KR20100116765A - Methods to screen materials to inhibit parkinson's disease - Google Patents

Abstract

PURPOSE: A method for screening a therapeutic agent for Parkinson's disease is provided to simply and economically search for a compound which can be used as a therapeutic agent for Parkinson's disease. CONSTITUTION: A method for screening a therapeutic agent for Parkinson's disease comprises: a step of expressing a LRRK2(leucine rich repeat kinase 2) mutant in cells; a step of treating a material which causes oxidative stress or mitochondria toxicity to cells; a step of contacting a test material to the cells; a step of contacting the cells contacted to the test material with cells which are not contacted; and a step of measuring the reduction of cell apoptosis by contact of test material. The used cells are a cell group which secretes MN9D, SN4741, SH-SY5Y, SK-N-BE2C, or PC12 dopamine or a cell group which does not secrete HEK293T, HeLa, or COS-7 dopamine.

Description

Parkinson's disease drug screening method {Methods to screen materials to inhibit Parkinson's disease}

The present invention expresses a LRRK2 (leucine rich repeat kinase 2) mutant protein in a cell, adds an oxidative stress or mitochondrial toxic substance to the cell, and then contacts the test substance to the cell, thereby contacting the cell with the test substance. Compare cells not in contact with the substance to determine whether cell death by contact with the test substance is reduced or transformed with the test gene and transformed with the test gene and cells not transformed with the test gene The present invention relates to a method for screening Parkinson's disease therapeutic substances by measuring the reduction of cell death by transformation of the test genes, and to a Parkinson's disease therapeutic substance screening kit.

Parkinson's disease, along with Alzheimer's dementia, is a representative neurodegenerative disorder seen in older age. About 1% of the 65-year-old population develops, and the incidence increases with age (Gasser 2007; Thomas and Beal 2007) .Pakinson's disease exhibits mobility impairment, which is characterized by stable tremor, stiffness, slow motion, and postural instability. It is a symptom and pathologically caused by the progressive death of dopamine neurons in the midbrain black brain (Olanow and Tatton 1999).

Most cases of Parkinson's disease occur sporadically, but 5-10% of patients have a family history, and studies of these patient samples have revealed the locus of PARK 1-13 to date, due to mutations in several loci. Genes that cause Parkinson's disease have been identified (Lewthwaite and Nicholl 2005; Gasser 2007). Parkinson's disease-causing genes caused by mutations are known as parkin, PINK1, DJ-1, α-synuclein, and LRRK2. (Moore, West et al. 2005; Gasser 2007; Thomas and Beal 2007)

Among them, the LRRK2 gene, like α-synuclein, was first reported in 2004 as a dominant gene of homologous chromosomes (Paisan-Ruiz, Jain et al. 2004; Zimprich, Biskup et al. 2004). Parkinson's disease patients with LRRK2 mutations, unlike other Parkinson's disease genes, have very similar symptoms to sporadic Parkinson's disease patients (Mata, Wedemeyer et al. 2006). In addition, the LRRK2 mutation is found in patients with sporadic Parkinson's disease as well as patients with family history of Parkinson's disease. Therefore, identifying the mechanism of Parkinson's disease caused by the mutation of this gene will be helpful in understanding the mechanism of development of Parkinson's disease and in developing a therapeutic agent. The LRRK2 protein includes the functional domains of GTPase and kinase involved in cellular signal transduction, and the domains of WD40, leucine-rich repeat (LRR) involved in protein interaction (Figure 1, (Paisan-Ruiz, Jain et. al. 2004; Zimprich, Biskup et al. 2004)). Parkinson's disease-causing LRRK2 mutations have been reported with R1441G, R1441C in the GTPase moiety, G2019S in the kinase moiety, I2020T, and Y1699C between the GTPase and kinase domains (Paisan-Ruiz, Jain et al. 2004; Zimprich, Biskup et al. 2004) In addition, a large number of polymorphisms have been reported (Mata, Wedemeyer et al. 2006).

G2019S mutations have been shown that overexpression increases kinase activity, induces cytotoxicity, and reduces the length of neuronal axons (Smith, Pei et al. 2005; Smith, Pei et al. 2006; West, Moore et al. 2007 MacLeod et al. 2006), which specifically account for 85% of Parkinson's disease patients due to LRRK2 mutations (Healy, Falchi et al. 2008).

For this reason, patents have been registered to search for compounds that eliminate or reduce the phenomena caused by mutant genes of LRRK2, in particular G2019S (increased kinase activity, reduced length of nerve axons, etc.). WO / 2008/091799 (PCT / US2008 / 051485) utilizes the fact that when the LRRK2 mutant protein is overexpressed, the filament is formed by the protein, thereby over-expressing various mutant proteins of LRRK2 and then reducing the filament formation. A patent for a method of searching in a cell. WO / 2008/122789 (PCT / GB2008 / 001211) also regulates the phosphorylation of ERM protein by LRRK2 protein using the fact that LRRK2 protein uses Ezrin / Radixin / Moesin (ERM) proteins as its kinase substrate. A patent for a method of searching for a compound. In addition, WO / 2007/124096 (PCT / US2007 / 009736) overexpresses the LRRK2 mutant protein by taking advantage of the fact that when Parkinson's disease-induced mutant protein of LRRK2 is expressed in a cell, it reduces the length and number of branches of neuronal axons in that cell. The patent relates to a method for searching for a compound which does not reduce the length or the number of branches by observing its shape such as the length and number of branches of nerve axons in a cell.

However, these patents require observation of each cell with expensive equipment such as a fluorescence microscope or a high magnification microscope (WO / 2008/091799, WO / 2007/124096), or a reaction with radioisotopes or fluorescent substances (WO / 2008). / 122789) There is a disadvantage.

In addition, there is an invention using alpha-synuclein to search for Parkinson's disease therapeutics using neuronal toxicity of Parkinson's disease related genes (WO / 2008/063779). However, in view of the fact that the number of patients with genetic Parkinson's disease caused by mutation or overexpression of alpha-synucelin gene is very small compared to the number of patients with LRRK2 gene mutation, LRRK2 is more effective than alpha-synucelin. something to do. In addition, LRRK2 is found in 1-2% of sporadic patients as well as genetic patients with a family history of the mutation (Gilks, Abou-Sleiman et al. 2005, Mata, Wedemeyer et al. 2006). Given that GTPases and kinases play important roles in intracellular signal transduction and regulation, it is more efficient to search for therapeutic compounds against LRRK2 proteins than with alpha-synuclein.

Accordingly, the present inventors have found that applying the cytotoxicity of the LRRK2 mutant protein to a screening method for searching for a compound or gene that inhibits the toxicity can solve the above disadvantages and completed the present invention.

It is an object of the present invention to provide a method for screening a Parkinson's disease therapeutic substance and a Parkinson's disease therapeutic substance screening kit.

In one aspect, the present invention comprises the steps of expressing leucine rich repeat kinase 2 (LRRK2) mutant protein in a cell; Treating the cells with oxidative stress or mitochondrial toxic substances; Contacting the test substance with the cell; Comparing cells in contact with the test substance with cells not in contact with the test substance; And it provides a method for screening for Parkinson's disease treatment material comprising the step of measuring whether the reduction of cell death by the contact of the test substance.

In another embodiment, the present invention provides a method of expressing a LRRK2 mutant protein in a cell; Treating the cells with oxidative stress or mitochondrial toxic substances; Transforming said cell with a test gene; Comparing the cells transformed with the test gene with the cells not transformed with the test gene; And it provides a method for screening for Parkinson's disease treatment material comprising the step of measuring whether the cell death by the transformation of the test gene.

When searching for a compound with a specific purpose in a compound library, there is a need for a simple and inexpensive way to search for a specific compound that causes high-throughput, purposeful changes.

In order to effectively screen for Parkinson's disease therapeutics, the neuronal cytotoxicity caused by the overexpression of the LRRK2 mutant protein should be used to overexpress the mutant protein in the majority of cells, and the majority of the expressed cells are killed. In order to satisfy the former condition, it is preferable to use a dopaminergic neuronal cell line with high transformation rate, and in particular, it is preferable to use SN4741 or MN9D. To satisfy the latter condition, a certain amount of oxidative stress or mitochondrial toxic substance is applied to the cells. It is desirable to increase the sensitivity of the cells to oxidative stress or mitochondrial toxic substances by treating the cells. Apoptosis under both conditions is apoptosis showing synergy beyond the apoptosis induced by simply applying both conditions simultaneously. At this time, more preferably, the number of cells killed by oxidative stress (mitochondrial toxic substance) alone treatment without expression of the LRRK2 mutant protein is minimized, and under the two conditions of expression of LRRK2 mutant protein and oxidative stress (mitochondrial toxic substance) treatment The number of dead cells should be maximized.

As shown in the specific examples of the present invention, the expression of the mutant protein was significantly increased in the presence of oxidative stress (mitochondrial toxin) compared to the control vector or LRRK2 wild species protein. In a specific embodiment of the present invention, G2019S is transformed to express G2019S and treated with oxidative stress (for example, hydrogen peroxide) in the SN4741 cell line, compared to the case where only G2019S is transformed by expression or oxidative stress. In some cases, compounds that interfered with cytotoxicity of LRRK2 mutants were searched under conditions that significantly increased apoptosis.

Leucine rich repeat kinase 2 (LRRK2) is a Parkinson's disease gene whose mutations have been found in familial Parkinson's disease patients. Various methods known in the art may be applied to express the LRRK2 mutant protein, but specific embodiments of the present invention express the mutant protein by transforming the LRRK2 gene, in which case the expression of the mutant protein is high.

After expression of the LRRK2 mutant protein in cells, treatment with oxidative stress or mitochondrial toxicants results in higher cell killing than cell lines expressing wild species or control vectors.

Preferably, before screening for a Parkinson's disease therapeutic agent using the screening method of the present invention, first, a Parkinson's disease therapeutic agent is searched for a LRRK2 mutant protein-expressing cell line, and then a difference in apoptosis is first selected as a primary test substance. . Then, among these test substances alone, such conditions as the expression of oxidative stress (mitochondrial toxicant) or LRRK2 wild species alone showed no difference in apoptosis, but the presence of oxidative stress (mitochondrial toxicant) and G2019S expression. If present at the same time, it is preferable to select a test substance that shows a difference in the degree of cell death compared to other cases.

The cells are preferably selected from a group of cells that secrete dopamine consisting of MN9D, SN4741, SH-SY5Y, SK-N-BE2C, and PC12 or a group of cells that do not secrete dopamine consisting of HEK293T, HeLa, and COS-7 cells. More preferably, it is MN9D or SN4741 which is a dopaminergic neuron which secretes a lot of dopamine. In a specific embodiment of the present invention, the SN4741 cell line was used in the experiment to use physiological conditions similar to the killing of dopamine neurons in the striatum that occur in Parkinson's disease.

The LRRK2 mutant protein is selected from the group consisting of G2019S represented by SEQ ID NO: 2, R1441C represented by SEQ ID NO: 4, R1441G represented by SEQ ID NO: 6, Y1699C represented by SEQ ID NO: 8, and I2020T represented by SEQ ID NO: 10. It is preferably at least one protein.

The LRRK2 G2019S gene sequence is SEQ ID NO: 1, the LRRK2 R1441C gene sequence is SEQ ID NO: 3, the LRRK2 R1441G gene sequence is SEQ ID NO: 5, the LRRK2 Y1699C gene sequence is SEQ ID NO: 7, and the LRRK2 I2020T gene sequence is SEQ ID NO: 9.

The G2019S means that the 2019 amino acid glycine (glycin) is substituted with serine, R1441C means that the 1441th amino acid arginine is substituted with cysteine, and R1441G is the 1441th amino acid arginine This means that it was substituted with glycine, Y1699C means that the 1699th amino acid tyrosine was replaced with cysteine, and I2020T replaced the 2020 amino acid isoleucine with threonine. It means.

The oxidative stress may be induced by various methods known in the art, but preferably induced by hydrogen peroxide generating reactive oxygen species. The oxidative stress refers to a phenomenon in which free radicals, which are unstable molecules of normal cells, react with oxygen compounds in the body and cause inflammation in cells and tissues.

In addition, the toxicity of the mitochondria may be caused by various methods known in the art, but is preferably caused by paraquat.

As the test substance, it is possible to use any substance that a person skilled in the art can expect to inhibit cell death, such as an existing compound, a natural compound, or a drug candidate.

In addition, searching by the same method using a gene library instead of a compound library may provide a method of searching for genes below a cell mechanism in which LRRK2 mutant inheritance causes apoptosis. The test gene may use any gene that one of ordinary skill in the art would expect to inhibit cell death, such as an existing gene, a new gene, or an siRNA that inhibits the expression of the gene.

In another aspect, the present invention provides a Parkin's disease therapeutic screening kit comprising a cell expressing a LRRK2 mutant protein and a device for measuring cell death.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention, it will be apparent to those skilled in the art that the scope of the present invention is not to be construed as limited by these examples.

