Tyr Ala Ala Pro Asp Pro Lys Ala Leu Arg Leu 355 360 365 Gly Val Leu Lys Lys Lys Ala Met Leu His Gln Glu Gly His Met Asp 370 375 380 Asp Ala Leu Ser Leu Thr Arg Cys Gln Gln Glu Glu Ser Gln Ala Ala 385 390 395 400 Arg Met Ile His Ser Thr Asn Gly Leu Tyr Asn Gln Phe Ile Lys Ser 405 410 415 Leu Asp Ser Phe Ser Gly Lys Pro Arg Gly Ser Gly Pro Pro Ala Gly 420 425 430 Thr Ala Leu Pro Ile Glu Gly Val Ile Leu Ser Leu Gln Asp Leu Ile 435 440 445 Ile Tyr Phe Glu Pro Pro Ser Glu Asp Leu Gln His Glu Glu Lys Gln 450 455 460 Ser Lys Leu Arg Ser Leu Arg Asn Arg Gln Ser Leu Phe Gln Glu Glu 465 470 475 480 Gly Met Leu Ser Met Val Leu Asn Cys Ile Asp Arg Leu Asn Val Tyr 485 490 495 Thr Thr Ala Ala His Phe Ala Glu Phe Ala Gly Glu Glu Ala Ala Glu 500 505 510 Ser Trp Lys Glu Ile Val Asn Leu Leu Tyr Glu Leu Leu Ala Ser Leu 515 520 525 Ile Arg Gly Asn Arg Ser Asn Cys Ala Leu Phe Ser Thr Asn Leu Asp 530 535 540 Trp Leu Val Ser Lys Leu Asp Arg Leu Glu Ala Ser Ser Gly Ile Leu 545 550 555 560 Glu Val Leu Tyr Cys Val Leu Ile Glu Ser Pro Glu Val Leu Asn Ile 565 570 575 Ile Gln Glu Asn His Ile Lys Ser Ile Ile Ser Leu Leu Asp Lys His 580 585 590 Gly Arg Asn His Lys Val Leu Asp Val Leu Cys Ser Leu Cys Val Cys 595 600 605 Asn Gly Val Ala Val Arg Ser Asn Gln Asp Leu Ile Thr Glu Asn Leu 610 615 620 Leu Pro Gly Arg Glu Leu Leu Leu Gln Thr Asn Leu Ile Asn Tyr Val 625 630 635 640 Thr Ser Ile Arg Pro Asn Ile Phe Val Gly Arg Ala Glu Gly Thr Thr 645 650 655 Gln Tyr Ser Lys Trp Tyr Phe Glu Val Met Val Asp Glu Val Thr Pro 660 665 670 Phe Leu Thr Ala Gln Ala Thr His Leu Arg Val Gly Trp Ala Leu Thr 675 680 685 Glu Gly Tyr Thr Pro Tyr Pro Gly Ala Gly Glu Gly Trp Gly Gly Asn 690 695 700 Gly Val Gly Asp Asp Leu Tyr Ser Tyr Gly Phe Asp Gly Leu His Leu 705 710 715 720 Trp Thr Gly His Val Ala Arg Pro Val Thr Ser Pro Gly Gln His Leu 725 730 735 Leu Ala Pro Glu Asp Val Ile Ser Cys Cys Leu Asp Leu Ser Val Pro 740 745 750 Ser Ile Ser Phe Arg Ile Asn Gly Cys Pro Val Gln Gly Val Phe Glu 755 760 765 Ser Phe Asn Leu Asp Gly Leu Phe Phe Pro Val Val Ser Phe Ser Ala 770 775 780 Gly Val Lys Val Arg Phe Leu Leu Gly Gly Arg His Gly Glu Phe Lys 785 790 795 800 Phe Leu Pro Pro Gly Tyr Ala Pro Cys His Glu Ala Val Leu Pro 805 810 815 Arg Glu Arg Leu His Leu Glu Pro Ile Lys Glu Tyr Arg Arg Glu Gly 820 825 830 Pro Arg Gly Pro His Leu Val Gly Pro Ser Arg Cys Leu Ser His Thr 835 840 845 Asp Phe Val Pro Cys Pro Val Asp Thr Val Gln Ile Val Leu Pro Pro 850 855 860 His Leu Glu Arg Ile Arg Glu Lys Leu Ala Glu Asn Ile His Glu Leu 865 870 875 880 Trp Ala Leu Thr Arg Ile Glu Gln Gly Trp Thr Tyr Gly Pro Val Arg 885 890 895 Asp Asp Asn Lys Arg Leu His Pro Cys Leu Val Asp Phe His Ser Leu 900 905 910 Pro Glu Pro Glu Arg Asn Tyr Asn Leu Gln Met Ser Gly Glu Thr Leu 915 920 925 Lys Thr Leu Leu Ala Leu Gly Cys His Val Gly Met Ala Asp Glu Lys 930 935 940 Ala Glu Asp Asn Leu Lys Lys Thr Lys Leu Pro Lys Thr Tyr Met Met 945 950 955 960 Ser Asn Gly Tyr Lys Pro Ala Pro Leu Asp Leu Ser His Val Arg Leu 965 970 975 Thr Pro Ala Gln Thr Thr Leu Val Asp Arg Leu Ala Glu Asn Gly His 980 985 990 Asn Val Trp Ala Arg Asp Arg Val Gly Gln Gly Trp Ser Tyr Ser Ala 995 1000 1005 Val Gln Asp Ile Pro Ala Arg Arg Asn Pro Arg Leu Val Pro Tyr Arg 1010 1015 1020 Leu Leu Asp Glu Ala Thr Lys Arg Ser Asn Arg Asp Ser Leu Cys Gln 1025 1030 1035 1040 Ala Val Arg Thr Leu Leu Gly Tyr Gly Tyr Asn Ile Glu Pro Pro Asp 1045 1050 1055 Gln Glu Pro Ser Gln Val Glu Asn Gln Ser Arg Cys Asp Arg Val Arg 1060 1065 1070 Ile Phe Arg Ala Glu Lys Ser Tyr Thr Val Gln Ser Gly Arg Trp Tyr 1075 1080 1085 Phe Glu Phe Glu Ala Val Thr Thr Gly Glu Met Arg Val Gly Trp Ala 1090 1095 1100 Arg Pro Glu Leu Arg Pro Asp Val Glu Leu Gly Ala Asp Glu Leu Ala 1105 1110 1115 1120 Tyr Val Phe Asn Gly His Arg Gly Gln Arg Trp His Leu Gly Ser Glu 1125 1130 1135 Pro Phe Gly Arg Pro Trp Gln Pro Gly Asp Val Val Gly Cys Met Ile 1140 1145 1150 Asp Leu Thr Glu Asn Thr Ile Ile Phe Thr Leu Asn Gly Glu Val Leu 1155 1160 1165 Met Ser Asp Ser Gly Ser Glu Thr Ala Phe Arg Glu Ile Glu Ile Gly 1170 1175 1180 Asp Gly Phe Leu Pro Val Cys Ser Leu Gly Pro Gly Gln Val Gly His 1185 1190 1195 1200 Leu Asn Leu Gly Gln Asp Val Ser Ser Leu Arg Phe Phe Ala Ile Cys 1205 1210 1215 Gly Leu Gln Glu Gly Phe Glu Pro Phe Ala Ile Asn Met Gln Arg Pro 1220 1225 1230 Val Thr Thr Trp Phe Ser Lys Gly Leu Pro Gln Phe Glu Pro Val Pro 1235 1240 1245 Leu Glu His Pro His Tyr Glu Val Ser Arg Val Asp Gly Thr Val Asp 1250 1255 1260 Thr Pro Pro Cys Leu Arg Leu Thr His Arg Thr Trp Gly Ser Gln Asn 1265 1270 1275 1280 Ser Leu Val Glu Met Leu Phe Leu Arg Leu Ser Leu Pro Val Gln Phe 1285 1290 1295 His Gln His Phe Arg Cys Thr Ala Gly Ala Thr Pro Leu Ala Pro Pro 1300 1305 1310 Gly Leu Gln Pro Pro Ala Glu Asp Glu Ala Arg Ala Ala Glu Pro Asp 1315 1320 1325 Pro Asp Tyr Glu Asn Leu Arg Arg Ser Ala Gly Gly Trp Ser Glu Ala 1330 1335 1340 Glu Asn Gly Lys Glu Gly Thr Ala Lys Glu Gly Ala Pro Gly Gly Thr 1345 1350 1355 1360 Pro Gln Ala Gly Gly Glu Ala Gln Pro Ala Arg Ala Glu Asn Glu Lys 1365 1370 1375 Asp Ala Thr Thr Glu Lys Asn Lys Lys Arg Gly Phe Leu Phe Lys Ala 1380 1385 1390 Lys Lys Val Ala Met Met Thr Gln Pro Pro Ala Thr Pro Thr Leu Pro 1395 1400 1405 Arg Leu Pro His Asp Val Val Pro Ala Asp Asn Arg Asp Asp Pro Glu 1410 1415 1420 Ile Ile Leu Asn Thr Thr Thr Tyr Tyr Tyr Ser Val Arg Val Phe Ala 1425 1430 1435 1440 Gly Gln Glu Pro Ser Cys Val Trp Ala Gly Trp Val Thr Pro Asp Tyr 1445 1450 1455 His Gln His Asp Met Ser Phe Asp Leu Ser Lys Val Arg Val Val Thr 1460 1465 1470 Val Thr Met Gly Asp Glu Gin Gly Asn Val His Ser Ser Leu Lys Cys 1475 1480 1485 Ser Asn Cys Tyr Met Val Trp Gly Gly Asp Phe Val Ser Pro Gly Gln 1490 1495 1500 Gln Gly Arg Ile Ser His Thr Asp Leu Val Ile Gly Cys Leu Val Asp 1505 1510 1515 1520 Leu Ala Thr Gly Leu Met Thr Phe Thr Ala Asn Gly Lys Glu Ser Asn 1525 1530 1535 Thr Phe Phe Gln Val Glu Pro Asn Thr Lys Leu Phe Pro Ala Val Phe 1540 1545 1550 Val Leu Pro Thr His Gln Asn Val Ile Gln Phe Glu Leu Gly Lys Gln 1555 1560 1565 Lys Asn Ile Met Pro Leu Ser Ala Ala Met Phe Gln Ser Glu Arg Lys 1570 1575 1580 Asn Pro Ala Pro Gln Cys Pro Pro Arg Leu Glu Met Gln Met Leu Met 1585 1590 1595 1600 Pro Val Ser Trp Ser Arg Met Pro Asn His Phe Leu Gln Val Glu Thr 1605 1610 1615 Arg Arg Ala Gly Glu Arg Leu Gly Trp Ala Val Gln Cys Gln Glu Pro 1620 1625 1630 Leu Thr Met Met Ala Leu His Ile Pro Glu Glu Asn Arg Cys Met Asp 1635 1640 1645 Ile Leu Glu Leu Ser Glu Arg Leu Asp Leu Gln Arg Phe His Ser His 1650 1655 1660 Thr Leu Arg Leu Tyr Arg Ala Val Cys Ala Leu Gly Asn Asn Arg Val 1665 1670 1675 1680 Ala His Ala Leu Cys Ser His Val Asp Gln Ala Gln Leu Leu His Ala 1685 1690 1695 Leu Glu Asp Ala His Leu Pro Gly Pro Leu Arg Ala Gly Tyr Tyr Asp 1700 1705 1710 Leu Leu Ile Ser Ile His Leu Glu Ser Ala Cys Arg Ser Arg Arg Ser 1715 1720 1725 Met Leu Ser Glu Tyr Ile Val Pro Leu Thr Pro Glu Thr Arg Ala Ile 1730 1735 1740 Thr Leu Phe Pro Gly Arg Ser Thr Glu Asn Gly His Pro Arg His 1745 1750 1755 1760 Gly Leu Pro Gly Val Gly Val Thr Thr Ser Leu Arg Pro His His 1765 1770 1775 Phe Ser Pro Pro Cys Phe Val Ala Ala Leu Pro Ala Ala Gly Ala Ala 1780 1785 1790 Glu Ala Pro Ala Arg Leu Ser Pro Ala Ile Pro Leu Glu Ala Leu Arg 1795 1800 1805 Asp Lys Ala Leu Arg Met Leu Gly Glu Ala Val Arg Asp Gly Gly Gln 1810 1815 1820 His Ala Arg Asp Pro Val Gly Gly Ser Val Glu Phe Gln Phe Val Pro 1825 1830 1835 1840 Val Leu Lys Leu Val Ser Thr Leu Leu Val Met Gly Ile Phe Gly Asp 1845 1850 1855 Glu Asp Val Lys Gln Ile Leu Lys Met Ile Glu Pro Glu Val Phe Thr 1860 1865 1870 Glu Glu Glu Glu Glu Glu Asp Glu Glu Glu Glu Gly Glu Glu Glu Asp 1875 1880 1885 Glu Glu Glu Lys Glu Glu Asp Glu Glu Glu Thr Ala Gln Glu Lys Glu 1890 1895 1900 Asp Glu Glu Lys Glu Glu Glu Glu Ala Ala Glu Gly Glu Lys Glu Glu 1905 1910 1915 1920 Gly Leu Glu Glu Gly Leu Leu Gln Met Lys Leu Pro Glu Ser Val Lys 1925 1930 1935 Leu Gln Met Cys His Leu Leu Glu Tyr Phe Cys Asp Gln Glu Leu Gln 1940 1945 1950 His Arg Val Glu Ser Leu Ala Ala Phe Ala Glu Arg Tyr Val Asp Lys 1955 1960 1965 Leu Gln Ala Asn Gln Arg Ser Arg Tyr Gly Leu Leu Ile Lys Ala Phe 1970 1975 1980 Ser Met Thr Ala Ala Glu Thr Ala Arg Arg Thr Arg Glu Phe Arg Ser 1985 1990 1995 2000 Pro Pro Gln Glu Gln Ile Asn Met Leu Leu Gln Phe Lys Asp Gly Thr 2005 2010 2015 Asp Glu Glu Asp Cys Pro Leu Pro Glu Glu Ile Arg Gln Asp Leu Leu 2020 2025 2030 Asp Phe His Gln Asp Leu Leu Ala His Cys Gly Ile Gln Leu Asp Gly 2035 2040 2045 Glu Glu Glu Glu Pro Glu Glu Glu Thr Thr Leu Gly Ser