Example 1 Transformation Rate of SN4741 Cells

Green fluorescent protein (GFP) was expressed in SN4741 and its expression was observed by fluorescence microscopy. The SN4741 cell line is a dopamine neuronal cell line using cells from mouse striatum (Son, Chun et al. 1999). In the present invention, the SN4741 cell line was used in the experiment to use physiological conditions similar to the killing of dopaminergic neurons of the striatum that occur in Parkinson's disease. Place the cover slip on a 12 well plate, place SN4741 cells at 1X10 ⁵ / well and incubate in Dubecco's modified minimal medium (DMEM) containing 10% fetal bovine serum (FBS) for 1 day. / well was transformed by the calcium chloride method. After incubation for 2 days, the expression was observed by staining using an antibody against GFP.

Figure 2 shows the results, 1x10 ⁵ cells / well was placed on a 12 well plate and then transformed 0.5 μg and 2 days after the immunostaining with antibody (b) against GFP. a is a dye stained with Hoechst H33258, a nuclear dye, and c is a merge of a and b. The bar under angle is 150 μm. As shown in FIG. 2, the transformation rate was about 20%.

Example 2 Survival of SN4741 Cells after Treatment of Hydrogen Peroxide to SN4741 Cells Expressing LRRK2 Wild Species or Mutant Proteins

SN4741 cells were seeded in 48 well plates at 5X10 ⁴ / well, and then cultured in the same conditions as in Example 1, followed by control empty vector (pcDNA3.1 / HisMyc, Invitrogen Co. USA), LRRK2 wild species or G2019S mutant gene. PcDNA3.1 / HisMyc plasmid containing 1 μg / well was transformed into each well by the calcium chloride method. Three wells were used for each sample. After culturing for 2 days, 100 μM of hydrogen peroxide was treated and after 24 hours, cell viability was measured by absorbance of each well by crystal violet staining.

Crystal violet staining was performed as follows. After removing the culture medium, make 0.5% crystal violet solution with 50% methanol, put 100μl per well and react for 30 minutes at room temperature. Wash each well three times with water, remove water, add 400μl of 50% methanol, and react at room temperature for 30 minutes to completely dissolve the intracellular staining solution. Transfer the solution to a 96 well plate and measure the absorbance at 540 nm. Was determined.

Cell viability in each case was compared with each other in FIG. 3 with the survival rate of the cells transformed with the control vector pcDNA3.1 / HisMyc as 100. In this experimental condition, the cytotoxicity of the G2019S mutant was greater than that of the LRRK2 wild species.

Example 3 Optimization Conditions to Maximize the Difference in Toxicity With and Without Overexpression of LRRK2 Protein Under Hydrogen Peroxide Treatment

In order to maximize the cell death rate when transformed with LRRK2 G2019S and treated with hydrogen peroxide, the cell survival rate was investigated by changing the culture time and the hydrogen peroxide treatment concentration after transformation. As shown in FIG. 4, the cell survival rate of each sample was slightly different from the control group according to the concentration of hydrogen peroxide, but there was no significant difference compared to the difference in Example 2, and thus the conditions of Example 2 were used in other experiments such as screening. Was used.

Example 4 Establishment of Cell Lines that Stablely Express LRRK2 Wild Species or G2019S

Since mutations in the LRRK2 cell line, in particular G2019S, are cytotoxic, a cell line was constructed that conditionally and stably induced expression of the LRRK2 protein only when needed. For this purpose, a dopaminergic neuronal MN9D cell line and a Rheo-switch mammalian inducible expression system (New England Biolab Co., Mass., USA) were used.

DMEM medium was used to culture the MN9D cell line. First, NEBR-R1 plasmids were transformed into MN9D cells and treated with G418 at 900 μg / ml for 3 weeks, and each colony was separated into each well of a 96 well plate. After each of these colonies was incubated, transformed with NEBR-gluc plasmid (control protein luciferase expression plasmid) to select the colony that responds best to the ligand RSL1, and the ligand RSL1 of the system was 500 nM / well. After treatment with luciferase activity expressed by NEBR-gluc was measured. Through this method, colonies that express the most luciferase by RSL1 ligand were selected and named as L14. The NERK-X1 plasmid cloned with LRRK2 wild species or G2019S mutant gene in the L14 cell line or NEBR-X1, an empty vector, was transformed and treated with 600 μg / ml of hygromycin for 3 weeks to separate colonies into each well of a 96 well plate. . After culturing these colonies, the ligands were treated with RSL1 at 500 nM / well for each colony, and the expression level of LRRK2 protein was analyzed by western blot within 24 hours. At this time, LRRK2 wild species and colony expressing the most G2019S protein were selected by ligand, respectively, and named HL2 and HMG15 (FIG. 5).

5 a shows the result of western blot analysis in which LRRK2 protein was stained with an antibody to Myc tag (above) or LRRK2 antibody (middle). HV, HL, and HMG refer to cell lines into which control vectors are inserted (HV), LRRK2 wild species or (HL), or plasmids expressing G2019S mutant protein (HMG). Myc tag is fused only to the G2019S protein and therefore appears only in HMG cell lines. The same blot was stained with beta-actin antibody to confirm the amount of protein used (Figure below). The number on the left is the molecular weight (kd) of the protein used as a marker. In addition, in Figure 5b shows the relative expression of LRRK2, corrected by dividing each LRRK2 expression amount (a middle degree) by the beta-actin expression amount.

In addition, it was confirmed by RT-PCR that the LRRK2 gene was inserted into the chromosome in the cell and expressed by separating the RNA of each cell using a primer pair specific to the inserted gene. RNA was isolated using trizol (Invitrogen Co.), cDNA was prepared using reverse transcriptase by a general method, followed by PCR with the corresponding primer pairs and analyzed by electrophoresis on an agarose gel (FIG. 6).

In FIG. 6, 500 nM of HL2 and HMG15 were treated with RSL1, and after 3 days, cells were collected to separate total RNA, reverse transcription was carried out by a general method, and cDNA was prepared as a template. PCR was performed using primer pairs indicated in d as a template. . The PCR product was analyzed by agarose gel electrophoresis and showed a, b, c together with the corresponding primer pairs. HL2 and HMG15 refer to each clone described in FIG. 5 and the numbers are clone numbers selected for use in the experiment. M is the size marker DNA, P is the result of the same PCR using the plasmid as a template. PCR was performed for GAPDH to confirm that the same amount of cDNA was used. The conditions of each PCR are as follows. a: 95 degree 30 second, 45 degree 30 second, 72 degree 30 second 40 cycles, 72 degree 7 minute reaction after 95 degree 5 minutes reaction. b: 95 degrees 30 seconds, 48 degrees 30 seconds, 72 degrees 1 minute 40 cycles, 72 degrees 7 minutes reaction after 95 degrees 5 minutes reaction. c: 95 degrees 30 seconds, 95 degrees 30 seconds, 59 degrees 30 seconds, 72 degrees 30 seconds 26 cycles, 72 degrees 7 minutes reaction The primer sequences used in each PCR are as follows.

LRRK2-F: GTCATGATGACAGCACAGC, pNEBR-R: TAATACGACTCACTATAGGC, LRRK2-R: CTTCATTCTCATTCTTTTCCTC, pNEBR-F: GCCAAGCTTCTCTGCAGGATATC, GAPDH-F: GCCCACTGAAGGGCATCTTG, GAPDHGGR.GCCATGAGTAG.

Cell lines constructed in this manner were treated with RSL1 to compare cell viability in each case. Each cell was placed in a 48 well plate and treated with RSL1 after 24 hours, and survival rate was determined by crystal violet assay after 2-4 days (FIG. 7). Three wells were used for each sample, and the survival rate of the other samples was converted to 100% cell viability of the HV sample cultured for 2 days without RSL1 treatment.

Example 7 Methods for Searching for Genes That Inhibit Cytotoxicity of LRRK2 G2019S

After MN9D cell line stably expressing the G2019S gene in a 100 mm dish, and transformed with a 4: 1 mixture of cDNA library of human gene and plasmid with GFP (green fluorescence protein) gene one day later and transformed together in Example 6 Promote cell death according to established conditions. At this time, antibiotic resistance markers of GFP and gene library plasmids are used as kanamycin and ampicillin, respectively. Transformed cells from the remaining cells are separated by FACS (fluorecence-activated cell sorting) to separate total genomic DNA including plasmids from these cells.

To amplify the gene library, the isolated plasmid is transformed into Escherichia coli and cultured by treating ampicillin, which is a condition for amplifying only the gene library and not GFP. Mix the colonies after one day together to separate the plasmid library.

These plasmid library DNAs are transformed back into the MN9D cell line stably expressing the prepared G2019S gene, and the method is repeated to isolate the gene plasmid from the remaining cells and amplify it in E. coli. After 5-10 times of this screening, specific genes that reduce G2019S toxicity are amplified.

At this time, instead of FACS using GFP plasmid, cell separation by magnetic field may be used by using plasmid using MACS (magnetic-activated cell sorting). In addition, instead of the MN9D cell line stably expressing the G2019S gene, a plasmid expressing G2019S may be temporarily transformed into a SN4741 cell line like a gene library. Through this method, when apoptosis of the G2019S expressing cell line transformed by the gene plasmid combination is sufficiently higher than that of the G2019S expressing cell line transformed with the control vector without the gene, each of the E. coli strains is determined. Separate the plasmids from the colonies, respectively. Using the G2019S-expressing cell line on the isolated plasmid in a 48 well plate, apoptosis was compared with the case of transforming the control vector with the same method for each plasmid. If the isolated gene plasmid is transformed and there is a significant difference in survival rate from that of the control plasmid, the gene is sequenced to identify the gene. In addition, if a siRNA library preselected for a specific gene is available instead of a gene library, the library may be transformed into stable cell lines pre-populated with 96 wells to directly detect siRNAs that inhibit apoptosis through crystal violet assay. It may be.

Example 8 Methods for Searching for Compounds That Inhibit Cytotoxicity of LRRK2 G2019S

As in Example 7, the cell line is grown, and instead of the gene library, the compound library to be searched is treated one by one, and then the cell death degree is compared with that of the control group to select a compound having a significant difference.

To verify this example, an ERK (extraccellular signal-regulated kinase) inhibitor (Liou et al. 2008) reported as a compound that inhibits apoptosis by G2019S of LRRK2 was used. As shown in FIG. 8, the sample treated with ERK inhibitor PD98059 (Calbiochem Co., California, USA) expressing G2019S and treated with hydrogen peroxide showed higher cell viability as compared to the sample without ERK inhibitor treatment, as well as G2019S. Compared to the control vectors that did not express the expression of the control vector, the survival rate was slightly higher or nearly similar to that of the ERK inhibitor, indicating that the G2019S and the hydrogen peroxide-induced SN4741 cytotoxicity. However, since ERK inhibitor is not LRRK2 but its ERK is involved in various signaling circuits of cells, it cannot be a specific compound for treating Parkinson's disease. In fact, in the case of transforming only the control vector, treatment with hydrogen peroxide showed that ERK inhibitor treatment further promoted cell death.

In FIG. 8, 48 μl of LRRK2 wild species or plasmid expressing G2019S protein or control vector plasmid was transformed into SN4741 cell line, and then treated with 100 μM of hydrogen peroxide for 24 hours and subjected to crystal violet assay. ERK inhibitor PD98059 (Calbiochem Co., USA) was treated with 5 μM one hour before hydrogen peroxide treatment, and the result of crystal violet assay was 100% when the control plasmid was not treated with hydrogen peroxide. Converted. Three wells were used for each sample.

The specific parts of the present invention have been described in detail above, and it is apparent to those skilled in the art that such specific descriptions are merely preferred embodiments, and thus the scope of the present invention is not limited thereto. something to do. Thus, the substantial scope of the present invention will be defined by the appended claims and their equivalents.

references

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Gasser, T. (2007). "Update on the genetics of Parkinson's disease." Mov Disord 22 Suppl 17: S343-S350.

Healy, DG, M. Falchi, et al. (2008). "Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study." Lancet Neurol 7: 583-590.

Lewthwaite, AJ and DJ Nicholl (2005). "Genetics of parkinsonism." Curr Neurol Neurosci Rep 5: 397-404.

Liou A. K ,, RK Leak, et al. (2008) "Wild-type LRRK2 but not its mutant attenuates stress-induced cell death via ERK pathway." Neurobiol Dis . 32: 116-124.

Mata, IF, WJ Wedemeyer, et al. (2006). "LRRK2 in Parkinson's disease: protein domains and functional insights." Trends Neurosci 29: 286-293.

Macleod D, J. Dowman, et al. (2006). "The familial Parkinsonism gene LRRK2 regulates neurite process morphology." Neuron 52: 587-593.

Moore, DJ, AB West, et al. (2005). "Molecular pathophysiology of Parkinson's disease." Annu Rev Neurosci 28: 57-87.

Oh, YJ, SC Wong, et al. (1995). "Overexpression of Bcl-2 attenuates MPP +, but not 6-ODHA, induced cell death in a dopaminergic neuronal cell line." Neurobiol Dis 2: 157-167.

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Figure 1 shows a domain diagram according to the function of the LRRK2 protein consisting of 2527 amino acids. Mutations found in Parkinson's disease patients are indicated. LRR: leucine rich repeat, Roc: Ras of complex, COR: C-terminal of Roc, MAPKKK: mitogen-activated protein kinase kinase kinase.

Figure 2 shows the expression pattern of GFP protein of the SN4741 cell line transformed with green fluorescence protein (GFP).

Figure 3 shows the survival rate of SN4741 cells expressing LRRK2 mutant protein and wild species and treated with hydrogen peroxide.

Figure 4 shows the optimization conditions for maximizing the difference in toxicity with or without overexpression of LRRK2 protein in the hydrogen peroxide treatment conditions.

Figure 5 shows the LRRK2 expression of the MN9D cell line stably expressing the LRRK2 wild species and G2019S protein.

Figure 6 confirms the LRRK2 mRNA transcribed from the plasmid inserted into the constructed stable cell line by reverse transcription (RT) -PCR.

Figure 7 shows the results of treating the RSL1 with 500 nM after 24 hours in a stable cell line expressing LRRK2 protein in 1 x 10 ⁵ cells / well on a 48 well plate.

8 shows that after transforming the plasmid expressing the LRRK2 wild species or the G2019S protein or the control vector plasmid into the SN4741 cell line, ERK inhibitor PD98059 was treated with 5 μM after 47 hours, and 100 μM of hydrogen peroxide was treated for 24 hours after 1 hour. The results of the crystal violet assay are shown.

<110> Inje University Industry-Academic Cooperation Foundation <120> Methods to screen materials to inhibit Parkinson's disease <160> 10 <170> KopatentIn 1.71 <210> 1 <211> 7584 <212> DNA <213> Homo sapiens <400> 1 atggctagtg gcagctgtca ggggtgcgaa gaggacgagg aaactctgaa gaagttgata 60 gtcaggctga acaatgtcca ggaaggaaaa cagatagaaa cgctggtcca aatcctggag 120 gatctgctgg tgttcacgta ctccgagcac gcctccaagt tatttcaagg caaaaatatc 180 catgtgcctc tgttgatcgt cttggactcc tatatgagag tcgcgagtgt gcagcaggtg 240 ggttggtcac ttctgtgcaa attaatagaa gtctgtccag gtacaatgca aagcttaatg 300 ggaccccagg atgttggaaa tgattgggaa gtccttggtg ttcaccaatt gattcttaaa 360 atgctaacag ttcataatgc cagtgtaaac ttgtcagtga ttggactgaa gaccttagat 420 ctcctcctaa cttcaggtaa aatcaccttg ctgatactgg atgaagaaag tgatattttc 480 atgttaattt ttgatgccat gcactcattt ccagccaatg atgaagtcca gaaacttgga 540 tgcaaagctt tacatgtgct gtttgagaga gtctcagagg agcaactgac tgaatttgtt 600 gagaacaaag attatatgat attgttaagt gcgtcaacaa attttaaaga tgaagaggaa 660 attgtgcttc atgtgctgca ttgtttacat tccctagcga ttccttgcaa taatgtggaa 720 gtcctcatga gtggcaatgt caggtgttat aatattgtgg tggaagctat gaaagcattc 780 cctatgagtg aaagaattca agaagtgagt tgctgtttgc tccataggct tacattaggt 840 aattttttca atatcctggt attaaacgaa gtccatgagt ttgtggtgaa agctgtgcag 900 cagtacccag agaatgcagc attgcagatc tcagcgctca gctgtttggc cctcctcact 960 gagactattt tcttaaatca agatttagag gaaaagaatg agaatcaaga gaatgatgat 1020 gagggggaag aagataaatt gttttggctg gaagcctgtt acaaagcatt aacgtggcat 1080 agaaagaaca agcacgtgca ggaggccgca tgctgggcac taaataatct ccttatgtac 1140 caaaacagtt tacatgagaa gattggagat gaagatggcc atttcccagc tcatagggaa 1200 gtgatgctct ccatgctgat gcattcttca tcaaaggaag ttttccaggc atctgcgaat 1260 gcattgtcaa ctctcttaga acaaaatgtt aatttcagaa aaatactgtt atcaaaagga 1320 atacacctga atgttttgga gttaatgcag aagcatatac attctcctga agtggctgaa 1380 agtggctgta aaatgctaaa tcatcttttt gaaggaagca acacttccct ggatataatg 1440 gcagcagtgg tccccaaaat actaacagtt atgaaacgtc atgagacatc attaccagtg 1500 cagctggagg cgcttcgagc tattttacat tttatagtgc ctggcatgcc agaagaatcc 1560 agggaggata cagaatttca tcataagcta aatatggtta aaaaacagtg tttcaagaat 1620 gatattcaca aactggtcct agcagctttg aacaggttca ttggaaatcc tgggattcag 1680 aaatgtggat taaaagtaat ttcttctatt gtacattttc ctgatgcatt agagatgtta 1740 tccctggaag gtgctatgga ttcagtgctt cacacactgc agatgtatcc agatgaccaa 1800 gaaattcagt gtctgggttt aagtcttata ggatacttga ttacaaagaa gaatgtgttc 1860 ataggaactg gacatctgct ggcaaaaatt ctggtttcca gcttataccg atttaaggat 1920 gttgctgaaa tacagactaa aggatttcag acaatcttag caatcctcaa attgtcagca 1980 tctttttcta agctgctggt gcatcattca tttgacttag taatattcca tcaaatgtct 2040 tccaatatca tggaacaaaa ggatcaacag tttctaaacc tctgttgcaa gtgttttgca 2100 aaagtagcta tggatgatta cttaaaaaat gtgatgctag agagagcgtg tgatcagaat 2160 aacagcatca tggttgaatg cttgcttcta ttgggagcag atgccaatca agcaaaggag 2220 ggatcttctt taatttgtca ggtatgtgag aaagagagca gtcccaaatt ggtggaactc 2280 ttactgaata gtggatctcg tgaacaagat gtacgaaaag cgttgacgat aagcattggg 2340 aaaggtgaca gccagatcat cagcttgctc ttaaggaggc tggccctgga tgtggccaac 2400 aatagcattt gccttggagg attttgtata ggaaaagttg aaccttcttg gcttggtcct 2460 ttatttccag ataagacttc taatttaagg aaacaaacaa atatagcatc tacactagca 2520 agaatggtga tcagatatca gatgaaaagt gctgtggaag aaggaacagc ctcaggcagc 2580 gatggaaatt tttctgaaga tgtgctgtct aaatttgatg aatggacctt tattcctgac 2640 tcttctatgg acagtgtgtt tgctcaaagt gatgacctgg atagtgaagg aagtgaaggc 2700 tcatttcttg tgaaaaagaa atctaattca attagtgtag gagaatttta ccgagatgcc 2760 gtattacagc gttgctcacc aaatttgcaa agacattcca attccttggg gcccattttt 2820 gatcatgaag atttactgaa gcgaaaaaga aaaatactat cttcagatga ttcactcagg 2880 tcatcaaaac ttcaatccca tatgaggcat tcagacagca tttcttctct ggcttctgag 2940 agagaatata ttacatcact agacctttca gcaaatgaac taagagatat tgatgcccta 3000 agccagaaat gctgtataag tgttcatttg gagcatcttg aaaagctgga gcttcaccag 3060 aatgcactca cgagctttcc acaacagcta tgtgaaactc tgaagagttt gacacatttg 3120 gacttgcaca gtaataaatt tacatcattt ccttcttatt tgttgaaaat gagttgtatt 3180 gctaatcttg atgtctctcg aaatgacatt ggaccctcag tggttttaga tcctacagtg 3240 aaatgtccaa ctctgaaaca gtttaacctg tcatataacc agctgtcttt tgtacctgag 3300 aacctcactg atgtggtaga gaaactggag cagctcattt tagaaggaaa taaaatatca 3360 gggatatgct cccccttgag actgaaggaa ctgaagattt taaaccttag taagaaccac 3420 atttcatccc tatcagagaa ctttcttgag gcttgtccta aagtggagag tttcagtgcc 3480 agaatgaatt ttcttgctgc tatgcctttc ttgcctcctt ctatgacaat cctaaaatta 3540 tctcagaaca aattttcctg tattccagaa gcaattttaa atcttccaca cttgcggtct 3600 ttagatatga gcagcaatga tattcagtac ctaccaggtc ccgcacactg gaaatctttg 3660 aacttaaggg aactcttatt tagccataat cagatcagca tcttggactt gagtgaaaaa 3720 gcatatttat ggtctagagt agagaaactg catctttctc acaataaact gaaagagatt 3780 cctcctgaga ttggctgtct tgaaaatctg acatctctgg atgtcagtta caacttggaa 3840 ctaagatcct ttcccaatga aatggggaaa ttaagcaaaa tatgggatct tcctttggat 3900 gaactgcatc ttaactttga ttttaaacat ataggatgta aagccaaaga catcataagg 3960 tttcttcaac agcgattaaa aaaggctgtg ccttataacc gaatgaaact tatgattgtg 4020 ggaaatactg ggagtggtaa aaccacctta ttgcagcaat taatgaaaac caagaaatca 4080 gatcttggaa tgcaaagtgc cacagttggc atagatgtga aagactggcc tatccaaata 4140 agagacaaaa gaaagagaga tctcgtccta aatgtgtggg attttgcagg tcgtgaggaa 4200 ttctatagta ctcatcccca ttttatgacg cagcgagcat tgtaccttgc tgtctatgac 4260 ctcagcaagg gacaggctga agttgatgcc atgaagcctt ggctcttcaa tataaaggct 4320 cgcgcttctt cttcccctgt gattctcgtt ggcacacatt tggatgtttc tgatgagaag 4380 caacgcaaag cctgcatgag taaaatcacc aaggaactcc tgaataagcg agggttccct 4440 gccatacgag attaccactt tgtgaatgcc accgaggaat ctgatgcttt ggcaaaactt 4500 cggaaaacca tcataaacga gagccttaat ttcaagatcc gagatcagct tgttgttgga 4560 cagctgattc cagactgcta tgtagaactt gaaaaaatca ttttatcgga gcgtaaaaat 4620 gtgccaattg aatttcccgt aattgaccgg aaacgattat tacaactagt gagagaaaat 4680 cagctgcagt tagatgaaaa tgagcttcct cacgcagttc actttctaaa tgaatcagga 4740 gtccttcttc attttcaaga cccagcactg cagttaagtg acttgtactt tgtggaaccc 4800 aagtggcttt gtaaaatcat ggcacagatt ttgacagtga aagtggaagg ttgtccaaaa 4860 caccctaagg gcattatttc gcgtagagat gtggaaaaat ttctttcaaa aaaaaggaaa 4920 tttccaaaga actacatgtc acagtatttt aagctcctag aaaaattcca gattgctttg 4980 ccaataggag aagaatattt gctggttcca agcagtttgt ctgaccacag gcctgtgata 5040 gagcttcccc attgtgagaa ctctgaaatt atcatccgac tatatgaaat gccttatttt 5100 ccaatgggat tttggtcaag attaatcaat cgattacttg agatttcacc ttacatgctt 5160 tcagggagag aacgagcact tcgcccaaac agaatgtatt ggcgacaagg catttactta 5220 aattggtctc ctgaagctta ttgtctggta ggatctgaag tcttagacaa tcatccagag 5280 agtttcttaa aaattacagt tccttcttgt agaaaaggct gtattctttt gggccaagtt 5340 gtggaccaca ttgattctct catggaagaa tggtttcctg ggttgctgga gattgatatt 5400 tgtggtgaag gagaaactct gttgaagaaa tgggcattat atagttttaa tgatggcgaa 5460 gaacatcaaa aaatcttact tgatgacttg atgaagaaag cagaggaagg agatctctta 5520 gtaaatccag atcaaccaag gctcaccatt ccaatatctc agattgcccc tgacttgatt 5580 ttggctgacc tgcctagaaa tattatgttg aataatgatg agttggaatt tgaacaagct 5640 ccagagtttc tcctaggtga tggcagtttt ggatcagttt accgagcagc ctatgaagga 5700 gaagaagtgg ctgtgaagat ttttaataaa catacatcac tcaggctgtt aagacaagag 5760 cttgtggtgc tttgccacct ccaccacccc agtttgatat ctttgctggc agctgggatt 5820 cgtccccgga tgttggtgat ggagttagcc tccaagggtt ccttggatcg cctgcttcag 5880 caggacaaag ccagcctcac tagaacccta cagcacagga ttgcactcca cgtagctgat 5940 ggtttgagat acctccactc agccatgatt