Arg Leu Met 2050 2055 2060 Ser Leu Leu Glu Lys Val Arg Leu Val Lys Lys Lys Glu Glu Lys Pro 2065 2070 2075 2080 Glu Glu Glu Arg Ser Ala Glu Glu Ser Lys Pro Arg Ser Leu Gln Glu 2085 2090 2095 Leu Val Ser His Met Val Val Arg Trp Ala Gln Glu Asp Phe Val Gln 2100 2105 2110 Ser Pro Glu Leu Val Arg Ala Met Phe Ser Leu Leu His Arg Gln Tyr 2115 2120 2125 Asp Gly Leu Gly Glu Leu Leu Arg Ala Leu Pro Arg Ala Tyr Thr Ile 2130 2135 2140 Ser Pro Ser Ser Val Glu Asp Thr Met Ser Leu Leu Glu Cys Leu Gly 2145 2150 2155 2160 Gln Ile Arg Ser Leu Leu Ile Val Gln Met Gly Pro Gln Glu Glu Asn 2165 2170 2175 Leu Met Ile Gln Ser Ile Gly Asn Ile Met Asn Asn Lys Val Phe Tyr 2180 2185 2190 Gln His Pro Asn Leu Met Arg Ala Leu Gly Met His Glu Thr Val Met 2195 2200 2205 Glu Val Met Val Asn Val Leu Gly Gly Gly Glu Ser Lys Glu Ile Arg 2210 2215 2220 Phe Pro Lys Met Val Thr Ser Cys Cys Arg Phe Leu Cys Tyr Phe Cys 2225 2230 2235 2240 Arg Ile Ser Arg Gln Asn Gln Arg Ser Met Phe Asp His Leu Ser Tyr 2245 2250 2255 Leu Leu Glu Asn Ser Gly Ile Gly Leu Gly Met Gln Gly Ser Thr Pro 2260 2265 2270 Leu Asp Val Ala Ala Ala Ser Val Ile Asp Asn Asn Glu Leu Ala Leu 2275 2280 2285 Ala Leu Gln Glu Gln Asp Leu Glu Lys Val Val Ser Tyr Leu Ala Gly 2290 2295 2300 Cys Gly Leu Gln Ser Cys Pro Met Leu Val Ala Lys Gly Tyr Pro Asp 2305 2310 2315 2320 Ile Gly Trp Asn Pro Cys Gly Gly Glu Arg Tyr Leu Asp Phe Leu Arg 2325 2330 2335 Phe Ala Val Phe Val Asn Gly Glu Ser Val Glu Glu Asn Ala Asn Val 2340 2345 2350 Val Val Arg Leu Leu Ile Arg Lys Pro Glu Cys Phe Gly Pro Ala Leu 2355 2360 2365 Arg Gly Glu Gly Gly Ser Gly Leu Leu Ala Ala Ile Glu Glu Ala Ile 2370 2375 2380 Arg Ile Ser Glu Asp Pro Ala Arg Asp Gly Pro Gly Ile Arg Arg Asp 2385 2390 2395 2400 Arg Arg Arg Glu His Phe Gly Glu Glu Pro Pro Glu Glu Asn Arg Val 2405 2410 2415 His Leu Gly His Ala Ile Met Ser Phe Tyr Ala Ala Leu Ile Asp Leu 2420 2425 2430 Leu Gly Arg Cys Ala Pro Glu Met His Leu Ile Gln Ala Gly Lys Gly 2435 2440 2445 Glu Ala Leu Arg Ile Arg Ala Ile Leu Arg Ser Leu Val Pro Leu Glu 2450 2455 2460 Asp Leu Val Gly Ile Ile Ser Leu Pro Leu Gln Ile Pro Thr Leu Gly 2465 2470 2475 2480 Lys Asp Gly Ala Leu Val Gln Pro Lys Met Ser Ala Ser Phe Val Pro 2485 2490 2495 Asp His Lys Ala Ser Met Val Leu Phe Leu Asp Arg Val Tyr Gly Ile 2500 2505 2510 Glu Asn Gln Asp Phe Leu Leu His Val Leu Asp Val Gly Phe Leu Pro 2515 2520 2525 Asp Met Arg Ala Ala Ala Ser Leu Asp Thr Ala Thr Phe Ser Thr Thr 2530 2535 2540 Glu Met Ala Leu Ala Leu Asn Arg Tyr Leu Cys Leu Ala Val Leu Pro 2545 2550 2555 2560 Leu Ile Thr Lys Cys Ala Pro Leu Phe Ala Gly Thr Glu His Arg Ala 2565 2570 2575 Ile Met Val Asp Ser Met Leu His Thr Val Tyr Arg Leu Ser Arg Gly 2580 2585 2590 Arg Ser Leu Thr Lys Ala Gln Arg Asp Val Ile Glu Asp Cys Leu Met 2595 2600 2605 Ser Leu Cys Arg Tyr Ile Arg Pro Ser Met Leu Gln His Leu Leu Arg 2610 2615 2620 Arg Leu Val Phe Asp Val Pro Ile Leu Asn Glu Phe Ala Lys Met Pro 2625 2630 2635 2640 Leu Lys Leu Leu Thr Asn His Tyr Glu Arg Cys Trp Lys Tyr Tyr Cys 2645 2650 2655 Leu Pro Thr Gly Trp Ala Asn Phe Gly Val Thr Ser Glu Glu Glu Leu 2660 2665 2670 His Leu Thr Arg Lys Leu Phe Trp Gly Ile Phe Asp Ser Leu Ala His 2675 2680 2685 Lys Lys Tyr Asp Pro Glu Leu Tyr Arg Met Ala Met Pro Cys Leu Cys 2690 2695 2700 Ala Ile Ala Gly Ala Leu Pro Pro Asp Tyr Val Asp Ala Ser Tyr Ser 2705 2710 2715 2720 Ser Lys Ala Glu Lys Lys Ala Thr Val Asp Ala Glu Gly Asn Phe Asp 2725 2730 2735 Pro Arg Pro Val Glu Thr Leu Asn Val Ile Ile Pro Glu Lys Leu Asp 2740 2745 2750 Ser Phe Ile Asn Lys Phe Ala Glu Tyr Thr His Glu Lys Trp Ala Phe 2755 2760 2765 Asp Lys Ile Gln Asn Asn Trp Ser Tyr Gly Glu Asn Ile Asp Glu Glu 2770 2775 2780 Leu Lys Thr His Pro Met Leu Arg Pro Tyr Lys Thr Phe Ser Glu Lys 2785 2790 2795 2800 Asp Lys Glu Ile Tyr Arg Trp Pro Ile Lys Glu Ser Leu Lys Ala Met 2805 2810 2815 Ile Ala Trp Glu Trp Thr Ile Glu Lys Ala Arg Glu Gly Glu Glu Glu 2820 2825 2830 Lys Thr Glu Lys Lys Lys Thr Arg Lys Ile Ser Gln Ser Ala Gln Thr 2835 2840 2845 Tyr Asp Pro Arg Glu Gly Tyr Asn Pro Gln Pro Pro Asp Leu Ser Ala 2850 2855 2860 Val Thr Leu Ser Arg Glu Leu Gln Ala Met Ala Glu Gln Leu Ala Glu 2865 2870 2875 2880 Asn Tyr His Asn Thr Trp Gly Arg Lys Lys Lys Gln Glu Leu Glu Ala 2885 2890 2895 Lys Gly Gly Gly Thr His Pro Leu Leu Val Pro Tyr Asp Thr Leu Thr 2900 2905 2910 Ala Lys Glu Lys Ala Arg Asp Arg Glu Lys Ala Gln Glu Leu Leu Lys 2915 2920 2925 Phe Leu Gln Met Asn Gly Tyr Ala Val Thr Arg Gly Leu Lys Asp Met 2930 2935 2940 Glu Leu Asp Ser Ser Ser Ile Glu Lys Arg Phe Ala Phe Gly Phe Leu 2945 2950 2955 2960 Gln Gln Leu Leu Arg Trp Met Asp Ile Ser Gln Glu Phe Ile Ala His 2965 2970 2975 Leu Glu Ala Val Val Ser Ser Gly Arg Val Glu Lys Ser Pro His Glu 2980 2985 2990 Gln Glu Ile Lys Phe Phe Ala Lys Ile Leu Leu Pro Leu Ile Asn Gln 2995 3000 3005 Tyr Phe Thr Asn His Cys Leu Tyr Phe Leu Ser Thr Pro Ala Lys Val 3010 3015 3020 Leu Gly Ser Gly Gly His Ala Ser Asn Lys Glu Lys Glu Met Ile Thr 3025 3030 3035 3040 Ser Leu Phe Cys Lys Leu Ala Ala Leu Val Arg His Arg Val Ser Leu 3045 3050 3055 Phe Gly Thr Asp Ala Pro Ala Val Val Asn Cys Leu His Ile Leu Ala 3060 3065 3070 Arg Ser Leu Asp Ala Arg Thr Val Met Lys Ser Gly Pro Glu Ile Val 3075 3080 3085 Lys Ala Gly Leu Arg Ser Phe Phe Glu Ser Ala Ser Glu Asp Ile Glu 3090 3095 3100 Lys Met Val Glu Asn Leu Arg Leu Gly Lys Val Ser Gln Ala Arg Thr 3105 3110 3115 3120 Gln Val Lys Gly Val Gly Gln Asn Leu Thr Tyr Thr Thr Val Ala Leu 3125 3130 3135 Leu Pro Val Leu Thr Thr Leu Phe Gln His Ile Ala Gln His Gln Phe 3140 3145 3150 Gly Asp Asp Val Ile Leu Asp Asp Val Gln Val Ser Cys Tyr Arg Thr 3155 3160 3165 Leu Cys Ser Ile Tyr Ser Leu Gly Thr Thr Lys Asn Thr Tyr Val Glu 3170 3175 3180 Lys Leu Arg Pro Ala Leu Gly Glu Cys Leu Ala Arg Leu Ala Ala Ala 3185 3190 3195 3200 Met Pro Val Ala Phe Leu Glu Pro Gln Leu Asn Glu Tyr Asn Ala Cys 3205 3210 3215 Ser Val Tyr Thr Thr Lys Ser Pro Arg Glu Arg Ala Ile Leu Gly Leu 3220 3225 3230 Pro Asn Ser Val Glu Glu Met Cys Pro Asp Ile Pro Val Leu Glu Arg 3235 3240 3245 Leu Met Ala Asp Ile Gly Gly Leu Ala Glu Ser Gly Ala Arg Tyr Thr 3250 3255 3260 Glu Met Pro His Val Ile Glu Ile Thr Leu Pro Met Leu Cys Ser Tyr 3265 3270 3275 3280 Leu Pro Arg Trp Trp Glu Arg Gly Pro Glu Ala Pro Pro Ser Ala Leu 3285 3290 3295 Pro Ala Gly Ala Pro Pro Pro Cys Thr Ala Val Thr Ser Asp His Leu 3300 3305 3310 Asn Ser Leu Leu Gly Asn Ile Leu Arg Ile Ile Val Asn Asn Leu Gly 3315 3320 3325 Ile Asp Glu Ala Ser Trp Met Lys Arg Leu Ala Val Phe Ala Gln Pro 3330 3335 3340 Ile Val Ser Arg Ala Arg Pro Glu Leu Leu Gln Ser His Phe Ile Pro 3345 3350 3355 3360 Thr Ile Gly Arg Leu Arg Lys Arg Ala Gly Lys Val Val Ser Glu Glu 3365 3370 3375 Glu Gln Leu Arg Leu Glu Ala Lys Ala Glu Ala Gln Glu Gly Glu Leu 3380 3385 3390 Leu Val Arg Asp Glu Phe Ser Val Leu Cys Arg Asp Leu Tyr Ala Leu 3395 3400 3405 Tyr Pro Leu Leu Ile Arg Tyr Val Asp Asn Asn Arg Ala Gln Trp Leu 3410 3415 3420 Thr Glu Pro Asn Pro Ser Ala Glu Glu Leu Phe Arg Met Val Gly Glu 3425 3430 3435 3440 Ile Phe Ile Tyr Trp Ser Lys Ser His Asn Phe Lys Arg Glu Glu Gln 3445 3450 3455 Asn Phe Val Val Gln Asn Glu Ile Asn Asn Met Ser Phe Leu Thr Ala 3460 3465 3470 Asp Asn Lys Ser Lys Met Ala Lys Ala Gly Asp Ile Gln Ser Gly Gly 3475 3480 3485 Ser Asp Gln Glu Arg Thr Lys Lys Lys Arg Arg Gly Asp Arg Tyr Ser 3490 3495 3500 Val Gln Thr Ser Leu Ile Val Ala Thr Leu Lys Lys Met Leu Pro Ile 3505 3510 3515 3520 Gly Leu Asn Met Cys Ala Pro Thr Asp Gln Asp Leu Ile Thr Leu Ala 3525 3530 3535 Lys Thr Arg Tyr Ala Leu Lys Asp Thr Asp Glu Glu Val Arg Glu Phe 3540 3545 3550 Leu His Asn Asn Leu His Leu Gln Gly Lys Val Glu Gly Ser Pro Ser 3555 3560 3565 Leu Arg Trp Gln Met Ala Leu Tyr Arg Gly Val Pro Gly Arg Glu Glu 3570 3575 3580 Asp Ala Asp Asp Pro Glu Lys Ile Val Arg Arg Val Gln Glu Val Ser 3585 3590 3595 3600 Ala Val Leu Tyr Tyr Leu Asp Gln Thr Glu His Pro Tyr Lys Ser Lys 3605 3610 3615 Lys Ala Val Trp His Lys Leu Leu Ser Lys Gln Arg Arg Arg Ala Val 3620 3625 3630 Val Ala Cys Phe Arg Met Thr Pro Leu Tyr Asn Leu Pro Thr His Arg 3635 3640 3645 Ala Cys Asn Met Phe Leu Glu Ser Tyr Lys Ala Ala Trp Ile Leu Thr 3650 3655 3660 Glu Asp His Ser Phe Glu Asp Arg Met Ile Asp Asp Leu Ser Lys Ala 3665 3670 3675 3680 Gly Glu Gln Glu Glu Glu Glu Glu Glu Val Glu Glu Lys Lys Pro Asp 3685 3690 3695 Pro Leu His Gln Leu Val Leu His Phe Ser Arg Thr Ala Leu Thr Glu 3700 3705 3710 Lys Ser Lys Leu Asp Glu Asp Tyr Leu Tyr Met Ala Tyr Ala Asp Ile 3715 3720 3725 Met Ala Lys Ser Cys His