atataccgag acctgaaacc ccacaatgtg 6000 ctgcttttca cactgtatcc caatgctgcc atcattgcaa agattgctga ctacagcatt 6060 gctcagtact gctgtagaat ggggataaaa acatcagagg gcacaccagg gtttcgtgca 6120 cctgaagttg ccagaggaaa tgtcatttat aaccaacagg ctgatgttta ttcatttggt 6180 ttactactct atgacatttt gacaactgga ggtagaatag tagagggttt gaagtttcca 6240 aatgagtttg atgaattaga aatacaagga aaattacctg atccagttaa agaatatggt 6300 tgtgccccat ggcctatggt tgagaaatta attaaacagt gtttgaaaga aaatcctcaa 6360 gaaaggccta cttctgccca ggtctttgac attttgaatt cagctgaatt agtctgtctg 6420 acgagacgca ttttattacc taaaaacgta attgttgaat gcatggttgc tacacatcac 6480 aacagcagga atgcaagcat ttggctgggc tgtgggcaca ccgacagagg acagctctca 6540 tttcttgact taaatactga aggatacact tctgaggaag ttgctgatag tagaatattg 6600 tgcttagcct tggtgcatct tcctgttgaa aaggaaagct ggattgtgtc tgggacacag 6660 tctggtactc tcctggtcat caataccgaa gatgggaaaa agagacatac cctagaaaag 6720 atgactgatt ctgtcacttg tttgtattgc aattcctttt ccaagcaaag caaacaaaaa 6780 aattttcttt tggttggaac cgctgatggc aagttagcaa tttttgaaga taagactgtt 6840 aagcttaaag gagctgctcc tttgaagata ctaaatatag gaaatgtcag tactccattg 6900 atgtgtttga gtgaatccac aaattcaacg gaaagaaatg taatgtgggg aggatgtggc 6960 acaaagattt tctccttttc taatgatttc accattcaga aactcattga gacaagaaca 7020 agccaactgt tttcttatgc agctttcagt gattccaaca tcataacagt ggtggtagac 7080 actgctctct atattgctaa gcaaaatagc cctgttgtgg aagtgtggga taagaaaact 7140 gaaaaactct gtggactaat agactgcgtg cactttttaa gggaggtaat ggtaaaagaa 7200 aacaaggaat caaaacacaa aatgtcttat tctgggagag tgaaaaccct ctgccttcag 7260 aagaacactg ctctttggat aggaactgga ggaggccata ttttactcct ggatctttca 7320 actcgtcgac ttatacgtgt aatttacaac ttttgtaatt cggtcagagt catgatgaca 7380 gcacagctag gaagccttaa aaatgtcatg ctggtattgg gctacaaccg gaaaaatact 7440 gaaggtacac aaaagcagaa agagatacaa tcttgcttga ccgtttggga catcaatctt 7500 ccacatgaag tgcaaaattt agaaaaacac attgaagtga gaaaagaatt agctgaaaaa 7560 atgagacgaa catctgttga gtaa 7584 <210> 2 <211> 2527 <212> PRT <213> Homo sapiens <400> 2 Met Ala Ser Gly Ser Cys Gln Gly Cys Glu Glu Asp Glu Glu Thr Leu   1 5 10 15 Lys Lys Leu Ile Val Arg Leu Asn Asn Val Gln Glu Gly Lys Gln Ile              20 25 30 Glu Thr Leu Val Gln Ile Leu Glu Asp Leu Leu Val Phe Thr Tyr Ser          35 40 45 Glu His Ala Ser Lys Leu Phe Gln Gly Lys Asn Ile His Val Pro Leu      50 55 60 Leu Ile Val Leu Asp Ser Tyr Met Arg Val Ala Ser Val Gln Gln Val  65 70 75 80 Gly Trp Ser Leu Leu Cys Lys Leu Ile Glu Val Cys Pro Gly Thr Met                  85 90 95 Gln Ser Leu Met Gly Pro Gln Asp Val Gly Asn Asp Trp Glu Val Leu             100 105 110 Gly Val His Gln Leu Ile Leu Lys Met Leu Thr Val His Asn Ala Ser         115 120 125 Val Asn Leu Ser Val Ile Gly Leu Lys Thr Leu Asp Leu Leu Leu Thr     130 135 140 Ser Gly Lys Ile Thr Leu Leu Ile Leu Asp Glu Glu Ser Asp Ile Phe 145 150 155 160 Met Leu Ile Phe Asp Ala Met His Ser Phe Pro Ala Asn Asp Glu Val                 165 170 175 Gln Lys Leu Gly Cys Lys Ala Leu His Val Leu Phe Glu Arg Val Ser             180 185 190 Glu Glu Gln Leu Thr Glu Phe Val Glu Asn Lys Asp Tyr Met Ile Leu         195 200 205 Leu Ser Ala Leu Thr Asn Phe Lys Asp Glu Glu Glu Ile Val Leu His     210 215 220 Val Leu His Cys Leu His Ser Leu Ala Ile Pro Cys Asn Asn Val Glu 225 230 235 240 Val Leu Met Ser Gly Asn Val Arg Cys Tyr Asn Ile Val Val Glu Ala                 245 250 255 Met Lys Ala Phe Pro Met Ser Glu Arg Ile Gln Glu Val Ser Cys Cys             260 265 270 Leu Leu His Arg Leu Thr Leu Gly Asn Phe Phe Asn Ile Leu Val Leu         275 280 285 Asn Glu Val His Glu Phe Val Val Lys Ala Val Gln Gln Tyr Pro Glu     290 295 300 Asn Ala Ala Leu Gln Ile Ser Ala Leu Ser Cys Leu Ala Leu Leu Thr 305 310 315 320 Glu Thr Ile Phe Leu Asn Gln Asp Leu Glu Glu Lys Asn Glu Asn Gln                 325 330 335 Glu Asn Asp Asp Glu Gly Glu Glu Asp Lys Leu Phe Trp Leu Glu Ala             340 345 350 Cys Tyr Lys Ala Leu Thr Trp His Arg Lys Asn Lys His Val Gln Glu         355 360 365 Ala Ala Cys Trp Ala Leu Asn Asn Leu Leu Met Tyr Gln Asn Ser Leu     370 375 380 His Glu Lys Ile Gly Asp Glu Asp Gly His Phe Pro Ala His Arg Glu 385 390 395 400 Val Met Leu Ser Met Leu Met His Ser Ser Ser Lys Glu Val Phe Gln                 405 410 415 Ala Ser Ala Asn Ala Leu Ser Thr Leu Leu Glu Gln Asn Val Asn Phe             420 425 430 Arg Lys Ile Leu Leu Ser Lys Gly Ile His Leu Asn Val Leu Glu Leu         435 440 445 Met Gln Lys His Ile His Ser Pro Glu Val Ala Glu Ser Gly Cys Lys     450 455 460 Met Leu Asn His Leu Phe Glu Gly Ser Asn Thr Ser Leu Asp Ile Met 465 470 475 480 Ala Ala Val Val Pro Lys Ile Leu Thr Val Met Lys Arg His Glu Thr                 485 490 495 Ser Leu Pro Val Gln Leu Glu Ala Leu Arg Ala Ile Leu His Phe Ile             500 505 510 Val Pro Gly Met Pro Glu Glu Ser Arg Glu Asp Thr Glu Phe His His         515 520 525 Lys Leu Asn Met Val Lys Lys Gln Cys Phe Lys Asn Asp Ile His Lys     530 535 540 Leu Val Leu Ala Ala Leu Asn Arg Phe Ile Gly Asn Pro Gly Ile Gln 545 550 555 560 Lys Cys Gly Leu Lys Val Ile Ser Ser Ile Val His Phe Pro Asp Ala                 565 570 575 Leu Glu Met Leu Ser Leu Glu Gly Ala Met Asp Ser Val Leu His Thr             580 585 590 Leu Gln Met Tyr Pro Asp Asp Gln Glu Ile Gln Cys Leu Gly Leu Ser         595 600 605 Leu Ile Gly Tyr Leu Ile Thr Lys Lys Asn Val Phe Ile Gly Thr Gly     610 615 620 His Leu Leu Ala Lys Ile Leu Val Ser Ser Leu Tyr Arg Phe Lys Asp 625 630 635 640 Val Ala Glu Ile Gln Thr Lys Gly Phe Gln Thr Ile Leu Ala Ile Leu                 645 650 655 Lys Leu Ser Ala Ser Phe Ser Lys Leu Leu Val His His Ser Phe Asp             660 665 670 Leu Val Ile Phe His Gln Met Ser Ser Asn Ile Met Glu Gln Lys Asp         675 680 685 Gln Gln Phe Leu Asn Leu Cys Cys Lys Cys Phe Ala Lys Val Ala Met     690 695 700 Asp Asp Tyr Leu Lys Asn Val Met Leu Glu Arg Ala Cys Asp Gln Asn 705 710 715 720 Asn Ser Ile Met Val Glu Cys Leu Leu Leu Leu Gly Ala Asp Ala Asn                 725 730 735 Gln Ala Lys Glu Gly Ser Ser Leu Ile Cys Gln Val Cys Glu Lys Glu             740 745 750 Ser Ser Pro Lys Leu Val Glu Leu Leu Leu Asn Ser Gly Ser Arg Glu         755 760 765 Gln Asp Val Arg Lys Ala Leu Thr Ile Ser Ile Gly Lys Gly Asp Ser     770 775 780 Gln Ile Ile Ser Leu Leu Leu Arg Arg Leu Ala Leu Asp Val Ala Asn 785 790 795 800 Asn Ser Ile Cys Leu Gly Gly Phe Cys Ile Gly Lys Val Glu Pro Ser                 805 810 815 Trp Leu Gly Pro Leu Phe Pro Asp Lys Thr Ser Asn Leu Arg Lys Gln             820 825 830 Thr Asn Ile Ala Ser Thr Leu Ala Arg Met Val Ile Arg Tyr Gln Met         835 840 845 Lys Ser Ala Val Glu Glu Gly Thr Ala Ser Gly Ser Asp Gly Asn Phe     850 855 860 Ser Glu Asp Val Leu Ser Lys Phe Asp Glu Trp Thr Phe Ile Pro Asp 865 870 875 880 Ser Ser Met Asp Ser Val Phe Ala Gln Ser Asp Asp Leu Asp Ser Glu                 885 890 895 Gly Ser Glu Gly Ser Phe Leu Val Lys Lys Lys Ser Asn Ser Ile Ser             900 905 910 Val Gly Glu Phe Tyr Arg Asp Ala Val Leu Gln Arg Cys Ser Pro Asn         915 920 925 Leu Gln Arg His Ser Asn Ser Leu Gly Pro Ile Phe Asp His Glu Asp     930 935 940 Leu Leu Lys Arg Lys Arg Lys Ile Leu Ser Ser Asp Asp Ser Leu Arg 945 950 955 960 Ser Ser Lys Leu Gln Ser His Met Arg His Ser Asp Ser Ile Ser Ser                 965 970 975 Leu Ala Ser Glu Arg Glu Tyr Ile Thr Ser Leu Asp Leu Ser Ala Asn             980 985 990 Glu Leu Arg Asp Ile Asp Ala Leu Ser Gln Lys Cys Cys Ile Ser Val         995 1000 1005 His Leu Glu His Leu Glu Lys Leu Glu Leu His Gln Asn Ala Leu Thr    1010 1015 1020 Ser Phe Pro Gln Gln Leu Cys Glu Thr Leu Lys Ser Leu Thr His Leu 1025 1030 1035 1040 Asp Leu His Ser Asn Lys Phe Thr Ser Phe Pro Ser Tyr Leu Leu Lys                1045 1050 1055 Met Ser Cys Ile Ala Asn Leu Asp Val Ser Arg Asn Asp Ile Gly Pro            1060 1065 1070 Ser Val Val Leu Asp Pro Thr Val Lys Cys Pro Thr Leu Lys Gln Phe        1075 1080 1085 Asn Leu Ser Tyr Asn Gln Leu Ser Phe Val Pro Glu Asn Leu Thr Asp    1090 1095 1100 Val Val Glu Lys Leu Glu Gln Leu Ile Leu Glu Gly Asn Lys Ile Ser 1105 1110 1115 1120 Gly Ile Cys Ser Pro Leu Arg Leu Lys Glu Leu Lys Ile Leu Asn Leu                1125 1130 1135 Ser Lys Asn His Ile Ser Ser Leu Ser Glu Asn Phe Leu Glu Ala Cys            1140 1145 1150 Pro Lys Val Glu Ser Phe Ser Ala Arg Met Asn Phe Leu Ala Ala Met        1155 1160 1165 Pro Phe Leu Pro Pro Ser Met Thr Ile Leu Lys Leu Ser Gln Asn Lys    1170 1175 1180 Phe Ser Cys Ile Pro Glu Ala Ile Leu Asn Leu Pro His Leu Arg Ser 1185 1190 1195 1200 Leu Asp Met Ser Ser Asn Asp Ile Gln Tyr Leu Pro Gly Pro Ala His                1205 1210 1215 Trp Lys Ser Leu Asn Leu Arg Glu Leu Leu Phe Ser