Leu Glu Glu Gly Gly Glu Asn Gly Glu Ala 3730 3735 3740 Glu Glu Glu Val Glu Val Ser Phe Glu Glu Lys Gln Met Glu Lys Gln 3745 3750 3755 3760 Arg Leu Leu Tyr Gln Gln Ala Arg Leu His Thr Arg Gly Ala Ala Glu 3765 3770 3775 Met Val Leu Gln Met Ile Ser Ala Cys Lys Gly Glu Thr Gly Ala Met 3780 3785 3790 Val Ser Ser Thr Leu Lys Leu Gly Ile Ser Ile Leu Asn Gly Gly Asn 3795 3800 3805 Ala Glu Val Gln Gln Lys Met Leu Asp Tyr Leu Lys Asp Lys Lys Glu 3810 3815 3820 Val Gly Phe Phe Gln Ser Ile Gln Ala Leu Met Gln Thr Cys Ser Val 3825 3830 3835 3840 Leu Asp Leu Asn Ala Phe Glu Arg Gln Asn Lys Ala Glu Gly Leu Gly 3845 3850 3855 Met Val Asn Glu Asp Gly Thr Val Ile Asn Arg Gln Asn Gly Glu Lys 3860 3865 3870 Val Met Ala Asp Asp Glu Phe Thr Gln Asp Leu Phe Arg Phe Leu Gln 3875 3880 3885 Leu Leu Cys Glu Gly His Asn Asn Asp Phe Gln Asn Tyr Leu Arg Thr 3890 3895 3900 Gln Thr Gly Asn Thr Thr Thr Ile Asn Ile Ile Ile Cys Thr Val Asp 3905 3910 3915 3920 Tyr Leu Leu Arg Leu Gln Glu Ser Ile Ser Asp Phe Tyr Trp Tyr Tyr 3925 3930 3935 Ser Gly Lys Asp Val Ile Glu Glu Gln Gly Lys Arg Asn Phe Ser Lys 3940 3945 3950 Ala Met Ser Val Ala Lys Gln Val Phe Asn Ser Leu Thr Glu Tyr Ile 3955 3960 3965 Gln Gly Pro Cys Thr Gly Asn Gln Gln Ser Leu Ala His Ser Arg Leu 3970 3975 3980 Trp Asp Ala Val Val Gly Phe Leu His Val Phe Ala His Met Met Met 3985 3990 3995 4000 Lys Leu Ala Gln Asp Ser Ser Gln Ile Glu Leu Leu Lys Glu Leu Leu 4005 4010 4015 Asp Leu Gln Lys Asp Met Val Val Met Leu Leu Ser Leu Leu Glu Gly 4020 4025 4030 Asn Val Val Asn Gly Met Ile Ala Arg Gln Met Val Asp Met Leu Val 4035 4040 4045 Glu Ser Ser Ser Asn Val Glu Met Ile Leu Lys Phe Phe Asp Met Phe 4050 4055 4060 Leu Lys Leu Lys Asp Ile Val Gly Ser Glu Ala Phe Gln Asp Tyr Val 4065 4070 4075 4080 Thr Asp Pro Arg Gly Leu Ile Ser Lys Lys Asp Phe Gln Lys Ala Met 4085 4090 4095 Asp Ser Gln Lys Gln Phe Ser Gly Pro Glu Ile Gln Phe Leu Leu Ser 4100 4105 4110 Cys Ser Glu Ala Asp Glu Asn Glu Met Ile Asn Cys Glu Glu Phe Ala 4115 4120 4125 Asn Arg Phe Gln Glu Pro Ala Arg Asp Ile Gly Phe Asn Val Ala Val 4130 4135 4140 Leu Leu Thr Asn Leu Ser Glu His Val Pro His Asp Pro Arg Leu His 4145 4150 4155 4160 Asn Phe Leu Glu Leu Ala Glu Ser Ile Leu Glu Tyr Phe Arg Pro Tyr 4165 4170 4175 Leu Gly Arg Ile Glu Ile Met Gly Ala Ser Arg Arg Ile Glu Arg Ile 4180 4185 4190 Tyr Phe Glu Ile Ser Glu Thr Asn Arg Ala Gln Trp Glu Met Pro Gln 4195 4200 4205 Val Lys Glu Ser Lys Arg Gln Phe Ile Phe Asp Val Val Asn Glu Gly 4210 4215 4220 Gly Glu Ala Glu Lys Met Glu Leu Phe Val Ser Phe Cys Glu Asp Thr 4225 4230 4235 4240 Ile Phe Glu Met Gln Ile Ala Ala Gln Ile Ser Glu Pro Glu Gly Glu 4245 4250 4255 Pro Glu Thr Asp Glu Asp Glu Gly Ala Gly Ala Ala Glu Ala Gly Ala 4260 4265 4270 Glu Gly Ala Glu Glu Gly Ala Ala Gly Leu Glu Gly Thr Ala Ala Thr 4275 4280 4285 Ala Ala Ala Gly Ala Thr Ala Arg Val Val Ala Ala Ala Gly Arg Ala 4290 4295 4300 Leu Arg Gly Leu Ser Tyr Arg Ser Leu Arg Arg Arg Val Arg Arg Leu 4305 4310 4315 4320 Arg Arg Leu Thr Ala Arg Glu Ala Ala Thr Ala Val Ala Ala Leu Leu 4325 4330 4335 Trp Ala Ala Val Thr Arg Ala Gly Ala Ala Gly Ala Gly Ala Ala Ala 4340 4345 4350 Gly Ala Leu Gly Leu Leu Trp Gly Ser Leu Phe Gly Gly Gly Leu Val 4355 4360 4365 Glu Gly Ala Lys Lys Val Thr Val Thr Glu Leu Leu Ala Gly Met Pro 4370 4375 4380 Asp Pro Thr Ser Asp Glu Val His Gly Glu Gln Pro Ala Gly Pro Gly 4385 4390 4395 4400 Gly Asp Ala Asp Gly Glu Gly Ala Ser Glu Gly Ala Gly Asp Ala Ala 4405 4410 4415 Glu Gly Ala Gly Asp Glu Glu Glu Ala Val His Glu Ala Gly Pro Gly 4420 4425 4430 Gly Ala Asp Gly Ala Val Ala Val Thr Asp Gly Gly Pro Phe Arg Pro 4435 4440 4445 Glu Gly Ala Gly Gly Leu Gly Asp Met Gly Asp Thr Thr Pro Ala Glu 4450 4455 4460 Pro Pro Thr Pro Glu Gly Ser Pro Ile Leu Lys Arg Lys Leu Gly Val 4465 4470 4475 4480 Asp Gly Val Glu Glu Glu Leu Pro Pro Glu Pro Glu Pro Glu Pro Glu 4485 4490 4495 Pro Glu Leu Glu Pro Glu Lys Ala Asp Ala Glu Asn Gly Glu Lys Glu 4500 4505 4510 Glu Val Pro Glu Pro Thr Pro Glu Pro Pro Lys Lys Gln Ala Pro Pro 4515 4520 4525 Ser Pro Pro Pro Lys Lys Glu Glu Ala Gly Gly Glu Phe Trp Gly Glu 4530 4535 4540 Leu Glu Val Gln Arg Val Lys Phe Leu Asn Tyr Leu Ser Arg Asn Phe 4545 4550 4555 4560 Tyr Thr Leu Arg Phe Leu Ala Leu Phe Leu Ala Phe Ala Ile Asn Phe 4565 4570 4575 Ile Leu Leu Phe Tyr Lys Val Ser Asp Ser Pro Pro Gly Glu Asp Asp 4580 4585 4590 Met Glu Gly Ser Ala Ala Gly Asp Val Ser Gly Ala Gly Ser Gly Gly 4595 4600 4605 Ser Ser Gly Trp Gly Leu Gly Ala Gly Glu Glu Ala Glu Gly Asp Glu 4610 4615 4620 Asp Glu Asn Met Val Tyr Tyr Phe Leu Glu Glu Ser Thr Gly Tyr Met 4625 4630 4635 4640 Glu Pro Ala Leu Arg Cys Leu Ser Leu Leu His Thr Leu Val Ala Phe 4645 4650 4655 Leu Cys Ile Ile Gly Tyr Asn Cys Leu Lys Val Pro Leu Val Ile Phe 4660 4665 4670 Lys Arg Glu Lys Glu Leu Ala Arg Lys Leu Glu Phe Asp Gly Leu Tyr 4675 4680 4685 Ile Thr Glu Gln Pro Glu Asp Asp Asp Val Lys Gly Gln Trp Asp Arg 4690 4695 4700 Leu Val Leu Asn Thr Pro Ser Phe Pro Ser Asn Tyr Trp Asp Lys Phe 4705 4710 4715 4720 Val Lys Arg Lys Val Leu Asp Lys His Gly Asp Ile Tyr Gly Arg Glu 4725 4730 4735 Arg Ile Ala Glu Leu Leu Gly Met Asp Leu Ala Thr Leu Glu Ile Thr 4740 4745 4750 Ala His Asn Glu Arg Lys Pro Asn Pro Pro Pro Gly Leu Leu Thr Trp 4755 4760 4765 Leu Met Ser Ile Asp Val Lys Tyr Gln Ile Trp Lys Phe Gly Val Ile 4770 4775 4780 Phe Thr Asp Asn Ser Phe Leu Tyr Leu Gly Trp Tyr Met Val Met Ser 4785 4790 4795 4800 Leu Leu Gly His Tyr Asn Asn Phe Phe Phe Ala Ala His Leu Leu Asp 4805 4810 4815 Ile Ala Met Gly Val Lys Thr Leu Arg Thr Ile Leu Ser Ser Val Thr 4820 4825 4830 His Asn Gly Lys Gln Leu Val Met Thr Val Gly Leu Leu Ala Val Val 4835 4840 4845 Val Tyr Leu Tyr Thr Val Val Ala Phe Asn Phe Phe Arg Lys Phe Tyr 4850 4855 4860 Asn Lys Ser Glu Asp Glu Asp Glu Pro Asp Met Lys Cys Asp Asp Met 4865 4870 4875 4880 Met Thr Cys Tyr Leu Phe His Met Tyr Val Gly Val Arg Ala Gly Gly 4885 4890 4895 Gly Ile Gly Asp Glu Ile Glu Asp Pro Ala Gly Asp Glu Tyr Glu Leu 4900 4905 4910 Tyr Arg Val Val Phe Asp Ile Thr Phe Phe Phe Phe Val Ile Val Ile 4915 4920 4925 Leu Leu Ala Ile Ile Ile Gln Gly Leu Ile Ile Asp Ala Phe Gly Glu Leu 4930 4935 4940 Arg Asp Gln Gln Glu Gln Val Lys Glu Asp Met Glu Thr Lys Cys Phe 4945 4950 4955 4960 Ile Cys Gly Ile Gly Ser Asp Tyr Phe Asp Thr Thr Pro His Gly Phe 4965 4970 4975 Glu Thr His Thr Leu Glu Glu His Asn Leu Ala Asn Tyr Met Phe Phe 4980 4985 4990 Leu Met Tyr Leu Ile Asn Lys Asp Glu Thr Glu His Thr Gly Gln Glu 4995 5000 5005 Ser Tyr Val Trp Lys Met Tyr Gln Glu Arg Cys Trp Asp Phe Phe Pro 5010 5015 5020 Ala Gly Asp Cys Phe Arg Lys Gln Tyr Glu Asp Gln Leu Ser 5025 5030 5035 <210> 35 <211> 1054 <212> PRT <213> Homo sapiens <400> 35 Met Glu Gln Asp Thr Ala Ala Val Ala Ala Thr Val Ala Ala Ala Asp 1 5 10 15 Ala Thr Ala Thr Ile Val Val Ile Glu Asp Glu Gln Pro Gly Pro Ser 20 25 30 Thr Ser Gln Glu Glu Gly Ala Ala Ala Ala Ala Thr Glu Ala Thr Ala 35 40 45 Ala Thr Glu Lys Gly Glu Lys Lys Lys Glu Lys Asn Val Ser Ser Phe 50 55 60 Gln Leu Lys Leu Ala Ala Lys Ala Pro Lys Ser Glu Lys Glu Met Asp 65 70 75 80 Pro Glu Tyr Glu Glu Lys Met Lys Ala Asp Arg Ala Lys Arg Phe Glu 85 90 95 Phe Leu Leu Lys Gln Thr Glu Leu Phe Ala His Phe Ile Gln Pro Ser 100 105 110 Ala Gln Lys Ser Pro Thr Ser Pro Leu Asn Met Lys Leu Gly Arg Pro 115 120 125 Arg Ile Lys Lys Asp Glu Lys Gln Ser Leu Ile Ser Ala Gly Asp Tyr 130 135 140 Arg His Arg Arg Thr Glu Gln Glu Glu Asp Glu Glu Leu Leu Ser Glu 145 150 155 160 Ser Arg Lys Thr Ser Asn Val Cys Ile Arg Phe Glu Val Ser Pro Ser 165 170 175 Tyr Val Lys Gly Gly Pro Leu Arg Asp Tyr Gln Ile Arg Gly Leu Asn 180 185 190 Trp Leu Ile Ser Leu Tyr Glu Asn Gly Val Asn Gly Ile Leu Ala Asp 195 200 205 Glu Met Gly Leu Gly Lys Thr Leu Gln Thr Ile Ala Leu Leu Gly Tyr 210 215 220 Leu Lys His Tyr Arg Asn Ile Pro Gly Pro His Met Val Leu Val Pro 225 230 235 240 Lys Ser Thr Leu His Asn Trp Met Asn Glu Phe Lys Arg Trp Val Pro 245 250 255 Ser Leu Arg Val Ile Cys Phe Val Gly Asp Lys Asp Ala Arg Ala Ala 260 265 270 Phe Ile Arg Asp Glu Met Met Pro Gly Glu Trp Asp Val Cys Val Thr 275 280 285 Ser Tyr Glu Met Val Ile Lys Glu Lys Ser Val Phe Lys Lys Phe His 290 295 300 Trp Arg Tyr Leu Val Ile Asp Glu Ala His Arg Ile Lys Asn Glu Lys 305 310 315 320 Ser Lys Leu Ser Glu Ile Val Arg Glu Phe Lys Ser Thr Asn Arg Leu 325 330 335 Leu Leu Thr Gly Thr Pro Leu Gln Asn Asn Leu His Glu Leu Trp Ala 340 345 350 Leu Leu Asn Phe Leu Leu Pro Asp Val Phe Asn Ser Ala Asp Asp Phe 355 360 365 Asp Ser Trp Phe Asp Thr Lys Asn Cys Leu Gly Asp Gln Lys Leu Val 370 375 380 Glu Arg Leu His Ala Val Leu Lys Pro Phe Leu Leu Arg Arg Ile Lys 385 390 395 400 Thr Asp Val Glu Lys Ser Leu Pro Lys Lys Glu Ile Lys Ile Tyr 405 410 415 Leu Gly Leu Ser Lys Met Gln Arg Glu Trp Tyr Thr Lys Ile Leu Met 420 425 430 Lys Asp Ile Asp Val Leu Asn Ser Ser Gly Lys Met Asp Lys Met Arg 435 440 445 Leu Leu Asn Ile Leu Met Gln Leu Arg Lys Cys Cys Asn His Pro Tyr 450 455 460 Leu Phe Asp Gly Ala Glu Pro Gly Pro Tyr Thr Thr Asp Glu His 465 470 475 480 Ile Val Ser Asn Ser Gly Lys Met Val Val Leu Asp Lys Leu Leu Ala 485 490 495 Lys Leu Lys Glu Gln Gly Ser Arg Val Leu Ile Phe Ser Gln Met Thr 500 505 510 Arg Leu Leu Asp Ile Leu Glu Asp Tyr Cys Met Trp Arg Gly Tyr Glu 515 520 525 Tyr Cys Arg Leu Asp Gly Gln Thr Pro His Glu Glu Arg Glu Asp Lys 530 535 540 Phe Leu Glu Val Glu Phe Leu Gly Gln Arg Glu Ala Ile Glu Ala Phe 545 550 555 560 Asn Ala Pro Asn Ser Ser Lys Phe Ile Phe Met Leu Ser Thr Arg Ala 565 570 575 Gly Gly Leu Gly Ile Asn Leu Ala Ser Ala Asp Val Val Ile Leu Tyr 580 585 590 Asp Ser Asp Trp Asn Pro Gln Val Asp Leu Gln Ala Met Asp Arg Ala 595 600 605 His Arg Ile Gly Gln Lys Lys Pro Val Arg Val Phe Arg Leu Ile Thr 610 615 620 Asp Asn Thr Val Glu Glu Arg Ile Val Glu Arg Ala Glu Ile Lys Leu 625 630 635 640 Arg Leu Asp Ser Ile Val Ile Gln Gln Gly Arg Leu Ile Asp Gln Gln 645 650 655 Ser Asn Lys Leu Ala Lys Glu Glu Met Leu Gln Met Ile Arg His Gly 660 665 670 Ala Thr His Val Phe Ala Ser Lys Glu Ser Glu Leu Thr Asp Glu Asp 675 680 685 Ile Thr Thr Ile Leu Glu Arg Gly Glu Lys Lys Thr Ala Glu Met Asn 690 695 700 Glu Arg Leu Gln Lys Met Gly Glu Ser Ser Leu Arg Asn Phe Arg Met 705 710 715 720 Asp Ile Glu Gln Ser Leu Tyr Lys Phe Glu Gly Glu Asp Tyr Arg Glu 725 730 735 Lys Gln Lys Leu Gly Met Val Glu Trp Ile Glu Pro Pro Lys Arg Glu 740 745 750 Arg Lys Ala Asn Tyr Ala Val Asp Ala Tyr Phe Arg Glu Ala Leu Arg 755 760 765 Val Ser Glu Pro Lys Ile Pro Lys Ala Pro Arg Pro Pro Lys Gln Pro 770 775 780 Asn Val Gln Asp Phe Gln Phe Phe Pro Pro Arg Leu Phe Glu Leu Leu 785 790 795 800 Glu Lys Glu Ile Leu Tyr Tyr Arg Lys Thr Ile Gly Tyr Lys Val Pro 805 810 815 Arg Asn Pro Asp Ile Pro Asn Pro Ala Leu Ala Gln Arg Glu Glu Gln 820 825 830 Lys Lys Ile Asp Gly Ala Glu Pro Leu Thr Pro Glu Glu Thr Glu Glu 835 840 845 Lys Glu Lys Leu Leu Thr Gln Gly Phe Thr Asn Trp Thr Lys Arg Asp 850 855 860 Phe Asn Gln Phe Ile Lys Ala Asn Glu Lys Tyr Gly Arg Asp Asp Ile 865 870 875 880 Asp Asn Ile Ala Arg Glu Val Glu Gly Lys Ser Pro Glu Glu Val Met 885 890 895 Glu Tyr Ser Ala Val Phe Trp Glu Arg Cys Asn Glu Leu Gln Asp Ile 900 905 910 Glu Lys Ile Met Ala Gln Ile Glu Arg Gly Glu Ala Arg Ile Gln Arg 915 920 925 Arg Ile Ser Ile Lys Lys Ala Leu Asp Ala Lys Ile Ala Arg Tyr Lys 930 935 940 Ala Pro Phe His Gln Leu Arg Ile Gln Tyr Gly Thr Ser Lys Gly Lys 945 950 955 960 Asn Tyr Thr Glu Glu Glu Asp Arg Phe Leu Ile Cys Met Leu His Lys 965 970 975 Met Gly Phe Asp Arg Glu Asn Val Tyr Glu Glu Leu Arg Gln Cys Val 980 985 990 Arg Asn Ala Pro Gln Phe Arg Phe Asp Trp Phe Ile Lys Ser Arg Thr 995 1000 1005 Ala Met Glu Phe Gln Arg Arg Cys Asn Thr Leu Ile Ser Leu Ile Glu 1010 1015 1020 Lys Glu Asn Met Glu Ile Glu Glu Arg Glu Arg Ala Glu Lys Lys Lys 1025 1030 1035 1040 Arg Ala Thr Lys Thr Pro Met Val Lys Phe Ser Ala Phe Ser 1045 1050 <210> 36 <211> 451 <212> PRT <213> Homo sapiens <400> 36 Met Glu Gly Glu Arg Arg Ala Ser Gln Ala Pro Ser Ser Gly Leu Pro 1 5 10 15 Ala Gly Gly Ala Asn Gly Glu Ser Pro Gly Gly Gly Ala Pro Phe Pro 20 25 30 Gly Ser Ser Gly Ser Ser Ser Ala Leu Leu Gln Ala Glu Val Leu Asp Leu 35 40 45 Asp Glu Asp Glu Asp Asp Leu Glu Val Phe Ser Lys Asp Ala Ser Leu 50 55 60 Met Asp Met Asn Ser Phe Ser Pro Met Met Pro Thr Ser Pro Leu Ser 65 70 75 80 Met Ile Asn Gln Ile Lys Phe Glu Asp Glu Pro Asp Leu Lys Asp Leu 85 90 95 Phe Ile Thr Val Asp Glu Pro Glu Ser His Val Thr Thr Ile Glu Thr 100 105 110 Phe Ile Thr Tyr Arg Ile Ile Thr Lys Thr Ser Arg Gly Glu Phe Asp 115 120 125 Ser Ser Glu Phe Glu Val Arg Arg Arg Tyr Gln Asp Phe Leu Trp Leu 130 135 140 Lys Gly Lys Leu Glu Glu Ala His Pro Thr Leu Ile Ile Pro Leu 145 150 155 160 Pro Glu Lys Phe Ile Val Lys Gly Met Val Glu Arg Phe Asn Asp Asp 165 170 175 Phe Ile Glu Thr Arg Arg Lys Ala Leu His Lys Phe Leu Asn Arg Ile 180 185 190 Ala Asp His Pro Thr Leu Thr Phe Asn Glu Asp Phe Lys Ile Phe Leu 195 200 205 Thr Ala Gln Ala Trp Glu Leu Ser Ser His Lys Lys Gln Gly Pro Gly 210 215 220 Leu Leu Ser Arg Met Gly Gln Thr Val Arg Ala Val Ala Ser Ser Met 225 230 235 240 Arg Gly Val Lys Asn Arg Pro Glu Glu Phe Met Glu Met Asn Asn Phe 245 250 255 Ile Glu Leu Phe Ser Gln Lys Ile Asn Leu Ile Asp Lys Ile Ser Gln 260 265 270 Arg Ile Tyr Lys Glu Glu Arg Glu Tyr Phe Asp Glu Met Lys Glu Tyr 275 280 285 Gly Pro Ile His Ile Leu Trp Ser Ala Ser Glu Glu Asp Leu Val Asp 290 295 300 Thr Leu Lys Asp Val Ala Ser Cys Ile Asp Arg Cys Cys Lys Ala Thr 305 310 315 320 Glu Lys Arg Met Ser Gly Leu Ser Glu Ala Leu Leu Pro Val Val His 325 330 335 Glu Tyr Val Leu Tyr Ser Glu Met Leu Met Gly Val Met Lys Arg Arg 340 345 350 Asp Gln Ile Gln Ala Glu Leu Asp Ser Lys Val Glu Val Leu Thr Tyr 355 360 365 Lys Lys Ala Asp Thr Asp Leu Leu Pro Glu Glu Ile Gly Lys Leu Glu 370 375 380 Asp Lys Val Glu Cys Ala Asn Asn Ala Leu Lys Ala Asp Trp Glu Arg 385 390 395 400 Trp Lys Gln Asn Met Gln Asn Asp Ile Lys Leu Ala Phe Thr Asp Met 405 410 415 Ala Glu Glu Asn Ile His Tyr Tyr Glu Gln Cys Leu Ala Thr Trp Glu 420 425 430 Ser Phe Leu Thr Ser Gln Thr Asn Leu His Leu Glu Glu Ala Ser Glu 435 440 445 Asp Lys Pro 450 <210> 37 <211> 614 <212> PRT <213> Homo sapiens <400> 37 Met Gly Asp Trp Met Thr Val Thr Asp Pro Gly Leu Ser Ser Glu Ser 1 5 10 15 Lys Thr Ile Ser Gln Tyr Thr Ser Glu Thr Lys Met Ser Pro Ser Ser 20 25 30 Leu Tyr Ser Gln Gln Val Leu Cys Ser Ser Ile Pro Leu Ser Lys Asn 35 40 45 Val His Ser Phe Phe Ser Ala Phe Cys Thr Glu Asp Asn Ile Glu Gln 50 55 60 Ser Ile Ser Tyr Leu Asp Gln Glu Leu Thr Thr Phe Gly Phe Pro Ser 65 70 75 80 Leu Tyr Glu Glu Ser Lys Gly Lys Glu Thr Lys Arg Glu Leu Asn Ile 85 90 95 Val Ala Val Leu Asn Cys Met Asn Glu Leu Leu Val Leu Gln Arg Lys 100 105 110 Asn Leu Leu Ala Gln Glu Asn Val Glu Thr Gln Asn Leu Lys Leu Gly 115 120 125 Ser Asp Met Asp His Leu Gln Ser Cys Tyr Ser Lys Leu Lys Glu Gln 130 135 140 Leu Glu Thr Ser Arg Arg Glu Met Ile Gly Leu Gln Glu Arg Asp Arg 145 150 155 160 Gln Leu Gln Cys Lys Asn Arg Asn Leu His Gln Leu Leu Lys Asn Glu 165 170 175 Lys Asp Glu Val Gln Lys Leu Gln Asn Ile Ile Ala Ser Arg Ala Thr 180 185 190 Gln Tyr Asn His Asp Met Lys Arg Lys Glu Arg Glu Tyr Asn Lys Leu 195 200 205 Lys Glu Arg Leu His Gln Leu Val Met Asn Lys Lys Asp Lys Lys Ile 210 215 220 Ala Met Asp Ile Leu Asn Tyr Val Gly Arg Ala Asp Gly Lys Arg Gly 225 230 235 240 Ser Trp Arg Thr Gly Lys Thr Glu Ala Arg Asn Glu Asp Glu Met Tyr 245 250 255 Lys Ile Leu Leu Asn Asp Tyr Glu Tyr Arg Gln Lys Gln Ile Leu Met 260 265 270 Glu Asn Ala Glu Leu Lys Lys Val Leu Gln Gln Met Lys Lys Glu Met 275 280 285 Ile Ser Leu Leu Ser Pro Gln Lys Lys Lys Pro Arg Glu Arg Val Asp 290 295 300 Asp Ser Thr Gly Thr Val Ile Ser Asp Val Glu Glu Asp Ala Gly Glu 305 310 315 320 Leu Ser Arg Glu Ser Met Trp Asp Leu Ser Cys Glu Thr Val Arg Glu 325 330 335 Gln Leu Thr Asn Ser Ile Arg Lys Gln Trp Arg Ile Leu Lys Ser His 340 345 350 Val Glu Lys Leu Asp Asn Gln Val Ser Lys Val His Leu Glu Gly Phe 355 360 365 Asn Asp Glu Asp Val Ile Ser Arg Gln Asp His Glu Gln Glu Thr Glu 370 375 380 Lys Leu Glu Leu Glu Ile Gln Gln Cys Lys Glu Met Ile Lys Thr Gln 385 390 395 400 Gln Gln Leu Leu Gln Gln Gln Leu Ala Thr Ala Tyr Asp Asp Asp Thr 405 410 415 Thr Ser Leu Leu Arg Asp Cys Tyr Leu Leu Glu Glu Lys Glu Arg Leu 420 425 430 Lys Glu Glu Trp Ser Leu Phe Lys Glu Gln Lys Lys Asn Phe Glu Arg 435 440 445 Glu Arg Arg Ser Phe Thr Glu Ala Ala Ile Arg Leu Gly Leu Glu Arg 450 455 460 Lys Ala Phe Glu Glu Glu Arg Ala Ser Trp Leu Lys Gln Gln Phe Leu 465 470 475 480 Asn Met Thr Thr Phe Asp His Gln Asn Ser Glu Asn Val Lys Leu Phe 485 490 495 Ser Ala Phe Ser Gly Ser Ser Asp Trp Asp Asn Leu Ile Val His Ser 500 505 510 Arg Gln Pro Gln Lys Lys Pro His Ser Val Ser Asn Gly Ser Pro Val 515 520 525 Cys Met Ser Lys Leu Thr Lys Ser Leu Pro Ala Ser Pro Ser Thr Ser 530 535 540 Asp Phe Cys Gln Thr Arg Ser Cys Ile Ser Glu His Ser Ser Ile Asn 545 550 555 560 Val Leu Asn Ile Thr Ala Glu Glu Ile Lys Pro Asn Gln Val Gly Gly 565 570 575 Glu Cys Thr Asn Gln Lys Trp Ser Val Ala Ser Arg Pro Gly Ser Gln 580 585 590 Glu Gly Cys Tyr Ser Gly Cys