His Asn Gln Ile            1220 1225 1230 Ser Ile Leu Asp Leu Ser Glu Lys Ala Tyr Leu Trp Ser Arg Val Glu        1235 1240 1245 Lys Leu His Leu Ser His Asn Lys Leu Lys Glu Ile Pro Pro Glu Ile    1250 1255 1260 Gly Cys Leu Glu Asn Leu Thr Ser Leu Asp Val Ser Tyr Asn Leu Glu 1265 1270 1275 1280 Leu Arg Ser Phe Pro Asn Glu Met Gly Lys Leu Ser Lys Ile Trp Asp                1285 1290 1295 Leu Pro Leu Asp Glu Leu His Leu Asn Phe Asp Phe Lys His Ile Gly            1300 1305 1310 Cys Lys Ala Lys Asp Ile Ile Arg Phe Leu Gln Gln Arg Leu Lys Lys        1315 1320 1325 Ala Val Pro Tyr Asn Arg Met Lys Leu Met Ile Val Gly Asn Thr Gly    1330 1335 1340 Ser Gly Lys Thr Thr Leu Leu Gln Gln Leu Met Lys Thr Lys Lys Ser 1345 1350 1355 1360 Asp Leu Gly Met Gln Ser Ala Thr Val Gly Ile Asp Val Lys Asp Trp                1365 1370 1375 Pro Ile Gln Ile Arg Asp Lys Arg Lys Arg Asp Leu Val Leu Asn Val            1380 1385 1390 Trp Asp Phe Ala Gly Arg Glu Glu Phe Tyr Ser Thr His Pro His Phe        1395 1400 1405 Met Thr Gln Arg Ala Leu Tyr Leu Ala Val Tyr Asp Leu Ser Lys Gly    1410 1415 1420 Gln Ala Glu Val Asp Ala Met Lys Pro Trp Leu Phe Asn Ile Lys Ala 1425 1430 1435 1440 Arg Ala Ser Ser Ser Pro Val Ile Leu Val Gly Thr His Leu Asp Val                1445 1450 1455 Ser Asp Glu Lys Gln Arg Lys Ala Cys Met Ser Lys Ile Thr Lys Glu            1460 1465 1470 Leu Leu Asn Lys Arg Gly Phe Pro Ala Ile Arg Asp Tyr His Phe Val        1475 1480 1485 Asn Ala Thr Glu Glu Ser Asp Ala Leu Ala Lys Leu Arg Lys Thr Ile    1490 1495 1500 Ile Asn Glu Ser Leu Asn Phe Lys Ile Arg Asp Gln Leu Val Val Gly 1505 1510 1515 1520 Gln Leu Ile Pro Asp Cys Tyr Val Glu Leu Glu Lys Ile Ile Leu Ser                1525 1530 1535 Glu Arg Lys Asn Val Pro Ile Glu Phe Pro Val Ile Asp Arg Lys Arg            1540 1545 1550 Leu Leu Gln Leu Val Arg Glu Asn Gln Leu Gln Leu Asp Glu Asn Glu        1555 1560 1565 Leu Pro His Ala Val His Phe Leu Asn Glu Ser Gly Val Leu Leu His    1570 1575 1580 Phe Gln Asp Pro Ala Leu Gln Leu Ser Asp Leu Tyr Phe Val Glu Pro 1585 1590 1595 1600 Lys Trp Leu Cys Lys Ile Met Ala Gln Ile Leu Thr Val Lys Val Glu                1605 1610 1615 Gly Cys Pro Lys His Pro Lys Gly Ile Ile Ser Arg Arg Asp Val Glu            1620 1625 1630 Lys Phe Leu Ser Lys Lys Arg Lys Phe Pro Lys Asn Tyr Met Ser Gln        1635 1640 1645 Tyr Phe Lys Leu Leu Glu Lys Phe Gln Ile Ala Leu Pro Ile Gly Glu    1650 1655 1660 Glu Tyr Leu Leu Val Pro Ser Ser Leu Ser Asp His Arg Pro Val Ile 1665 1670 1675 1680 Glu Leu Pro His Cys Glu Asn Ser Glu Ile Ile Ile Arg Leu Tyr Glu                1685 1690 1695 Met Pro Tyr Phe Pro Met Gly Phe Trp Ser Arg Leu Ile Asn Arg Leu            1700 1705 1710 Leu Glu Ile Ser Pro Tyr Met Leu Ser Gly Arg Glu Arg Ala Leu Arg        1715 1720 1725 Pro Asn Arg Met Tyr Trp Arg Gln Gly Ile Tyr Leu Asn Trp Ser Pro    1730 1735 1740 Glu Ala Tyr Cys Leu Val Gly Ser Glu Val Leu Asp Asn His Pro Glu 1745 1750 1755 1760 Ser Phe Leu Lys Ile Thr Val Pro Ser Cys Arg Lys Gly Cys Ile Leu                1765 1770 1775 Leu Gly Gln Val Val Asp His Ile Asp Ser Leu Met Glu Glu Trp Phe            1780 1785 1790 Pro Gly Leu Leu Glu Ile Asp Ile Cys Gly Glu Gly Glu Thr Leu Leu        1795 1800 1805 Lys Lys Trp Ala Leu Tyr Ser Phe Asn Asp Gly Glu Glu His Gln Lys    1810 1815 1820 Ile Leu Leu Asp Asp Leu Met Lys Lys Ala Glu Glu Gly Asp Leu Leu 1825 1830 1835 1840 Val Asn Pro Asp Gln Pro Arg Leu Thr Ile Pro Ile Ser Gln Ile Ala                1845 1850 1855 Pro Asp Leu Ile Leu Ala Asp Leu Pro Arg Asn Ile Met Leu Asn Asn            1860 1865 1870 Asp Glu Leu Glu Phe Glu Gln Ala Pro Glu Phe Leu Leu Gly Asp Gly        1875 1880 1885 Ser Phe Gly Ser Val Tyr Arg Ala Ala Tyr Glu Gly Glu Glu Val Ala    1890 1895 1900 Val Lys Ile Phe Asn Lys His Thr Ser Leu Arg Leu Leu Arg Gln Glu 1905 1910 1915 1920 Leu Val Val Leu Cys His Leu His His Pro Ser Leu Ile Ser Leu Leu                1925 1930 1935 Ala Ala Gly Ile Arg Pro Arg Met Leu Val Met Glu Leu Ala Ser Lys            1940 1945 1950 Gly Ser Leu Asp Arg Leu Leu Gln Gln Asp Lys Ala Ser Leu Thr Arg        1955 1960 1965 Thr Leu Gln His Arg Ile Ala Leu His Val Ala Asp Gly Leu Arg Tyr    1970 1975 1980 Leu His Ser Ala Met Ile Ile Tyr Arg Asp Leu Lys Pro His Asn Val 1985 1990 1995 2000 Leu Leu Phe Thr Leu Tyr Pro Asn Ala Ala Ile Ile Ala Lys Ile Ala                2005 2010 2015 Asp Tyr Ser Ile Ala Gln Tyr Cys Cys Arg Met Gly Ile Lys Thr Ser            2020 2025 2030 Glu Gly Thr Pro Gly Phe Arg Ala Pro Glu Val Ala Arg Gly Asn Val        2035 2040 2045 Ile Tyr Asn Gln Gln Ala Asp Val Tyr Ser Phe Gly Leu Leu Leu Tyr    2050 2055 2060 Asp Ile Leu Thr Thr Gly Gly Arg Ile Val Glu Gly Leu Lys Phe Pro 2065 2070 2075 2080 Asn Glu Phe Asp Glu Leu Glu Ile Gln Gly Lys Leu Pro Asp Pro Val                2085 2090 2095 Lys Glu Tyr Gly Cys Ala Pro Trp Pro Met Val Glu Lys Leu Ile Lys            2100 2105 2110 Gln Cys Leu Lys Glu Asn Pro Gln Glu Arg Pro Thr Ser Ala Gln Val        2115 2120 2125 Phe Asp Ile Leu Asn Ser Ala Glu Leu Val Cys Leu Thr Arg Arg Ile    2130 2135 2140 Leu Leu Pro Lys Asn Val Ile Val Glu Cys Met Val Ala Thr His His 2145 2150 2155 2160 Asn Ser Arg Asn Ala Ser Ile Trp Leu Gly Cys Gly His Thr Asp Arg                2165 2170 2175 Gly Gln Leu Ser Phe Leu Asp Leu Asn Thr Glu Gly Tyr Thr Ser Glu            2180 2185 2190 Glu Val Ala Asp Ser Arg Ile Leu Cys Leu Ala Leu Val His Leu Pro        2195 2200 2205 Val Glu Lys Glu Ser Trp Ile Val Ser Gly Thr Gln Ser Gly Thr Leu    2210 2215 2220 Leu Val Ile Asn Thr Glu Asp Gly Lys Lys Arg His Thr Leu Glu Lys 2225 2230 2235 2240 Met Thr Asp Ser Val Thr Cys Leu Tyr Cys Asn Ser Phe Ser Lys Gln                2245 2250 2255 Ser Lys Gln Lys Asn Phe Leu Leu Val Gly Thr Ala Asp Gly Lys Leu            2260 2265 2270 Ala Ile Phe Glu Asp Lys Thr Val Lys Leu Lys Gly Ala Ala Pro Leu        2275 2280 2285 Lys Ile Leu Asn Ile Gly Asn Val Ser Thr Pro Leu Met Cys Leu Ser    2290 2295 2300 Glu Ser Thr Asn Ser Thr Glu Arg Asn Val Met Trp Gly Gly Cys Gly 2305 2310 2315 2320 Thr Lys Ile Phe Ser Phe Ser Asn Asp Phe Thr Ile Gln Lys Leu Ile                2325 2330 2335 Glu Thr Arg Thr Ser Gln Leu Phe Ser Tyr Ala Ala Phe Ser Asp Ser            2340 2345 2350 Asn Ile Ile Thr Val Val Val Asp Thr Ala Leu Tyr Ile Ala Lys Gln        2355 2360 2365 Asn Ser Pro Val Val Glu Val Trp Asp Lys Lys Thr Glu Lys Leu Cys    2370 2375 2380 Gly Leu Ile Asp Cys Val His Phe Leu Arg Glu Val Met Val Lys Glu 2385 2390 2395 2400 Asn Lys Glu Ser Lys His Lys Met Ser Tyr Ser Gly Arg Val Lys Thr                2405 2410 2415 Leu Cys Leu Gln Lys Asn Thr Ala Leu Trp Ile Gly Thr Gly Gly Gly            2420 2425 2430 His Ile Leu Leu Leu Asp Leu Ser Thr Arg Arg Leu Ile Arg Val Ile        2435 2440 2445 Tyr Asn Phe Cys Asn Ser Val Arg Val Met Met Thr Ala Gln Leu Gly    2450 2455 2460 Ser Leu Lys Asn Val Met Leu Val Leu Gly Tyr Asn Arg Lys Asn Thr 2465 2470 2475 2480 Glu Gly Thr Gln Lys Gln Lys Glu Ile Gln Ser Cys Leu Thr Val Trp                2485 2490 2495 Asp Ile Asn Leu Pro His Glu Val Gln Asn Leu Glu Lys His Ile Glu            2500 2505 2510 Val Arg Lys Glu Leu Ala Glu Lys Met Arg Arg Thr Ser Val Glu        2515 2520 2525 <210> 3 <211> 7584 <212> DNA <213> Homo sapiens <400> 3 atggctagtg gcagctgtca ggggtgcgaa gaggacgagg aaactctgaa gaagttgata 60 gtcaggctga acaatgtcca ggaaggaaaa cagatagaaa cgctggtcca aatcctggag 120 gatctgctgg tgttcacgta ctccgagcac gcctccaagt tatttcaagg caaaaatatc 180 catgtgcctc tgttgatcgt cttggactcc tatatgagag tcgcgagtgt gcagcaggtg 240 ggttggtcac ttctgtgcaa attaatagaa gtctgtccag gtacaatgca aagcttaatg 300 ggaccccagg atgttggaaa tgattgggaa gtccttggtg ttcaccaatt gattcttaaa 360 atgctaacag ttcataatgc cagtgtaaac ttgtcagtga ttggactgaa gaccttagat 420 ctcctcctaa cttcaggtaa aatcaccttg ctgatactgg atgaagaaag tgatattttc 480 atgttaattt ttgatgccat gcactcattt ccagccaatg atgaagtcca gaaacttgga 540 tgcaaagctt tacatgtgct gtttgagaga gtctcagagg agcaactgac tgaatttgtt 600 gagaacaaag attatatgat attgttaagt gcgtcaacaa attttaaaga tgaagaggaa 660 attgtgcttc atgtgctgca ttgtttacat tccctagcga ttccttgcaa taatgtggaa 720 gtcctcatga gtggcaatgt caggtgttat aatattgtgg tggaagctat gaaagcattc 780 cctatgagtg aaagaattca agaagtgagt tgctgtttgc tccataggct tacattaggt 840 aattttttca atatcctggt attaaacgaa gtccatgagt ttgtggtgaa agctgtgcag 900 cagtacccag agaatgcagc attgcagatc tcagcgctca gctgtttggc cctcctcact 960 gagactattt tcttaaatca agatttagag gaaaagaatg agaatcaaga gaatgatgat 1020 gagggggaag aagataaatt gttttggctg gaagcctgtt acaaagcatt aacgtggcat 1080 agaaagaaca agcacgtgca ggaggccgca tgctgggcac taaataatct