Ser Leu Ser Tyr Thr Asn Ser His Val 595 600 605 Glu Lys Asp Asp Leu Pro 610 <210> 38 <211> 839 <212> PRT <213> Homo sapiens <400> 38 Met Gly Pro Arg Ala Lys Thr Ile Ser Ser Leu Phe Phe Leu Leu Trp 1 5 10 15 Val Leu Ala Glu Pro Ala Glu Asn Ser Asp Phe Tyr Leu Pro Gly Asp 20 25 30 Tyr Leu Leu Gly Gly Leu Phe Ser Leu His Ala Asn Met Lys Gly Ile 35 40 45 Val His Leu Asn Phe Leu Gln Val Pro Met Cys Lys Glu Tyr Glu Val 50 55 60 Lys Val Ile Gly Tyr Asn Leu Met Gln Ala Met Arg Phe Ala Val Glu 65 70 75 80 Glu Ile Asn Asn Asp Ser Ser Leu Leu Pro Gly Val Leu Leu Gly Tyr 85 90 95 Glu Ile Val Asp Val Cys Tyr Ile Ser Asn Asn Val Gln Pro Val Leu 100 105 110 Tyr Phe Leu Ala His Glu Asp Asn Leu Leu Pro Ile Gln Glu Asp Tyr 115 120 125 Ser Asn Tyr Ile Ser Arg Val Val Ala Val Ile Gly Pro Asp Asn Ser 130 135 140 Glu Ser Val Met Thr Val Ala Asn Phe Leu Ser Leu Phe Leu Leu Pro 145 150 155 160 Gln Ile Thr Tyr Ser Ala Ile Ser Asp Glu Leu Arg Asp Lys Val Arg 165 170 175 Phe Pro Ala Leu Leu Arg Thr Thr Pro Ser Ala Asp His His Ile Glu 180 185 190 Ala Met Val Gln Leu Met Leu His Phe Arg Trp Asn Trp Ile Ile Val 195 200 205 Leu Val Ser Ser Asp Thr Tyr Gly Arg Asp Asn Gly Gln Leu Leu Gly 210 215 220 Glu Arg Val Ala Arg Arg Asp Ile Cys Ile Ala Phe Gln Glu Thr Leu 225 230 235 240 Pro Thr Leu Gln Pro Asn Gln Asn Met Thr Ser Glu Glu Arg Gln Arg 245 250 255 Leu Val Thr Ile Val Asp Lys Leu Gln Gln Ser Thr Ala Arg Val Val 260 265 270 Val Val Phe Ser Pro Asp Leu Thr Leu Tyr His Phe Phe Asn Glu Val 275 280 285 Leu Arg Gln Asn Phe Thr Gly Ala Val Trp Ile Ala Ser Glu Ser Trp 290 295 300 Ala Ile Asp Pro Val Leu His Asn Leu Thr Glu Leu Arg His Leu Gly 305 310 315 320 Thr Phe Leu Gly Ile Thr Ile Gln Ser Val Pro Ile Pro Gly Phe Ser 325 330 335 Glu Phe Arg Glu Trp Gly Pro Gln Ala Gly Pro Pro Pro Leu Ser Arg 340 345 350 Thr Ser Gln Ser Tyr Thr Cys Asn Gln Glu Cys Asp Asn Cys Leu Asn 355 360 365 Ala Thr Leu Ser Phe Asn Thr Ile Leu Arg Leu Ser Gly Glu Arg Val 370 375 380 Val Tyr Ser Val Tyr Ser Ala Val Tyr Ala Val Ala His Ala Leu His 385 390 395 400 Ser Leu Leu Gly Cys Asp Lys Ser Thr Cys Thr Lys Arg Val Val Tyr 405 410 415 Pro Trp Gln Leu Leu Glu Glu Ile Trp Lys Val Asn Phe Thr Leu Leu 420 425 430 Asp His Gln Ile Phe Phe Asp Pro Gln Gly Asp Val Ala Leu His Leu 435 440 445 Glu Ile Val Gln Trp Gln Trp Asp Arg Ser Gln Asn Pro Phe Gln Ser 450 455 460 Val Ala Ser Tyr Tyr Pro Leu Gln Arg Gln Leu Lys Asn Ile Gln Asp 465 470 475 480 Ile Ser Trp His Thr Ile Asn Asn Thr Ile Pro Met Ser Met Cys Ser 485 490 495 Lys Arg Cys Gln Ser Gly Gln Lys Lys Lys Pro Val Gly Ile His Val 500 505 510 Cys Cys Phe Glu Cys Ile Asp Cys Leu Pro Gly Thr Phe Leu Asn His 515 520 525 Thr Glu Asp Glu Tyr Glu Cys Gln Ala Cys Pro Asn Asn Glu Trp Ser 530 535 540 Tyr Gln Ser Glu Thr Ser Cys Phe Lys Arg Gln Leu Val Phe Leu Glu 545 550 555 560 Trp His Glu Ala Pro Thr Ile Ala Val Ala Leu Leu Ala Ala Leu Gly 565 570 575 Phe Leu Ser Thr Leu Ala Ile Leu Val Ile Phe Trp Arg His Phe Gln 580 585 590 Thr Pro Ile Val Arg Ser Ala Gly Gly Pro Met Cys Phe Leu Met Leu 595 600 605 Thr Leu Leu Leu Val Ala Tyr Met Val Val Pro Val Tyr Val Gly Pro 610 615 620 Pro Lys Val Ser Thr Cys Leu Cys Arg Gln Ala Leu Phe Pro Leu Cys 625 630 635 640 Phe Thr Ile Cys Ile Ser Cys Ile Ala Val Arg Ser Phe Gln Ile Val 645 650 655 Cys Ala Phe Lys Met Ala Ser Arg Phe Pro Arg Ala Tyr Ser Tyr Trp 660 665 670 Val Arg Tyr Gln Gly Pro Tyr Val Ser Met Ala Phe Ile Thr Val Leu 675 680 685 Lys Met Val Ile Val Val Ile Gly Met Leu Ala Thr Gly Leu Ser Pro 690 695 700 Thr Thr Arg Thr Asp Pro Asp Asp Pro Lys Ile Thr Ile Val Ser Cys 705 710 715 720 Asn Pro Asn Tyr Arg Asn Ser Leu Leu Phe Asn Thr Ser Leu Asp Leu 725 730 735 Leu Leu Ser Val Val Gly Phe Ser Phe Ala Tyr Met Gly Lys Glu Leu 740 745 750 Pro Thr Asn Tyr Asn Glu Ala Lys Phe Ile Thr Leu Ser Met Thr Phe 755 760 765 Tyr Phe Thr Ser Ser Val Ser Leu Cys Thr Phe Met Ser Ala Tyr Ser 770 775 780 Gly Val Leu Val Thr Ile Val Asp Leu Leu Val Thr Val Leu Asn Leu 785 790 795 800 Leu Ala Ile Ser Leu Gly Tyr Phe Gly Pro Lys Cys Tyr Met Ile Leu 805 810 815 Phe Tyr Pro Glu Arg Asn Thr Pro Ala Tyr Phe Asn Ser Met Ile Gln 820 825 830 Gly Tyr Thr Met Arg Arg Asp 835 <210> 39 <211> 503 <212> PRT <213> Homo sapiens <400> 39 Met Ser Glu Ala Arg Gly Glu Pro Gly Ser Gly Pro Glu Ala Gly Ala 1 5 10 15 Arg Phe Phe Cys Thr Ala Gly Arg Gly Leu Glu Pro Phe Val Met Arg 20 25 30 Glu Val Arg Ala Arg Leu Ala Ala Thr Gln Val Glu Tyr Ile Ser Gly 35 40 45 Lys Val Phe Phe Thr Thr Cys Ser Asp Leu Asn Met Leu Lys Lys Leu 50 55 60 Lys Ser Ala Glu Arg Leu Phe Leu Leu Ile Lys Lys Gln Phe Pro Leu 65 70 75 80 Ile Ile Ser Ser Val Ser Lys Gly Lys Ile Phe Asn Glu Met Gln Arg 85 90 95 Leu Ile Asn Glu Asp Pro Gly Ser Trp Leu Asn Ala Ile Ser Ile Trp 100 105 110 Lys Asn Leu Leu Glu Leu Asp Ala Lys Lys Glu Lys Leu Ser Gln Arg 115 120 125 Asp Asp Asn Gln Leu Lys Arg Lys Val Gly Glu Asn Glu Ile Ile Ala 130 135 140 Lys Lys Leu Lys Ile Glu Gln Met Gln Lys Ile Glu Glu Asn Arg Asp 145 150 155 160 Cys Gln Leu Glu Lys Gln Ile Lys Glu Glu Thr Leu Glu Gln Arg Asp 165 170 175 Phe Thr Thr Lys Ser Glu Lys Phe Gln Glu Glu Glu Phe Gln Asn Asp 180 185 190 Ile Glu Lys Ala Ile Asp Thr His Asn Gln Asn Asp Leu Thr Phe Arg 195 200 205 Val Ser Cys Arg Cys Ser Gly Thr Ile Gly Lys Ala Phe Thr Ala Gln 210 215 220 Glu Val Gly Lys Val Ile Gly Ile Ala Ile Met Lys His Phe Gly Trp 225 230 235 240 Lys Ala Asp Leu Arg Asn Pro Gln Leu Glu Ile Phe Ile His Leu Asn 245 250 255 Asp Ile Tyr Ser Val Val Gly Ile Pro Val Phe Arg Val Ser Leu Ala 260 265 270 Ser Arg Ala Tyr Ile Lys Thr Ala Gly Leu Arg Ser Thr Ile Ala Trp 275 280 285 Ala Met Ala Ser Leu Ala Asp Ile Lys Ala Gly Ala Phe Val Leu Asp 290 295 300 Pro Met Cys Gly Leu Gly Thr Ile Leu Leu Glu Ala Ala Lys Glu Trp 305 310 315 320 Pro Asp Val Tyr Tyr Val Gly Ala Asp Val Ser Asp Ser Gln Leu Leu 325 330 335 Gly Thr Trp Asp Asn Leu Lys Ala Ala Gly Leu Glu Asp Lys Ile Glu 340 345 350 Leu Leu Lys Ile Ser Val Ile Glu Leu Pro Leu Pro Ser Glu Ser Val 355 360 365 Asp Ile Ile Ile Ser Asp Ile Pro Phe Gly Lys Lys Phe Lys Leu Gly 370 375 380 Lys Asp Ile Lys Ser Ile Leu Gln Glu Met Glu Arg Val Leu His Val 385 390 395 400 Gly Gly Thr Ile Val Leu Leu Leu Ser Glu Asp His His Arg Arg Leu 405 410 415 Thr Asp Cys Lys Glu Ser Asn Ile Pro Phe Asn Ser Lys Asp Ser His 420 425 430 Thr Asp Glu Pro Gly Ile Lys Lys Cys Leu Asn Pro Glu Glu Lys Thr 435 440 445 Gly Ala Phe Lys Thr Ala Ser Thr Ser Phe Glu Ala Ser Asn His Lys 450 455 460 Phe Leu Asp Arg Met Ser Pro Phe Gly Ser Leu Val Pro Val Glu Cys 465 470 475 480 Tyr Lys Val Ser Leu Gly Lys Thr Asp Ala Phe Ile Cys Lys Tyr Lys 485 490 495 Lys Ser His Ser Ser Gly Leu 500 <210> 40 <211> 4388 <212> PRT <213> Homo sapiens <400> 40 Met Leu Glu Gly Leu Val Ala Trp Val Leu Asn Thr Tyr Leu Gly Lys 1 5 10 15 Tyr Val Asn Asn Leu Asn Thr Asp Gln Leu Ser Val Ala Leu Leu Lys 20 25 30 Gly Ala Val Glu Leu Glu Asn Leu Pro Leu Lys Lys Asp Ala Leu Lys 35 40 45 Glu Leu Glu Leu Pro Phe Glu Val Lys Ala Gly Phe Ile Gly Lys Val 50 55 60 Thr Leu Gln Ile Pro Phe Tyr Arg Pro His Val Asp Pro Trp Val Ile 65 70 75 80 Ser Ile Ser Ser Leu His Leu Ile Gly Ala Pro Glu Lys Ile Gln Asp 85 90 95 Phe Asn Asp Glu Lys Glu Lys Leu Leu Glu Arg Glu Arg Lys Lys Ala 100 105 110 Leu Leu Gln Ala Leu Glu Glu Lys Trp Lys Asn Asp Arg Gln Gln Lys 115 120 125 Gly Glu Ser Tyr Trp Tyr Ser Val Thr Ala Ser Val Val Thr Arg Ile 130 135 140 Val Glu Asn Ile Glu Leu Lys Ile Gln Asp Val His Leu Arg Phe Glu 145 150 155 160 Asp Gly Val Thr Asn Pro Ser His Pro Phe Ala Phe Gly Ile Cys Ile 165 170 175 Lys Asn Val Ser Met Gln Asn Ala Val Asn Glu Pro Val Gln Lys Leu 180 185 190 Met Arg Lys Lys Gln Leu Asp Val Ala Glu Phe Ser Ile Tyr Trp Asp 195 200 205 Val Asp Cys Thr Leu Leu Gly Asp Leu Pro Gln Met Glu Leu Gln Glu 210 215 220 Ala Met Ala Arg Ser Met Glu Ser Arg Ser His His Tyr Val Leu Glu 225 230 235 240 Pro Val Phe Ala Ser Ala Leu Leu Lys Arg Asn Cys Ser Lys Lys Pro 245 250 255 Leu Arg Ser Arg His Ser Pro Arg Ile Asp Cys Asp Ile Gln Leu Glu 260 265 270 Thr Ile Pro Leu Lys Leu Ser Gln Leu Gln Tyr Arg Gln Ile Met Glu 275 280 285 Phe Leu Lys Glu Leu Glu Arg Lys Glu Arg Gln Val Lys Phe Arg Arg 290 295 300 Trp Lys Pro Lys Val Ala Ile Ser Lys Asn Cys Arg Glu Trp Trp Tyr 305 310 315 320 Phe Ala Leu Asn Ala Asn Leu Tyr Glu Ile Arg Glu Gln Arg Lys Arg 325 330 335 Cys Thr Trp Asp Phe Met Leu His Arg Ala Arg Asp Ala Val Ser Tyr 340 345 350 Thr Asp Lys Tyr Phe Asn Lys Leu Lys Gly Gly Leu Leu Ser Thr Asp 355 360 365 Asp Lys Glu Glu Met Cys Arg Ile Glu Glu Glu Gln Ser Phe Glu Glu 370 375 380 Leu Lys Ile Leu Arg Glu Leu Val His Asp Arg Phe His Lys Gln Glu 385 390 395 400 Glu Leu Ala Glu Ser Leu Arg Glu Pro Gln Phe Asp Ser Pro Gly Ala 405 410 415 Cys Pro Gly Ala Pro Glu Pro Gly Gly Gly Ser Gly Met Leu Gln Tyr 420 425 430 Leu Gln Ser Trp Phe Pro Gly Trp Gly Gly Trp Tyr Gly Gln Gln Thr 435 440 445 Pro Glu Gly Asn Val Val Glu Gly Leu Ser Ala Glu Gln Gln Glu Gln 450 455 460 Trp Ile Pro Glu Glu Ile Leu Gly Thr Glu Glu Phe Phe Phe Asp Pro Thr 465 470 475 480 Ala Asp Ala Ser Cys Met Asn Thr Tyr Thr Lys Arg Asp His Val Phe 485 490 495 Ala Lys Leu Asn Leu Gln Leu Gln Arg Gly Thr Val Thr Leu Leu His 500 505 510 Lys Glu Gln Gly Thr Pro Gln Met Asn Glu Ser Ala Phe Met Gln Leu 515 520 525 Glu Phe Ser Asp Val Lys Leu Leu Ala Glu Ser Leu Pro Arg Arg Asn 530 535 540 Ser Ser Leu Leu Ser Val Arg Leu Gly Gly Leu Phe Leu Arg Asp Leu 545 550 555 560 Ala Thr Glu Gly Thr Met Phe Pro Leu Leu Val Phe Pro Asn Pro Gln 565 570 575 Lys Glu Val Gly Arg Val Ser Gln Ser Phe Gly Leu Gln Thr Thr Ser 580 585 590 Ala Asp Arg Ser Asp His Tyr Pro Ala Ala Asp Pro Asp Gly Pro Val 595 600 605 Phe Glu Met Leu Tyr Glu Arg Asn Pro Ala His Ser His Phe Glu Arg 610 615 620 Arg Leu Asn Val Ser Thr Arg Pro Leu Asn Ile Ile Tyr Asn Pro Gln 625 630 635 640 Ala Ile Lys Lys Val Ala Asp Phe Phe Tyr Lys Gly Lys Val His Thr 645 650 655 Ser Gly Phe Gly Tyr Gln Ser Glu Leu Glu Leu Arg Val Ala Glu Ala 660 665 670 Ala Arg Arg Gln Tyr Asn Lys Leu Lys Met Gln Thr Lys Ala Glu Ile 675 680 685 Arg Gln Thr Leu Asp Arg Leu Leu Val Gly Asp Phe Ile Glu Glu Ser 690 695 700 Lys Arg Trp Thr Val Arg Leu Asp Ile Ser Ala Pro Gln Val Ile Phe 705 710 715 720 Pro Asp Asp Phe Lys Phe Lys Asn Pro Val Leu Val Val Val Val Asp Leu 725 730 735 Gly Arg Met Leu Leu Thr Asn Thr Gln Asp Asn Ser Arg Arg Lys Ser 740 745 750 Arg Asp Gly Ser Ala Ser Glu Glu Thr Gln Phe Ser Asp Asp Glu Tyr 755 760 765 Lys Thr Pro Leu Ala Thr Pro Pro Asn Thr Pro Pro Glu Ser Ser 770 775 780 Ser Ser Asn Gly Glu Lys Thr Pro Pro Phe Ser Gly Val Glu Phe Ser 785 790 795 800 Glu Glu Gln Leu Gln Ala His Leu Met Ser Thr Lys Met Tyr Glu Arg 805 810 815 Tyr Ser Leu Ser Phe Met Asp Leu Gln Ile Met Val Gly Arg Val Lys 820 825 830 Asp Asn Trp Lys His Val Gln Asp Ile Asp Val Gly Pro Thr His Val 835 840 845 Val Glu Lys Phe Asn Val His Leu Gln Leu Glu Arg Arg Leu Ile Tyr 850 855 860 Thr Ser Asp Pro Lys Tyr Pro Gly Ala Val Leu Ser Gly Asn Leu Pro 865 870 875 880 Asp Leu Lys Ile His Ile Asn Glu Asp Lys Ile Ser Ala Leu Lys Asn 885 890 895 Cys Phe Ala Leu Leu Thr Thr Pro Glu Met Lys Thr Ser Asp Thr Gln 900 905 910 Ile Lys Glu Lys Ile Phe Pro Gln Glu Glu Gln Arg Gly Ser Leu Gln 915 920 925 Asp Ser Val Met Asn Leu Thr Gln Ser Ile Val Leu Leu Glu Gln His 930 935 940 Thr Arg Glu Val Leu Val Glu Ser Gln Leu Leu Leu Ala Glu Phe Lys 945 950 955 960 Val Asn Cys Met Gln Leu Gly Val Glu Ser Asn Gly Arg Tyr Ile Ser 965 970 975 Val Leu Lys Val Phe Gly Thr Asn Ala His Phe Val Lys Arg Pro Tyr 980 985 990 Asp Ala Glu Val Ser Leu Thr Val His Gly Leu Leu Leu Val Asp Thr 995 1000 1005 Met Gln Thr Tyr Gly Ala Asp Phe Asp Leu Leu Met Ala Ser His Lys 1010 1015 1020 Asn Leu Ser Phe Asp Ile Pro Thr Gly Ser Leu Arg Asp Ser Arg Ala 1025 1030 1035 1040 Gln Ser Pro Val Ser Gly Pro Asn Val Ala His Leu Thr Asp Gly Ala 1045 1050 1055 Thr Leu Asn Asp Arg Ser Ala Thr Ser Val Ser Leu Asp Lys Ile Leu 1060 1065 1070 Thr Lys Glu Gln Glu Ser Leu Ile Lys Leu Glu Tyr Gln Phe Val Ser 1075 1080 1085 Ser Glu Cys Pro Ser Met Asn Leu Asp Ser Thr Leu Gln Val Ile Ser 1090 1095 1100 Leu Gln Val Asn Asn Leu Asp Ile Ile Leu Asn Pro Glu Thr Ile Val 1105 1110 1115 1120 Glu Leu Ile Gly Phe Leu Gln Lys Ser Phe Pro Lys Glu Lys Asp Asp 1125 1130 1135 Leu Ser Pro Gln Pro Leu Met Thr Asp Phe Glu Arg Ser Phe Arg Glu 1140 1145 1150 Gln Gly Thr Tyr Gln Ser Thr Tyr Glu Gln Asn Thr Glu Val Ala Val 1155 1160 1165 Glu Ile His Arg Leu Asn Leu Leu Leu Leu Arg Thr Val Gly Met Ala 1170 1175 1180 Asn Arg Glu Lys Tyr Gly Arg Lys Ile Ala Thr Ala Ser Ile Gly Gly 1185 1190 1195 1200 Thr Lys Val Asn Val Ser Met Gly Ser Thr Phe Asp Met Asn Gly Ser 1205 1210 1215 Leu Gly Cys Leu Gln Leu Met Asp Leu Thr Gln Asp Asn Val Lys Asn 1220 1225 1230 Gln Tyr Val Val Ser Ile Gly Asn Ser Val Gly Tyr Glu Asn Ile Ile 1235 1240 1245 Ser Asp Ile Gly Tyr Phe Glu Ser Val Phe Val Arg Met Glu Asp Ala 1250 1255 1260 Ala Leu Thr Glu Ala Leu Ser Phe Thr Phe Val Glu Arg Ser Lys Gln 1265 1270 1275 1280 Glu Cys Phe Leu Asn Leu Lys Met Ala Ser Leu His Tyr Asn His Ser 1285 1290 1295 Ala Lys Phe Leu Lys Glu Leu Thr Leu Ser Met Asp Glu Leu Glu Glu 1300 1305 1310 Asn Phe Arg Gly Met Leu Lys Ser Ala Ala Thr Lys Val Thr Thr Val 1315 1320 1325 Leu Ala Thr Lys Thr Ala Glu Tyr Ser Glu Met Val Ser Leu Phe Glu 1330 1335 1340 Thr Pro Arg Lys Thr Arg Glu Pro Phe Ile Leu Glu Glu Asn Glu Ile 1345 1350 1355 1360 Tyr Gly Phe Asp Leu Ala Ser Ser His Leu Asp Thr Val Lys Leu Ile 1365 1370 1375 Leu Asn Ile Asn Ile Glu Ser Pro Val Val Ser Ile Pro Arg Lys Pro 1380 1385 1390 Gly Ser Pro Glu Leu Leu Val Gly His Leu Gly Gln Ile Phe Ile Gln 1395 1400 1405 Asn Phe Val Ala Gly Asp Asp Glu Ser Arg Ser Asp Arg Leu Gln Val 1410 1415 1420 Glu Ile Lys Asp Ile Lys Leu Tyr Ser Leu Asn Cys Thr Gln Leu Ala 1425 1430 1435 1440 Gly Arg Glu Ala Val Gly Ser Glu Gly Ser Arg Met Phe Cys Pro Pro 1445 1450 1455 Ser Gly Ser Gly Ser Ala Asn Ser Gln Glu Glu Ala His Phe Thr Arg 1460 1465 1470 His Asp Phe Phe Glu Ser Leu His Arg Gly Gin Ala Phe His Ile Leu 1475 1480 1485 Asn Asn Thr Thr Ile Gln Phe Lys Leu Glu Lys Ile Pro Ile Glu Arg 1490 1495 1500 Glu Ser Glu Leu Thr Phe Ser Leu Ser Pro Asp Asp Leu Gly Thr Ser 1505 1510 1515 1520 Ser Ile Met Lys Ile Glu Gly Lys Phe Val Asn Pro Val Gln Val Val 1525 1530 1535 Leu Ala Lys His Val Tyr Glu Gln Val Leu Gln Thr Leu Asp Asn Leu 1540 1545 1550 Val Tyr Ser Glu Asp Leu Asn Lys Tyr Pro Ala Ser Ala Thr Ser Ser 1555 1560 1565 Pro Cys Pro Asp Ser Pro Leu Pro Pro Leu Ser Thr Cys Gly Glu Ser 1570 1575 1580 Ser Val Glu Arg Lys Glu Asn Gly Leu Phe Ser His Ser Ser Leu Ser 1585 1590 1595 1600 Asn Thr Ser Gln Lys Ser Leu Ser Val Lys Glu Val Lys Ser Phe Thr 1605 1610 1615 Gln Ile Gln Ala Thr Phe Cys Ile Ser Glu Leu Gln Val Gln Leu Ser 1620 1625 1630 Gly Asp Leu Thr Leu Gly Ala Gln Gly Leu Val Ser Leu Lys Phe Gln 1635 1640 1645 Asp Phe Glu Val Glu Phe Ser Lys Asp His Pro Gln Thr Leu Ser Ile 1650 1655 1660 Gln Ile Ala Leu His Ser Leu Leu Met Glu Asp Leu Leu Glu Lys Asn 1665 1670 1675 1680 Pro Asp Ser Lys Tyr Lys Asn Leu Met Val Ser Arg Gly Ala Pro Lys 1685 1690 1695 Pro Ser Ser Leu Ala Gln Lys Glu Tyr Leu Ser Gln Ser Cys Pro Ser 1700 1705 1710 Val Ser Asn Val Glu Tyr Pro Asp Met Pro Arg Ser Leu Pro Ser His 1715 1720 1725 Met Glu Glu Ala Pro Asn Val Phe Gln Leu Tyr Gln Arg Pro Thr Ser 1730 1735 1740 Ala Ser Arg Lys Lys Gln Lys Glu Val Gln Asp Lys Asp Tyr Pro Leu 1745 1750 1755 1760 Thr Pro Pro Pro Ser Pro Thr Val Asp Glu Pro Lys Ile Leu Val Gly 1765 1770 1775 Lys Ser Lys Phe Asp Asp Ser Leu Val His Ile Asn Ile Phe Leu Val 1780 1785 1790 Asp Lys Lys His Pro Glu Phe Ser Ser Ser Tyr Asn Arg Val Asn Arg 1795 1800 1805 Ser Ile Asp Val Asp Phe Asn Cys Leu Asp Val Leu Ile Thr Leu Gln 1810 1815 1820 Thr Trp Val Val Ile Leu Asp Phe Phe Gly Ile Gly Ser Thr Ala Asp 1825 1830 1835 1840 Asn His Ala Met Arg Leu Pro Pro Glu Gly Ile Leu His Asn Val Lys 1845 1850 1855 Leu Glu Pro His Ala Ser Met Glu Ser Gly Leu Gln Asp Pro Val Asn 1860 1865 1870 Thr Lys Leu Asp Leu Lys Val His Ser Leu Ser Leu Val Leu Asn Lys 1875 1880 1885 Thr Thr Ser Glu Leu Ala Lys Ala Asn Val Ser Lys Leu Val Ala His 1890 1895 1900 Leu Glu Met Ile Glu Gly Asp Leu Ala Leu Gln Gly Ser Ile Gly Ser 1905 1910 1915 1920 Leu Ser Leu Ser Asp Leu Thr Cys His Gly Glu Phe Tyr Arg Glu Arg 1925 1930 1935 Phe Thr Thr Ser Gly Glu Glu Ala Leu Ile Phe Gln Thr Phe Lys Tyr 1940 1945 1950 Gly Arg Pro Asp Pro Leu Leu Arg Arg Glu His Asp Ile Arg Val Ser 1955 1960 1965 Leu Arg Met Ala Ser Val Gln Tyr Val His Thr Gln Arg Phe Gln Ala 1970 1975 1980 Glu Val Val Ala Phe Ile Gln His Phe Thr Gln Leu Gln Asp Val Leu 1985 1990 1995 2000 Gly Arg Gln Arg Ala Ala Ile Glu Gly Gln Thr Val Arg Asp Gln Ala 2005 2010 2015 Gln Arg Cys Ser Arg Val Leu Leu Asp Ile Glu Ala Gly Ala Pro Val 2020 2025 2030 Leu Leu Ile Pro Glu Ser Ser Arg Ser Asn Asn Leu Ile Val Ala Asn 2035 2040 2045 Leu Gly Lys Leu Lys Val Lys Asn Lys Phe Leu Phe Ala Gly Phe Pro 2050 