ccttatgtac 1140 caaaacagtt tacatgagaa gattggagat gaagatggcc atttcccagc tcatagggaa 1200 gtgatgctct ccatgctgat gcattcttca tcaaaggaag ttttccaggc atctgcgaat 1260 gcattgtcaa ctctcttaga acaaaatgtt aatttcagaa aaatactgtt atcaaaagga 1320 atacacctga atgttttgga gttaatgcag aagcatatac attctcctga agtggctgaa 1380 agtggctgta aaatgctaaa tcatcttttt gaaggaagca acacttccct ggatataatg 1440 gcagcagtgg tccccaaaat actaacagtt atgaaacgtc atgagacatc attaccagtg 1500 cagctggagg cgcttcgagc tattttacat tttatagtgc ctggcatgcc agaagaatcc 1560 agggaggata cagaatttca tcataagcta aatatggtta aaaaacagtg tttcaagaat 1620 gatattcaca aactggtcct agcagctttg aacaggttca ttggaaatcc tgggattcag 1680 aaatgtggat taaaagtaat ttcttctatt gtacattttc ctgatgcatt agagatgtta 1740 tccctggaag gtgctatgga ttcagtgctt cacacactgc agatgtatcc agatgaccaa 1800 gaaattcagt gtctgggttt aagtcttata ggatacttga ttacaaagaa gaatgtgttc 1860 ataggaactg gacatctgct ggcaaaaatt ctggtttcca gcttataccg atttaaggat 1920 gttgctgaaa tacagactaa aggatttcag acaatcttag caatcctcaa attgtcagca 1980 tctttttcta agctgctggt gcatcattca tttgacttag taatattcca tcaaatgtct 2040 tccaatatca tggaacaaaa ggatcaacag tttctaaacc tctgttgcaa gtgttttgca 2100 aaagtagcta tggatgatta cttaaaaaat gtgatgctag agagagcgtg tgatcagaat 2160 aacagcatca tggttgaatg cttgcttcta ttgggagcag atgccaatca agcaaaggag 2220 ggatcttctt taatttgtca ggtatgtgag aaagagagca gtcccaaatt ggtggaactc 2280 ttactgaata gtggatctcg tgaacaagat gtacgaaaag cgttgacgat aagcattggg 2340 aaaggtgaca gccagatcat cagcttgctc ttaaggaggc tggccctgga tgtggccaac 2400 aatagcattt gccttggagg attttgtata ggaaaagttg aaccttcttg gcttggtcct 2460 ttatttccag ataagacttc taatttaagg aaacaaacaa atatagcatc tacactagca 2520 agaatggtga tcagatatca gatgaaaagt gctgtggaag aaggaacagc ctcaggcagc 2580 gatggaaatt tttctgaaga tgtgctgtct aaatttgatg aatggacctt tattcctgac 2640 tcttctatgg acagtgtgtt tgctcaaagt gatgacctgg atagtgaagg aagtgaaggc 2700 tcatttcttg tgaaaaagaa atctaattca attagtgtag gagaatttta ccgagatgcc 2760 gtattacagc gttgctcacc aaatttgcaa agacattcca attccttggg gcccattttt 2820 gatcatgaag atttactgaa gcgaaaaaga aaaatactat cttcagatga ttcactcagg 2880 tcatcaaaac ttcaatccca tatgaggcat tcagacagca tttcttctct ggcttctgag 2940 agagaatata ttacatcact agacctttca gcaaatgaac taagagatat tgatgcccta 3000 agccagaaat gctgtataag tgttcatttg gagcatcttg aaaagctgga gcttcaccag 3060 aatgcactca cgagctttcc acaacagcta tgtgaaactc tgaagagttt gacacatttg 3120 gacttgcaca gtaataaatt tacatcattt ccttcttatt tgttgaaaat gagttgtatt 3180 gctaatcttg atgtctctcg aaatgacatt ggaccctcag tggttttaga tcctacagtg 3240 aaatgtccaa ctctgaaaca gtttaacctg tcatataacc agctgtcttt tgtacctgag 3300 aacctcactg atgtggtaga gaaactggag cagctcattt tagaaggaaa taaaatatca 3360 gggatatgct cccccttgag actgaaggaa ctgaagattt taaaccttag taagaaccac 3420 atttcatccc tatcagagaa ctttcttgag gcttgtccta aagtggagag tttcagtgcc 3480 agaatgaatt ttcttgctgc tatgcctttc ttgcctcctt ctatgacaat cctaaaatta 3540 tctcagaaca aattttcctg tattccagaa gcaattttaa atcttccaca cttgcggtct 3600 ttagatatga gcagcaatga tattcagtac ctaccaggtc ccgcacactg gaaatctttg 3660 aacttaaggg aactcttatt tagccataat cagatcagca tcttggactt gagtgaaaaa 3720 gcatatttat ggtctagagt agagaaactg catctttctc acaataaact gaaagagatt 3780 cctcctgaga ttggctgtct tgaaaatctg acatctctgg atgtcagtta caacttggaa 3840 ctaagatcct ttcccaatga aatggggaaa ttaagcaaaa tatgggatct tcctttggat 3900 gaactgcatc ttaactttga ttttaaacat ataggatgta aagccaaaga catcataagg 3960 tttcttcaac agcgattaaa aaaggctgtg ccttataacc gaatgaaact tatgattgtg 4020 ggaaatactg ggagtggtaa aaccacctta ttgcagcaat taatgaaaac caagaaatca 4080 gatcttggaa tgcaaagtgc cacagttggc atagatgtga aagactggcc tatccaaata 4140 agagacaaaa gaaagagaga tctcgtccta aatgtgtggg attttgcagg tcgtgaggaa 4200 ttctatagta ctcatcccca ttttatgacg cagcgagcat tgtaccttgc tgtctatgac 4260 ctcagcaagg gacaggctga agttgatgcc atgaagcctt ggctcttcaa tataaaggct 4320 tgcgcttctt cttcccctgt gattctcgtt ggcacacatt tggatgtttc tgatgagaag 4380 caacgcaaag cctgcatgag taaaatcacc aaggaactcc tgaataagcg agggttccct 4440 gccatacgag attaccactt tgtgaatgcc accgaggaat ctgatgcttt ggcaaaactt 4500 cggaaaacca tcataaacga gagccttaat ttcaagatcc gagatcagct tgttgttgga 4560 cagctgattc cagactgcta tgtagaactt gaaaaaatca ttttatcgga gcgtaaaaat 4620 gtgccaattg aatttcccgt aattgaccgg aaacgattat tacaactagt gagagaaaat 4680 cagctgcagt tagatgaaaa tgagcttcct cacgcagttc actttctaaa tgaatcagga 4740 gtccttcttc attttcaaga cccagcactg cagttaagtg acttgtactt tgtggaaccc 4800 aagtggcttt gtaaaatcat ggcacagatt ttgacagtga aagtggaagg ttgtccaaaa 4860 caccctaagg gcattatttc gcgtagagat gtggaaaaat ttctttcaaa aaaaaggaaa 4920 tttccaaaga actacatgtc acagtatttt aagctcctag aaaaattcca gattgctttg 4980 ccaataggag aagaatattt gctggttcca agcagtttgt ctgaccacag gcctgtgata 5040 gagcttcccc attgtgagaa ctctgaaatt atcatccgac tatatgaaat gccttatttt 5100 ccaatgggat tttggtcaag attaatcaat cgattacttg agatttcacc ttacatgctt 5160 tcagggagag aacgagcact tcgcccaaac agaatgtatt ggcgacaagg catttactta 5220 aattggtctc ctgaagctta ttgtctggta ggatctgaag tcttagacaa tcatccagag 5280 agtttcttaa aaattacagt tccttcttgt agaaaaggct gtattctttt gggccaagtt 5340 gtggaccaca ttgattctct catggaagaa tggtttcctg ggttgctgga gattgatatt 5400 tgtggtgaag gagaaactct gttgaagaaa tgggcattat atagttttaa tgatggcgaa 5460 gaacatcaaa aaatcttact tgatgacttg atgaagaaag cagaggaagg agatctctta 5520 gtaaatccag atcaaccaag gctcaccatt ccaatatctc agattgcccc tgacttgatt 5580 ttggctgacc tgcctagaaa tattatgttg aataatgatg agttggaatt tgaacaagct 5640 ccagagtttc tcctaggtga tggcagtttt ggatcagttt accgagcagc ctatgaagga 5700 gaagaagtgg ctgtgaagat ttttaataaa catacatcac tcaggctgtt aagacaagag 5760 cttgtggtgc tttgccacct ccaccacccc agtttgatat ctttgctggc agctgggatt 5820 cgtccccgga tgttggtgat ggagttagcc tccaagggtt ccttggatcg cctgcttcag 5880 caggacaaag ccagcctcac tagaacccta cagcacagga ttgcactcca cgtagctgat 5940 ggtttgagat acctccactc agccatgatt atataccgag acctgaaacc ccacaatgtg 6000 ctgcttttca cactgtatcc caatgctgcc atcattgcaa agattgctga ctacggcatt 6060 gctcagtact gctgtagaat ggggataaaa acatcagagg gcacaccagg gtttcgtgca 6120 cctgaagttg ccagaggaaa tgtcatttat aaccaacagg ctgatgttta ttcatttggt 6180 ttactactct atgacatttt gacaactgga ggtagaatag tagagggttt gaagtttcca 6240 aatgagtttg atgaattaga aatacaagga aaattacctg atccagttaa agaatatggt 6300 tgtgccccat ggcctatggt tgagaaatta attaaacagt gtttgaaaga aaatcctcaa 6360 gaaaggccta cttctgccca ggtctttgac attttgaatt cagctgaatt agtctgtctg 6420 acgagacgca ttttattacc taaaaacgta attgttgaat gcatggttgc tacacatcac 6480 aacagcagga atgcaagcat ttggctgggc tgtgggcaca ccgacagagg acagctctca 6540 tttcttgact taaatactga aggatacact tctgaggaag ttgctgatag tagaatattg 6600 tgcttagcct tggtgcatct tcctgttgaa aaggaaagct ggattgtgtc tgggacacag 6660 tctggtactc tcctggtcat caataccgaa gatgggaaaa agagacatac cctagaaaag 6720 atgactgatt ctgtcacttg tttgtattgc aattcctttt ccaagcaaag caaacaaaaa 6780 aattttcttt tggttggaac cgctgatggc aagttagcaa tttttgaaga taagactgtt 6840 aagcttaaag gagctgctcc tttgaagata ctaaatatag gaaatgtcag tactccattg 6900 atgtgtttga gtgaatccac aaattcaacg gaaagaaatg taatgtgggg aggatgtggc 6960 acaaagattt tctccttttc taatgatttc accattcaga aactcattga gacaagaaca 7020 agccaactgt tttcttatgc agctttcagt gattccaaca tcataacagt ggtggtagac 7080 actgctctct atattgctaa gcaaaatagc cctgttgtgg aagtgtggga taagaaaact 7140 gaaaaactct gtggactaat agactgcgtg cactttttaa gggaggtaat ggtaaaagaa 7200 aacaaggaat caaaacacaa aatgtcttat tctgggagag tgaaaaccct ctgccttcag 7260 aagaacactg ctctttggat aggaactgga ggaggccata ttttactcct ggatctttca 7320 actcgtcgac ttatacgtgt aatttacaac ttttgtaatt cggtcagagt catgatgaca 7380 gcacagctag gaagccttaa aaatgtcatg ctggtattgg gctacaaccg gaaaaatact 7440 gaaggtacac aaaagcagaa agagatacaa tcttgcttga ccgtttggga catcaatctt 7500 ccacatgaag tgcaaaattt agaaaaacac attgaagtga gaaaagaatt agctgaaaaa 7560 atgagacgaa catctgttga gtaa 7584 <210> 4 <211> 2527 <212> PRT <213> Homo sapiens <400> 4 Met Ala Ser Gly Ser Cys Gln Gly Cys Glu Glu Asp Glu Glu Thr Leu   1 5 10 15 Lys Lys Leu Ile Val Arg Leu Asn Asn Val Gln Glu Gly Lys Gln Ile              20 25 30 Glu Thr Leu Val Gln Ile Leu Glu Asp Leu Leu Val Phe Thr Tyr Ser          35 40 45 Glu His Ala Ser Lys Leu Phe Gln Gly Lys Asn Ile His Val Pro Leu      50 55 60 Leu Ile Val Leu Asp Ser Tyr Met Arg Val Ala Ser Val Gln Gln Val  65 70 75 80 Gly Trp Ser Leu Leu Cys Lys Leu Ile Glu Val Cys Pro Gly Thr Met                  85 90 95 Gln Ser Leu Met Gly Pro Gln Asp Val Gly Asn Asp Trp Glu Val Leu             100 105 110 Gly Val His Gln Leu Ile Leu Lys Met Leu Thr Val His Asn Ala Ser         115 120 125 Val Asn Leu Ser Val Ile Gly Leu Lys Thr Leu Asp Leu Leu Leu Thr     130 135 140 Ser Gly Lys Ile Thr Leu Leu Ile Leu Asp