2055 2060 Gly Thr Phe Ser Leu Gln Asp Lys Glu Ser Val Pro Ser Ala Ser Pro 2065 2070 2075 2080 Thr Gly Ile Pro Lys His Ser Leu Arg Lys Thr Thr Ser Thr Glu Glu 2085 2090 2095 Pro Arg Gly Thr His Ser Gln Gly Gln Phe Thr Met Pro Leu Ala Gly 2100 2105 2110 Met Ser Leu Gly Ser Leu Lys Ser Glu Phe Val Pro Ser Thr Ser Thr 2115 2120 2125 Lys Gln Gln Gly Pro Gln Pro Thr Leu Ser Val Gly Gln Glu Ser Ser 2130 2135 2140 Ser Pro Glu Asp His Val Cys Leu Leu Asp Cys Val Val Val Asp Leu 2145 2150 2155 2160 Gln Asp Met Asp Ile Phe Ala Ala Glu Arg His Pro Arg Glu Tyr Ser 2165 2170 2175 Lys Ala Pro Glu Asp Ser Ser Gly Asp Leu Ile Phe Pro Ser Tyr Phe 2180 2185 2190 Val Arg Gln Thr Gly Gly Ser Leu Leu Thr Glu Pro Cys Arg Leu Lys 2195 2200 2205 Leu Gln Val Glu Arg Asn Leu Asp Lys Glu Ile Ser His Thr Val Pro 2210 2215 2220 Asp Ile Ser Ile His Gly Asn Leu Ser Ser Val His Cys Ser Leu Asp 2225 2230 2235 2240 Leu Tyr Lys Tyr Lys Leu Ile Arg Gly Leu Leu Glu Asn Asn Leu Gly 2245 2250 2255 Glu Pro Ile Glu Glu Phe Met Arg Pro Tyr Asp Leu Gln Asp Pro Arg 2260 2265 2270 Ile His Thr Val Leu Ser Gly Glu Val Tyr Thr Cys Met Cys Phe Leu 2275 2280 2285 Ile Asp Met Val Asn Val Ser Leu Glu Leu Lys Asp Pro Lys Arg Lys 2290 2295 2300 Glu Gly Ala Gly Ser Leu Ala Arg Phe Asp Phe Lys Lys Cys Lys Leu 2305 2310 2315 2320 Leu Tyr Glu Ser Phe Ser Asn Gln Thr Lys Ser Ile Asn Leu Val Ser 2325 2330 2335 His Ser Met Met Ala Phe Asp Thr Arg Tyr Ala Gly Gln Lys Thr Ser 2340 2345 2350 Pro Gly Met Thr Asn Val Phe Ser Cys Ile Phe Gln Pro Ala Lys Asn 2355 2360 2365 Ser Ser Thr Thr Gln Gly Ser Ile Gln Ile Glu Leu His Phe Arg Ser 2370 2375 2380 Thr Lys Asp Ser Ser Cys Phe Thr Val Val Leu Asn Asn Leu Arg Val 2385 2390 2395 2400 Phe Leu Ile Phe Asp Trp Leu Leu Leu Val His Asp Phe Leu His Thr 2405 2410 2415 Pro Ser Asp Ile Lys Lys Gln Asn His Val Thr Pro Ser Arg His Arg 2420 2425 2430 Asn Ser Ser Ser Glu Ser Ala Ile Val Pro Lys Thr Val Lys Ser Gly 2435 2440 2445 Val Val Thr Lys Arg Ser Ser Leu Pro Val Ser Asn Glu Arg His Leu 2450 2455 2460 Glu Val Lys Val Asn Val Thr Gly Thr Glu Phe Val Val Ile Glu Asp 2465 2470 2475 2480 Val Ser Cys Phe Asp Thr Asn Ala Ile Ile Leu Lys Gly Thr Thr Val 2485 2490 2495 Leu Thr Tyr Lys Pro Arg Phe Val Asp Arg Pro Phe Ser Gly Ser Leu 2500 2505 2510 Phe Gly Ile Glu Val Phe Ser Cys Arg Leu Gly Asn Glu His Asp Thr 2515 2520 2525 Ala Leu Ser Ile Val Asp Pro Val Gln Ile Gln Met Glu Leu Val Gly 2530 2535 2540 Asn Ser Ser Tyr Gln Asn Ser Ser Gly Leu Met Asp Ala Phe Asn Ser 2545 2550 2555 2560 Glu Asp Phe Pro Val Leu Glu Ile Gln Leu Gln Ala Leu Asp Ile 2565 2570 2575 Arg Leu Ser Tyr Asn Asp Val Gln Leu Phe Leu Ala Ile Ala Lys Ser 2580 2585 2590 Ile Pro Glu Gln Ala Asn Ala Ala Val Pro Asp Ser Val Ala Leu Glu 2595 2600 2605 Ser Asp Ser Val Gly Thr Tyr Leu Pro Gly Ala Ser Arg Val Gly Glu 2610 2615 2620 Glu Ile Arg Glu Gly Thr Arg His Thr Leu Asp Pro Val Leu Glu Leu 2625 2630 2635 2640 Gln Leu Ala Arg Leu Gln Glu Leu Gly Phe Ser Met Asp Asp Cys Arg 2645 2650 2655 Lys Ala Leu Leu Ala Cys Gln Gly Gln Leu Lys Lys Ala Ala Ser Trp 2660 2665 2670 Leu Phe Lys Asn Ala Glu Pro Leu Lys Ser Leu Ser Leu Ala Ser Thr 2675 2680 2685 Ser Arg Asp Ser Pro Gly Ala Val Ala Ala Pro Leu Ile Ser Gly Val 2690 2695 2700 Glu Ile Lys Ala Glu Ser Val Cys Ile Cys Phe Ile Asp Asp Cys Met 2705 2710 2715 2720 Asp Cys Asp Val Pro Leu Ala Glu Leu Thr Phe Ser Arg Leu Asn Phe 2725 2730 2735 Leu Gln Arg Val Arg Thr Ser Pro Glu Gly Tyr Ala His Phe Thr Leu 2740 2745 2750 Ser Gly Asp Tyr Tyr Asn Arg Ala Leu Ser Gly Trp Glu Pro Phe Ile 2755 2760 2765 Glu Pro Trp Pro Cys Ser Val Ser Trp Gln Gln Gln Ala Ala Ser Arg 2770 2775 2780 Leu His Pro Pro Arg Leu Lys Leu Glu Ala Lys Ala Lys Pro Arg Leu 2785 2790 2795 2800 Asp Ile Asn Ile Thr Ser Val Leu Ile Asp Gln Tyr Val Ser Thr Lys 2805 2810 2815 Glu Ser Trp Met Ala Asp Tyr Cys Lys Asp Asp Lys Asp Ile Glu Ser 2820 2825 2830 Ala Lys Ser Glu Asp Trp Met Gly Ser Ser Val Asp Pro Pro Cys Phe 2835 2840 2845 Gly Gln Ser Leu Pro Leu Val Tyr Leu Arg Thr Arg Ser Thr Ala Ser 2850 2855 2860 Leu Thr Asn Leu Glu His Gln Ile Tyr Ala Arg Ala Glu Val Lys Thr 2865 2870 2875 2880 Pro Lys Arg Arg Gln Pro Phe Val Pro Phe Ala Leu Arg Asn His Thr 2885 2890 2895 Gly Cys Thr Leu Trp Phe Ala Thr Leu Thr Thr Thr Pro Thr Arg Ala 2900 2905 2910 Ala Leu Ser His Ser Gly Ser Pro Gly Val Val Pro Glu Gly Asn Gly 2915 2920 2925 Thr Phe Leu Asp Asp Thr His Asn Val Ser Glu Trp Arg Glu Val Leu 2930 2935 2940 Thr Gly Glu Glu Ile Pro Phe Glu Phe Glu Ala Arg Gly Lys Leu Arg 2945 2950 2955 2960 His Arg His Thr His Asp Leu Arg Ile His Gln Leu Gln Val Arg Val 2965 2970 2975 Asn Gly Trp Glu Gln Val Ser Pro Val Ser Val Asp Lys Val Gly Thr 2980 2985 2990 Phe Phe Arg Tyr Ala Ala Pro Asp Lys Asn Ser Ser Ser Ser Ser Thr Ile 2995 3000 3005 Gly Ser Pro Ser Ser Arg Thr Asn Ile Ile His Pro Gln Val Tyr Phe 3010 3015 3020 Ser Ser Leu Pro Pro Val Arg Val Val Phe Ala Val Thr Met Glu Gly 3025 3030 3035 3040 Ser Ala Arg Lys Val Ile Thr Val Arg Ser Ala Leu Ile Val Arg Asn 3045 3050 3055 Arg Leu Glu Thr Pro Met Glu Leu Arg Leu Asp Ser Pro Ser Ala Pro 3060 3065 3070 Asp Lys Pro Val Val Leu Pro Ala Ile Met Pro Gly Asp Ser Phe Ala 3075 3080 3085 Val Pro Leu His Leu Thr Ser Trp Arg Leu Gln Ala Arg Pro Lys Gly 3090 3095 3100 Leu Gly Val Phe Phe Cys Lys Ala Pro Ile His Trp Thr Asn Val Val 3105 3110 3115 3120 Lys Thr Ala Glu Ile Ser Ser Ser Lys Arg Glu Cys His Ser Met Asp 3125 3130 3135 Thr Glu Lys Ser Arg Phe Phe Arg Phe Cys Val Ala Ile Lys Lys Glu 3140 3145 3150 Asn Tyr Pro Asp Tyr Met Pro Ser Asn Ile Phe Ser Asp Ser Ala Lys 3155 3160 3165 Gln Ile Phe Arg Gln Pro Gly His Thr Ile Tyr Leu Leu Pro Thr Val 3170 3175 3180 Val Ile Cys Asn Leu Leu Pro Cys Glu Leu Asp Phe Tyr Val Lys Gly 3185 3190 3195 3200 Met Pro Ile Asn Gly Thr Leu Lys Pro Gly Lys Glu Ala Ala Leu His 3205 3210 3215 Thr Ala Asp Thr Ser Gln Asn Ile Glu Leu Gly Val Ser Leu Glu Asn 3220 3225 3230 Phe Pro Leu Cys Lys Glu Leu Leu Ile Pro Pro Gly Thr Gln Asn Tyr 3235 3240 3245 Met Val Arg Met Arg Leu Tyr Asp Val Asn Arg Arg Gln Leu Asn Leu 3250 3255 3260 Thr Ile Arg Ile Val Cys Arg Ala Glu Gly Ser Leu Lys Ile Phe Ile 3265 3270 3275 3280 Ser Ala Pro Tyr Trp Leu Ile Asn Lys Thr Gly Leu Pro Leu Ile Phe 3285 3290 3295 Arg Gln Asp Asn Ala Lys Thr Asp Ala Ala Gly Gln Phe Glu Glu His 3300 3305 3310 Glu Leu Ala Arg Ser Leu Ser Pro Leu Leu Phe Cys Tyr Ala Asp Lys 3315 3320 3325 Glu Gln Pro Asn Leu Cys Thr Met Arg Ile Gly Arg Gly Ile His Pro 3330 3335 3340 Glu Gly Met Pro Gly Trp Cys Gin Gly Phe Ser Leu Asp Gly Gly Ser 3345 3350 3355 3360 Gly Val Arg Ala Leu Lys Val Ile Gln Gln Gly Asn Arg Pro Gly Leu 3365 3370 3375 Ile Tyr Asn Ile Gly Ile Asp Val Lys Lys Gly Arg Gly Arg Tyr Ile 3380 3385 3390 Asp Thr Cys Met Val Ile Phe Ala Pro Arg Tyr Leu Leu Asp Asn Lys 3395 3400 3405 Ser Ser His Lys Leu Ala Phe Ala Gln Arg Glu Phe Ala Arg Gly Gln 3410 3415 3420 Gly Thr Ala Asn Pro Glu Gly Tyr Ile Ser Thr Leu Pro Gly Ser Ser 3425 3430 3435 3440 Val Val Phe His Trp Pro Arg Asn Asp Tyr Asp Gln Leu Leu Cys Val 3445 3450 3455 Arg Leu Met Asp Val Pro Asn Cys Ile Trp Ser Gly Gly Phe Glu Val 3460 3465 3470 Asn Lys Asn Asn Ser Phe His Ile Asn Met Arg Asp Thr Leu Gly Lys 3475 3480 3485 Cys Phe Phe Leu Arg Val Glu Ile Thr Leu Arg Gly Ala Thr Tyr Arg 3490 3495 3500 Ile Ser Phe Ser Asp Thr Asp Gln Leu Pro Pro Pro Phe Arg Ile Asp 3505 3510 3515 3520 Asn Phe Ser Lys Val Pro Val Val Phe Thr Gln His Gly Val Ala Glu 3525 3530 3535 Pro Arg Leu Arg Thr Glu Val Lys Pro Met Thr Ser Leu Asp Tyr Ala 3540 3545 3550 Trp Asp Glu Pro Thr Leu Pro Pro Phe Ile Thr Leu Thr Val Lys Gly 3555 3560 3565 Ala Gly Ser Ser Glu Ile Asn Cys Asn Met Asn Asp Phe Gln Asp Asn 3570 3575 3580 Arg Gln Leu Tyr Tyr Glu Asn Phe Ile Tyr Ile Ala Ala Thr Tyr Thr 3585 3590 3595 3600 Phe Ser Gly Leu Gln Glu Gly Thr Gly Arg Pro Val Ala Ser Asn Lys 3605 3610 3615 Ala Ile Thr Cys Ala Glu Leu Val Leu Asp Val Ser Pro Lys Thr Gln 3620 3625 3630 Arg Val Ile Leu Lys Lys Lys Glu Pro Gly Lys Arg Ser Gln Leu Trp 3635 3640 3645 Arg Met Thr Gly Thr Gly Met Leu Ala His Glu Gly Ser Ser Ser Val Pro 3650 3655 3660 His Asn Pro Asn Lys Pro Ser Ala Ala Arg Ser Thr Glu Gly Ser Ala 3665 3670 3675 3680 Ile Leu Asp Ile Ala Gly Leu Ala Ala Val Thr Asp Asn Arg Tyr Glu 3685 3690 3695 Pro Leu Met Leu Arg Lys Pro Asp Arg Arg Arg Ser Thr Thr Gln Thr 3700 3705 3710 Trp Ser Phe Arg Glu Gly Lys Leu Thr Cys Gly Leu His Gly Leu Val 3715 3720 3725 Val Gln Ala Lys Gly Gly Leu Ser Gly