Glu Glu Ser Asp Ile Phe 145 150 155 160 Met Leu Ile Phe Asp Ala Met His Ser Phe Pro Ala Asn Asp Glu Val                 165 170 175 Gln Lys Leu Gly Cys Lys Ala Leu His Val Leu Phe Glu Arg Val Ser             180 185 190 Glu Glu Gln Leu Thr Glu Phe Val Glu Asn Lys Asp Tyr Met Ile Leu         195 200 205 Leu Ser Ala Leu Thr Asn Phe Lys Asp Glu Glu Glu Ile Val Leu His     210 215 220 Val Leu His Cys Leu His Ser Leu Ala Ile Pro Cys Asn Asn Val Glu 225 230 235 240 Val Leu Met Ser Gly Asn Val Arg Cys Tyr Asn Ile Val Val Glu Ala                 245 250 255 Met Lys Ala Phe Pro Met Ser Glu Arg Ile Gln Glu Val Ser Cys Cys             260 265 270 Leu Leu His Arg Leu Thr Leu Gly Asn Phe Phe Asn Ile Leu Val Leu         275 280 285 Asn Glu Val His Glu Phe Val Val Lys Ala Val Gln Gln Tyr Pro Glu     290 295 300 Asn Ala Ala Leu Gln Ile Ser Ala Leu Ser Cys Leu Ala Leu Leu Thr 305 310 315 320 Glu Thr Ile Phe Leu Asn Gln Asp Leu Glu Glu Lys Asn Glu Asn Gln                 325 330 335 Glu Asn Asp Asp Glu Gly Glu Glu Asp Lys Leu Phe Trp Leu Glu Ala             340 345 350 Cys Tyr Lys Ala Leu Thr Trp His Arg Lys Asn Lys His Val Gln Glu         355 360 365 Ala Ala Cys Trp Ala Leu Asn Asn Leu Leu Met Tyr Gln Asn Ser Leu     370 375 380 His Glu Lys Ile Gly Asp Glu Asp Gly His Phe Pro Ala His Arg Glu 385 390 395 400 Val Met Leu Ser Met Leu Met His Ser Ser Ser Lys Glu Val Phe Gln                 405 410 415 Ala Ser Ala Asn Ala Leu Ser Thr Leu Leu Glu Gln Asn Val Asn Phe             420 425 430 Arg Lys Ile Leu Leu Ser Lys Gly Ile His Leu Asn Val Leu Glu Leu         435 440 445 Met Gln Lys His Ile His Ser Pro Glu Val Ala Glu Ser Gly Cys Lys     450 455 460 Met Leu Asn His Leu Phe Glu Gly Ser Asn Thr Ser Leu Asp Ile Met 465 470 475 480 Ala Ala Val Val Pro Lys Ile Leu Thr Val Met Lys Arg His Glu Thr                 485 490 495 Ser Leu Pro Val Gln Leu Glu Ala Leu Arg Ala Ile Leu His Phe Ile             500 505 510 Val Pro Gly Met Pro Glu Glu Ser Arg Glu Asp Thr Glu Phe His His         515 520 525 Lys Leu Asn Met Val Lys Lys Gln Cys Phe Lys Asn Asp Ile His Lys     530 535 540 Leu Val Leu Ala Ala Leu Asn Arg Phe Ile Gly Asn Pro Gly Ile Gln 545 550 555 560 Lys Cys Gly Leu Lys Val Ile Ser Ser Ile Val His Phe Pro Asp Ala                 565 570 575 Leu Glu Met Leu Ser Leu Glu Gly Ala Met Asp Ser Val Leu His Thr             580 585 590 Leu Gln Met Tyr Pro Asp Asp Gln Glu Ile Gln Cys Leu Gly Leu Ser         595 600 605 Leu Ile Gly Tyr Leu Ile Thr Lys Lys Asn Val Phe Ile Gly Thr Gly     610 615 620 His Leu Leu Ala Lys Ile Leu Val Ser Ser Leu Tyr Arg Phe Lys Asp 625 630 635 640 Val Ala Glu Ile Gln Thr Lys Gly Phe Gln Thr Ile Leu Ala Ile Leu                 645 650 655 Lys Leu Ser Ala Ser Phe Ser Lys Leu Leu Val His His Ser Phe Asp             660 665 670 Leu Val Ile Phe His Gln Met Ser Ser Asn Ile Met Glu Gln Lys Asp         675 680 685 Gln Gln Phe Leu Asn Leu Cys Cys Lys Cys Phe Ala Lys Val Ala Met     690 695 700 Asp Asp Tyr Leu Lys Asn Val Met Leu Glu Arg Ala Cys Asp Gln Asn 705 710 715 720 Asn Ser Ile Met Val Glu Cys Leu Leu Leu Leu Gly Ala Asp Ala Asn                 725 730 735 Gln Ala Lys Glu Gly Ser Ser Leu Ile Cys Gln Val Cys Glu Lys Glu             740 745 750 Ser Ser Pro Lys Leu Val Glu Leu Leu Leu Asn Ser Gly Ser Arg Glu         755 760 765 Gln Asp Val Arg Lys Ala Leu Thr Ile Ser Ile Gly Lys Gly Asp Ser     770 775 780 Gln Ile Ile Ser Leu Leu Leu Arg Arg Leu Ala Leu Asp Val Ala Asn 785 790 795 800 Asn Ser Ile Cys Leu Gly Gly Phe Cys Ile Gly Lys Val Glu Pro Ser                 805 810 815 Trp Leu Gly Pro Leu Phe Pro Asp Lys Thr Ser Asn Leu Arg Lys Gln             820 825 830 Thr Asn Ile Ala Ser Thr Leu Ala Arg Met Val Ile Arg Tyr Gln Met         835 840 845 Lys Ser Ala Val Glu Glu Gly Thr Ala Ser Gly Ser Asp Gly Asn Phe     850 855 860 Ser Glu Asp Val Leu Ser Lys Phe Asp Glu Trp Thr Phe Ile Pro Asp 865 870 875 880 Ser Ser Met Asp Ser Val Phe Ala Gln Ser Asp Asp Leu Asp Ser Glu                 885 890 895 Gly Ser Glu Gly Ser Phe Leu Val Lys Lys Lys Ser Asn Ser Ile Ser             900 905 910 Val Gly Glu Phe Tyr Arg Asp Ala Val Leu Gln Arg Cys Ser Pro Asn         915 920 925 Leu Gln Arg His Ser Asn Ser Leu Gly Pro Ile Phe Asp His Glu Asp     930 935 940 Leu Leu Lys Arg Lys Arg Lys Ile Leu Ser Ser Asp Asp Ser Leu Arg 945 950 955 960 Ser Ser Lys Leu Gln Ser His Met Arg His Ser Asp Ser Ile Ser Ser                 965 970 975 Leu Ala Ser Glu Arg Glu Tyr Ile Thr Ser Leu Asp Leu Ser Ala Asn             980 985 990 Glu Leu Arg Asp Ile Asp Ala Leu Ser Gln Lys Cys Cys Ile Ser Val         995 1000 1005 His Leu Glu His Leu Glu Lys Leu Glu Leu His Gln Asn Ala Leu Thr    1010 1015 1020 Ser Phe Pro Gln Gln Leu Cys Glu Thr Leu Lys Ser Leu Thr His Leu 1025 1030 1035 1040 Asp Leu His Ser Asn Lys Phe Thr Ser Phe Pro Ser Tyr Leu Leu Lys                1045 1050 1055 Met Ser Cys Ile Ala Asn Leu Asp Val Ser Arg Asn Asp Ile Gly Pro            1060 1065 1070 Ser Val Val Leu Asp Pro Thr Val Lys Cys Pro Thr Leu Lys Gln Phe        1075 1080 1085 Asn Leu Ser Tyr Asn Gln Leu Ser Phe Val Pro Glu Asn Leu Thr Asp    1090 1095 1100 Val Val Glu Lys Leu Glu Gln Leu Ile Leu Glu Gly Asn Lys Ile Ser 1105 1110 1115 1120 Gly Ile Cys Ser Pro Leu Arg Leu Lys Glu Leu Lys Ile Leu Asn Leu                1125 1130 1135 Ser Lys Asn His Ile Ser Ser Leu Ser Glu Asn Phe Leu Glu Ala Cys            1140 1145 1150 Pro Lys Val Glu Ser Phe Ser Ala Arg Met Asn Phe Leu Ala Ala Met        1155 1160 1165 Pro Phe Leu Pro Pro Ser Met Thr Ile Leu Lys Leu Ser Gln Asn Lys    1170 1175 1180 Phe Ser Cys Ile Pro Glu Ala Ile Leu Asn Leu Pro His Leu Arg Ser 1185 1190 1195 1200 Leu Asp Met Ser Ser Asn Asp Ile Gln Tyr Leu Pro Gly Pro Ala His                1205 1210 1215 Trp Lys Ser Leu Asn Leu Arg Glu Leu Leu Phe Ser His Asn Gln Ile            1220 1225 1230 Ser Ile Leu Asp Leu Ser Glu Lys Ala Tyr Leu Trp Ser Arg Val Glu        1235 1240 1245 Lys Leu His Leu Ser His Asn Lys Leu Lys Glu Ile Pro Pro Glu Ile    1250 1255 1260 Gly Cys Leu Glu Asn Leu Thr Ser Leu Asp Val Ser Tyr Asn Leu Glu 1265 1270 1275 1280 Leu Arg Ser Phe Pro Asn Glu Met Gly Lys Leu Ser Lys Ile Trp Asp                1285 1290 1295 Leu Pro Leu Asp Glu Leu His Leu Asn Phe Asp Phe Lys His Ile Gly            1300 1305 1310 Cys Lys Ala Lys Asp Ile Ile Arg Phe Leu Gln Gln Arg Leu Lys Lys        1315 1320 1325 Ala Val Pro Tyr Asn Arg Met Lys Leu Met Ile Val Gly Asn Thr Gly    1330 1335 1340 Ser Gly Lys Thr Thr Leu Leu Gln Gln Leu Met Lys Thr Lys Lys Ser 1345 1350 1355 1360 Asp Leu Gly Met Gln Ser Ala Thr Val Gly Ile Asp Val Lys Asp Trp                1365 1370 1375 Pro Ile Gln Ile Arg Asp Lys Arg Lys Arg Asp Leu Val Leu Asn Val            1380 1385 1390 Trp Asp Phe Ala Gly Arg Glu Glu Phe Tyr Ser Thr His Pro His Phe        1395 1400 1405 Met Thr Gln Arg Ala Leu Tyr Leu Ala Val Tyr Asp Leu Ser Lys Gly    1410 1415 1420 Gln Ala Glu Val Asp Ala Met Lys Pro Trp Leu Phe Asn Ile Lys Ala 1425 1430 1435 1440 Cys Ala Ser Ser Ser Pro Val Ile Leu Val Gly Thr His Leu Asp Val                1445 1450 1455 Ser Asp Glu Lys Gln Arg Lys Ala Cys Met Ser Lys Ile Thr Lys Glu            1460 1465 1470 Leu Leu Asn Lys Arg Gly Phe Pro Ala Ile Arg Asp Tyr His Phe Val        1475 1480 1485 Asn Ala Thr Glu Glu Ser Asp Ala Leu Ala Lys Leu Arg Lys Thr Ile    1490 1495 1500 Ile Asn Glu Ser Leu Asn Phe Lys Ile Arg Asp Gln Leu Val Val Gly 1505 1510 1515 1520 Gln Leu Ile Pro Asp Cys Tyr Val Glu Leu Glu Lys Ile Ile Leu Ser                1525 1530 1535 Glu Arg Lys Asn Val Pro Ile Glu Phe Pro Val Ile Asp Arg Lys Arg            1540 1545 1550 Leu Leu Gln Leu Val Arg Glu Asn Gln Leu Gln Leu Asp Glu Asn Glu        1555 1560 1565 Leu Pro His Ala Val His Phe Leu Asn Glu Ser Gly Val Leu Leu His    1570 1575 1580 Phe Gln Asp Pro Ala Leu Gln Leu Ser Asp Leu Tyr Phe Val Glu Pro 1585 1590 1595 1600 Lys Trp Leu Cys Lys Ile Met Ala Gln Ile Leu Thr Val Lys Val Glu                1605 1610 1615 Gly Cys Pro Lys His Pro Lys Gly Ile Ile Ser Arg Arg Asp Val Glu            1620 1625 1630 Lys Phe Leu Ser Lys Lys Arg Lys Phe Pro Lys Asn Tyr Met Ser Gln        1635 1640 1645 Tyr Phe Lys Leu Leu Glu Lys Phe Gln Ile Ala Leu Pro Ile Gly Glu    1650 1655 1660 Glu Tyr Leu Leu Val Pro Ser Ser Leu Ser Asp His Arg Pro Val Ile 1665 1670 1675 1680 Glu Leu Pro His Cys Glu Asn Ser Glu Ile Ile Ile Arg Leu Tyr Glu                1685 1690 1695 Met Pro Tyr Phe Pro Met Gly Phe Trp Ser Arg Leu Ile Asn Arg Leu            1700 1705 1710 Leu Glu Ile Ser Pro Tyr Met Leu Ser Gly Arg Glu Arg Ala Leu Arg        1715 1720 1725 Pro Asn Arg