Leu Phe Asp Gly Ala Glu Val 3730 3735 3740 Val Leu Gly Pro Asp Thr Ser Met Glu Leu Leu Gly Pro Val Pro Pro 3745 3750 3755 3760 Glu Gln Gln Phe Ile Asn Gln Lys Met Arg Pro Gly Ser Gly Met Leu 3765 3770 3775 Ser Ile Arg Val Ile Pro Asp Gly Pro Thr Arg Ala Leu Gln Ile Thr 3780 3785 3790 Asp Phe Cys His Arg Lys Ser Ser Arg Ser Tyr Glu Val Asp Glu Leu 3795 3800 3805 Pro Val Thr Glu Gln Glu Leu Gln Lys Leu Lys Asn Pro Asp Thr Glu 3810 3815 3820 Gln Glu Leu Glu Val Leu Val Arg Leu Glu Gly Gly Ile Gly Leu Ser 3825 3830 3835 3840 Leu Ile Asn Lys Val Pro Glu Glu Leu Val Phe Ala Ser Leu Thr Gly 3845 3850 3855 Ile Asn Val His Tyr Thr Gln Leu Ala Thr Ser His Met Leu Glu Leu 3860 3865 3870 Ser Ile Gln Asp Val Gln Val Asp Asn Gln Leu Ile Gly Thr Thr Gln 3875 3880 3885 Pro Phe Met Leu Tyr Val Thr Pro Leu Ser Asn Glu Asn Glu Val Ile 3890 3895 3900 Glu Thr Gly Pro Ala Val Gln Val Asn Ala Val Lys Phe Pro Ser Lys 3905 3910 3915 3920 Ser Ala Leu Thr Asn Ile Tyr Lys His Leu Met Ile Thr Ala Gln Arg 3925 3930 3935 Phe Thr Val Gln Ile Glu Glu Lys Leu Leu Leu Lys Leu Leu Ser Phe 3940 3945 3950 Phe Gly Tyr Asp Gln Ala Glu Ser Glu Val Glu Lys Tyr Asp Glu Asn 3955 3960 3965 Leu His Glu Lys Thr Ala Glu Gln Gly Gly Thr Pro Ile Arg Tyr Tyr 3970 3975 3980 Phe Glu Asn Leu Lys Ile Ser Ile Pro Gln Ile Lys Leu Ser Val Phe 3985 3990 3995 4000 Thr Ser Asn Lys Leu Pro Leu Asp Leu Lys Ala Leu Lys Ser Thr Leu 4005 4010 4015 Gly Phe Pro Leu Ile Arg Phe Glu Asp Ala Val Ile Asn Leu Asp Pro 4020 4025 4030 Phe Thr Arg Val His Pro Tyr Glu Thr Lys Glu Phe Ile Ile Asn Asp 4035 4040 4045 Ile Leu Lys His Phe Gln Glu Glu Leu Leu Ser Gln Ala Ala Arg Ile 4050 4055 4060 Leu Gly Ser Val Asp Phe Leu Gly Asn Pro Met Gly Leu Leu Asn Asp 4065 4070 4075 4080 Val Ser Glu Gly Val Thr Gly Leu Ile Lys Tyr Gly Asn Val Gly Gly 4085 4090 4095 Leu Ile Arg Asn Val Thr His Gly Val Ser Asn Ser Ala Ala Lys Phe 4100 4105 4110 Ala Gly Thr Leu Ser Asp Gly Leu Gly Lys Thr Met Asp Asn Arg His 4115 4120 4125 Gln Ser Glu Arg Glu Tyr Ile Arg Tyr His Ala Ala Thr Ser Gly Glu 4130 4135 4140 His Leu Val Ala Gly Ile His Gly Leu Ala His Gly Ile Ile Gly Gly 4145 4150 4155 4160 Leu Thr Ser Val Ile Thr Ser Thr Val Glu Gly Val Lys Thr Glu Gly 4165 4170 4175 Gly Val Ser Gly Phe Ile Ser Gly Leu Gly Lys Gly Leu Val Gly Thr 4180 4185 4190 Val Thr Lys Pro Val Ala Gly Ala Leu Asp Phe Ala Ser Glu Thr Ala 4195 4200 4205 Gln Ala Val Arg Asp Thr Ala Thr Leu Ser Gly Pro Arg Thr Gln Ala 4210 4215 4220 Gln Arg Val Arg Lys Pro Arg Cys Cys Thr Gly Pro Gln Gly Leu Leu 4225 4230 4235 4240 Pro Arg Tyr Ser Glu Ser Gln Ala Glu Gly Gln Glu Gln Leu Phe Lys 4245 4250 4255 Leu Thr Asp Asn Ile Gln Asp Glu Phe Phe Ile Ala Val Glu Asn Ile 4260 4265 4270 Asp Ser Tyr Cys Val Leu Ile Ser Ser Lys Ala Val Tyr Phe Leu Lys 4275 4280 4285 Ser Gly Asp Tyr Val Asp Arg Glu Ala Ile Phe Leu Glu Val Lys Tyr 4290 4295 4300 Asp Asp Leu Tyr His Cys Leu Val Ser Lys Asp His Gly Lys Val Tyr 4305 4310 4315 4320 Val Gln Val Thr Lys Lys Ala Val Ser Thr Ser Ser Gly Val Ser Ile 4325 4330 4335 Pro Gly Pro Ser His Gln Lys Pro Met Val His Val Lys Ser Glu Val 4340 4345 4350 Leu Ala Val Lys Leu Ser Gln Glu Ile Asn Tyr Ala Lys Ser Leu Tyr 4355 4360 4365 Tyr Glu Gln Gln Leu Met Leu Arg Leu Ser Glu Asn Arg Glu Gln Leu 4370 4375 4380 Glu Leu Asp Ser 4385

Claims (10)

ACTR1B gene mutation, BPNT1 gene mutation, BRD4 gene mutation, TSPOAP1 gene mutation, TMEM266 gene mutation, C16orf72 gene mutation, CD1C gene mutation, CEP128 gene mutation, CIITA gene mutation, COL5A1 gene mutation, CYP51A1 gene mutation, DNAAF2 gene mutation, EPHB1 gene mutation, ESRP2 gene mutation, FBXW9 gene mutation, ITGA3 gene mutation, ITGA4 gene mutation, ITGA8 gene mutation, KIF5C gene mutation, KPRP gene mutation, MAOB gene mutation, MUC17 gene mutation, MYH10 gene mutation, OGFR gene mutation, OR1S1 gene mutation, PCBP4 gene mutation, PCGF2 gene mutation, PCSK2 gene mutation, PLEKHB2 gene mutation, PPM1F gene mutation, RAB40B gene mutation, RRP36 gene mutation, RTL1 gene mutation, RYR1 gene mutation, SMARCA1 gene mutation, SNX7 gene mutation, SSX2IP gene mutation, TAS1R2 gene mutation, THUMPD2 gene mutation and VPS13D gene mutation A composition for prognostic diagnosis of renal cancer comprising a reagent capable of detecting a survival-specific marker of a renal cancer patient comprising at least one selected from the group consisting of. The method according to claim 1,
The reagent is a composition comprising one or more selected from the group consisting of primers, probes, aptamers and antibodies. The method according to claim 1,
The survival-specific marker is ACTR1B gene mutation, BPNT1 gene mutation, BRD4 gene mutation, C16orf72 gene mutation, CD1C gene mutation, CEP128 gene mutation, CIITA gene mutation, CYP51A1 gene mutation, EPHB1 gene mutation , FBXW9 gene mutation, ITGA3 gene mutation, ITGA8 gene mutation, KIF5C gene mutation, KPRP gene mutation, MAOB gene mutation, MUC17 gene mutation, MYH10 gene mutation, OR1S1 gene mutation, PCSK2 gene mutation , PLEKHB2 gene mutation, PPM1F gene mutation, RAB40B gene mutation, RTL1 gene mutation, RYR1 gene mutation, SMARCA1 gene mutation, SNX7 gene mutation, SSX2IP gene mutation, TAS1R2 gene mutation, and THUMPD2 gene mutation At least one composition selected from the group consisting of. ACTR1B gene mutation, BPNT1 gene mutation, BRD4 gene mutation, TSPOAP1 gene mutation, TMEM266 gene mutation, C16orf72 gene mutation, CD1C gene mutation, CEP128 gene mutation, CIITA gene mutation, COL5A1 gene mutation, CYP51A1 gene mutation, DNAAF2 gene mutation, EPHB1 gene mutation, ESRP2 gene mutation, FBXW9 gene mutation, ITGA3 gene mutation, ITGA4 gene mutation, ITGA8 gene mutation, KIF5C gene mutation, KPRP gene mutation, MAOB gene mutation, MUC17 gene mutation, MYH10 gene mutation, OGFR gene mutation, OR1S1 gene mutation, PCBP4 gene mutation, PCGF2 gene mutation, PCSK2 gene mutation, PLEKHB2 gene mutation, PPM1F gene mutation, RAB40B gene mutation, RRP36 gene mutation, RTL1 gene mutation, RYR1 gene mutation, SMARCA1 gene mutation, SNX7 gene mutation, SSX2IP gene mutation, TAS1R2 gene mutation, THUMPD2 gene mutation and VPS13D gene mutation A kit for prognostic diagnosis of renal cancer comprising a reagent capable of detecting a survival-specific marker of a renal cancer patient comprising at least one selected from the group consisting of. 5. The method according to claim 4,
The reagent is a kit comprising at least one selected from the group consisting of primers, probes, aptamers and antibodies. 5. The method according to claim 4,
The survival-specific marker is ACTR1B gene mutation, BPNT1 gene mutation, BRD4 gene mutation, C16orf72 gene mutation, CD1C gene mutation, CEP128 gene mutation, CIITA gene mutation, CYP51A1 gene mutation, EPHB1 gene mutation , FBXW9 gene mutation, ITGA3 gene mutation, ITGA8 gene mutation, KIF5C gene mutation, KPRP gene mutation, MAOB gene mutation, MUC17 gene mutation, MYH10 gene mutation, OR1S1 gene mutation, PCSK2 gene mutation , PLEKHB2 gene mutation, PPM1F gene mutation, RAB40B gene mutation, RTL1 gene mutation, RYR1 gene mutation, SMARCA1 gene mutation, SNX7 gene mutation, SSX2IP gene mutation, TAS1R2 gene mutation, and THUMPD2 gene mutation At least one kit selected from the group consisting of. preparing sample DNA from a sample of a renal cancer patient;
Using the composition for diagnosing the prognosis of any one of claims 1 to 3 or the kit for diagnosing the prognosis of kidney cancer according to any one of claims 4 to 6 for the sample DNA, confirming the presence or absence of a survival-specific marker; A method of providing information necessary for prognostic diagnosis of renal cancer patients comprising a. 8. The method of claim 7,
The method further comprising the step of amplifying the sample DNA prepared from the sample of the renal cancer patient. 8. The method of claim 7,
The method further comprising; determining that the survival rate of a kidney cancer patient whose survival-specific marker is confirmed has a lower survival rate than that of a person whose survival-specific marker is not identified. 8. The method of claim 7,
The method further comprising a; determining that the survival-specific marker is confirmed kidney cancer patients have a higher rate of recurrence of kidney cancer than the survival-specific marker is not confirmed.

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