Met Tyr Trp Arg Gln Gly Ile Tyr Leu Asn Trp Ser Pro    1730 1735 1740 Glu Ala Tyr Cys Leu Val Gly Ser Glu Val Leu Asp Asn His Pro Glu 1745 1750 1755 1760 Ser Phe Leu Lys Ile Thr Val Pro Ser Cys Arg Lys Gly Cys Ile Leu                1765 1770 1775 Leu Gly Gln Val Val Asp His Ile Asp Ser Leu Met Glu Glu Trp Phe            1780 1785 1790 Pro Gly Leu Leu Glu Ile Asp Ile Cys Gly Glu Gly Glu Thr Leu Leu        1795 1800 1805 Lys Lys Trp Ala Leu Tyr Ser Phe Asn Asp Gly Glu Glu His Gln Lys    1810 1815 1820 Ile Leu Leu Asp Asp Leu Met Lys Lys Ala Glu Glu Gly Asp Leu Leu 1825 1830 1835 1840 Val Asn Pro Asp Gln Pro Arg Leu Thr Ile Pro Ile Ser Gln Ile Ala                1845 1850 1855 Pro Asp Leu Ile Leu Ala Asp Leu Pro Arg Asn Ile Met Leu Asn Asn            1860 1865 1870 Asp Glu Leu Glu Phe Glu Gln Ala Pro Glu Phe Leu Leu Gly Asp Gly        1875 1880 1885 Ser Phe Gly Ser Val Tyr Arg Ala Ala Tyr Glu Gly Glu Glu Val Ala    1890 1895 1900 Val Lys Ile Phe Asn Lys His Thr Ser Leu Arg Leu Leu Arg Gln Glu 1905 1910 1915 1920 Leu Val Val Leu Cys His Leu His His Pro Ser Leu Ile Ser Leu Leu                1925 1930 1935 Ala Ala Gly Ile Arg Pro Arg Met Leu Val Met Glu Leu Ala Ser Lys            1940 1945 1950 Gly Ser Leu Asp Arg Leu Leu Gln Gln Asp Lys Ala Ser Leu Thr Arg        1955 1960 1965 Thr Leu Gln His Arg Ile Ala Leu His Val Ala Asp Gly Leu Arg Tyr    1970 1975 1980 Leu His Ser Ala Met Ile Ile Tyr Arg Asp Leu Lys Pro His Asn Val 1985 1990 1995 2000 Leu Leu Phe Thr Leu Tyr Pro Asn Ala Ala Ile Ile Ala Lys Ile Ala                2005 2010 2015 Asp Tyr Gly Ile Ala Gln Tyr Cys Cys Arg Met Gly Ile Lys Thr Ser            2020 2025 2030 Glu Gly Thr Pro Gly Phe Arg Ala Pro Glu Val Ala Arg Gly Asn Val        2035 2040 2045 Ile Tyr Asn Gln Gln Ala Asp Val Tyr Ser Phe Gly Leu Leu Leu Tyr    2050 2055 2060 Asp Ile Leu Thr Thr Gly Gly Arg Ile Val Glu Gly Leu Lys Phe Pro 2065 2070 2075 2080 Asn Glu Phe Asp Glu Leu Glu Ile Gln Gly Lys Leu Pro Asp Pro Val                2085 2090 2095 Lys Glu Tyr Gly Cys Ala Pro Trp Pro Met Val Glu Lys Leu Ile Lys            2100 2105 2110 Gln Cys Leu Lys Glu Asn Pro Gln Glu Arg Pro Thr Ser Ala Gln Val        2115 2120 2125 Phe Asp Ile Leu Asn Ser Ala Glu Leu Val Cys Leu Thr Arg Arg Ile    2130 2135 2140 Leu Leu Pro Lys Asn Val Ile Val Glu Cys Met Val Ala Thr His His 2145 2150 2155 2160 Asn Ser Arg Asn Ala Ser Ile Trp Leu Gly Cys Gly His Thr Asp Arg                2165 2170 2175 Gly Gln Leu Ser Phe Leu Asp Leu Asn Thr Glu Gly Tyr Thr Ser Glu            2180 2185 2190 Glu Val Ala Asp Ser Arg Ile Leu Cys Leu Ala Leu Val His Leu Pro        2195 2200 2205 Val Glu Lys Glu Ser Trp Ile Val Ser Gly Thr Gln Ser Gly Thr Leu    2210 2215 2220 Leu Val Ile Asn Thr Glu Asp Gly Lys Lys Arg His Thr Leu Glu Lys 2225 2230 2235 2240 Met Thr Asp Ser Val Thr Cys Leu Tyr Cys Asn Ser Phe Ser Lys Gln                2245 2250 2255 Ser Lys Gln Lys Asn Phe Leu Leu Val Gly Thr Ala Asp Gly Lys Leu            2260 2265 2270 Ala Ile Phe Glu Asp Lys Thr Val Lys Leu Lys Gly Ala Ala Pro Leu        2275 2280 2285 Lys Ile Leu Asn Ile Gly Asn Val Ser Thr Pro Leu Met Cys Leu Ser    2290 2295 2300 Glu Ser Thr Asn Ser Thr Glu Arg Asn Val Met Trp Gly Gly Cys Gly 2305 2310 2315 2320 Thr Lys Ile Phe Ser Phe Ser Asn Asp Phe Thr Ile Gln Lys Leu Ile                2325 2330 2335 Glu Thr Arg Thr Ser Gln Leu Phe Ser Tyr Ala Ala Phe Ser Asp Ser            2340 2345 2350 Asn Ile Ile Thr Val Val Val Asp Thr Ala Leu Tyr Ile Ala Lys Gln        2355 2360 2365 Asn Ser Pro Val Val Glu Val Trp Asp Lys Lys Thr Glu Lys Leu Cys    2370 2375 2380 Gly Leu Ile Asp Cys Val His Phe Leu Arg Glu Val Met Val Lys Glu 2385 2390 2395 2400 Asn Lys Glu Ser Lys His Lys Met Ser Tyr Ser Gly Arg Val Lys Thr                2405 2410 2415 Leu Cys Leu Gln Lys Asn Thr Ala Leu Trp Ile Gly Thr Gly Gly Gly            2420 2425 2430 His Ile Leu Leu Leu Asp Leu Ser Thr Arg Arg Leu Ile Arg Val Ile        2435 2440 2445 Tyr Asn Phe Cys Asn Ser Val Arg Val Met Met Thr Ala Gln Leu Gly    2450 2455 2460 Ser Leu Lys Asn Val Met Leu Val Leu Gly Tyr Asn Arg Lys Asn Thr 2465 2470 2475 2480 Glu Gly Thr Gln Lys Gln Lys Glu Ile Gln Ser Cys Leu Thr Val Trp                2485 2490 2495 Asp Ile Asn Leu Pro His Glu Val Gln Asn Leu Glu Lys His Ile Glu            2500 2505 2510 Val Arg Lys Glu Leu Ala Glu Lys Met Arg Arg Thr Ser Val Glu        2515 2520 2525 <210> 5 <211> 7584 <212> DNA <213> Homo sapiens <400> 5 atggctagtg gcagctgtca ggggtgcgaa gaggacgagg aaactctgaa gaagttgata 60 gtcaggctga acaatgtcca ggaaggaaaa cagatagaaa cgctggtcca aatcctggag 120 gatctgctgg tgttcacgta ctccgagcac gcctccaagt tatttcaagg caaaaatatc 180 catgtgcctc tgttgatcgt cttggactcc tatatgagag tcgcgagtgt gcagcaggtg 240 ggttggtcac ttctgtgcaa attaatagaa gtctgtccag gtacaatgca aagcttaatg 300 ggaccccagg atgttggaaa tgattgggaa gtccttggtg ttcaccaatt gattcttaaa 360 atgctaacag ttcataatgc cagtgtaaac ttgtcagtga ttggactgaa gaccttagat 420 ctcctcctaa cttcaggtaa aatcaccttg ctgatactgg atgaagaaag tgatattttc 480 atgttaattt ttgatgccat gcactcattt ccagccaatg atgaagtcca gaaacttgga 540 tgcaaagctt tacatgtgct gtttgagaga gtctcagagg agcaactgac tgaatttgtt 600 gagaacaaag attatatgat attgttaagt gcgtcaacaa attttaaaga tgaagaggaa 660 attgtgcttc atgtgctgca ttgtttacat tccctagcga ttccttgcaa taatgtggaa 720 gtcctcatga gtggcaatgt caggtgttat aatattgtgg tggaagctat gaaagcattc 780 cctatgagtg aaagaattca agaagtgagt tgctgtttgc tccataggct tacattaggt 840 aattttttca atatcctggt attaaacgaa gtccatgagt ttgtggtgaa agctgtgcag 900 cagtacccag agaatgcagc attgcagatc tcagcgctca gctgtttggc cctcctcact 960 gagactattt tcttaaatca agatttagag gaaaagaatg agaatcaaga gaatgatgat 1020 gagggggaag aagataaatt gttttggctg gaagcctgtt acaaagcatt aacgtggcat 1080 agaaagaaca agcacgtgca ggaggccgca tgctgggcac taaataatct ccttatgtac 1140 caaaacagtt tacatgagaa gattggagat gaagatggcc atttcccagc tcatagggaa 1200 gtgatgctct ccatgctgat gcattcttca tcaaaggaag ttttccaggc atctgcgaat 1260 gcattgtcaa ctctcttaga acaaaatgtt aatttcagaa aaatactgtt atcaaaagga 1320 atacacctga atgttttgga gttaatgcag aagcatatac attctcctga agtggctgaa 1380 agtggctgta aaatgctaaa tcatcttttt gaaggaagca acacttccct ggatataatg 1440 gcagcagtgg tccccaaaat actaacagtt atgaaacgtc atgagacatc attaccagtg 1500 cagctggagg cgcttcgagc tattttacat tttatagtgc ctggcatgcc agaagaatcc 1560 agggaggata cagaatttca tcataagcta aatatggtta aaaaacagtg tttcaagaat 1620 gatattcaca aactggtcct agcagctttg aacaggttca ttggaaatcc tgggattcag 1680 aaatgtggat taaaagtaat ttcttctatt gtacattttc ctgatgcatt agagatgtta 1740 tccctggaag gtgctatgga ttcagtgctt cacacactgc agatgtatcc agatgaccaa 1800 gaaattcagt gtctgggttt aagtcttata ggatacttga ttacaaagaa gaatgtgttc 1860 ataggaactg gacatctgct ggcaaaaatt ctggtttcca gcttataccg atttaaggat 1920 gttgctgaaa tacagactaa aggatttcag acaatcttag caatcctcaa attgtcagca 1980 tctttttcta agctgctggt gcatcattca tttgacttag taatattcca tcaaatgtct 2040 tccaatatca tggaacaaaa ggatcaacag tttctaaacc tctgttgcaa gtgttttgca 2100 aaagtagcta tggatgatta cttaaaaaat gtgatgctag agagagcgtg tgatcagaat 2160 aacagcatca tggttgaatg cttgcttcta ttgggagcag atgccaatca agcaaaggag 2220 ggatcttctt taatttgtca ggtatgtgag aaagagagca gtcccaaatt ggtggaactc 2280 ttactgaata gtggatctcg tgaacaagat gtacgaaaag cgttgacgat aagcattggg 2340 aaaggtgaca gccagatcat cagcttgctc ttaaggaggc tggccctgga tgtggccaac 2400 aatagcattt gccttggagg attttgtata ggaaaagttg aaccttcttg gcttggtcct 2460 ttatttccag ataagacttc taatttaagg aaacaaacaa atatagcatc tacactagca 2520 agaatggtga tcagatatca gatgaaaagt gctgtggaag aaggaacagc ctcaggcagc 2580 gatggaaatt tttctgaaga tgtgctgtct aaatttgatg aatggacctt tattcctgac 2640 tcttctatgg acagtgtgtt tgctcaaagt gatgacctgg atagtgaagg aagtgaaggc 2700 tcatttcttg tgaaaaagaa atctaattca attagtgtag gagaatttta ccgagatgcc 2760 gtattacagc gttgctcacc aaatttgcaa agacattcca attccttggg gcccattttt 2820 gatcatgaag atttactgaa gcgaaaaaga aaaatactat cttcagatga ttcactcagg 2880 tcatcaaaac ttcaatccca tatgaggcat tcagacagca tttcttctct ggcttctgag 2940 agagaatata ttacatcact agacctttca gcaaatgaac taagagatat tgatgcccta 3000 agccagaaat gctgtataag tgttcatttg gagcatcttg aaaagctgga gcttcaccag 3060 aatgcactca cgagctttcc acaacagcta tgtgaaactc tgaagagttt gacacatttg 3120 gacttgcaca gtaataaatt tacatcattt ccttcttatt tgttgaaaat gagttgtatt 3180 gctaatcttg atgtctctcg aaatgacatt ggaccctcag tggttttaga tcctacagtg 3240 aaatgtccaa ctctgaaaca gtttaacctg tcatataacc agctgtcttt tgtacctgag 3300 aacctcactg atgtggtaga gaaactggag cagctcattt tagaaggaaa taaaatatca 3360 gggatatgct cccccttgag actgaaggaa ctgaagattt taaaccttag taagaaccac 3420 atttcatccc tatcagagaa ctttcttgag gcttgtccta aagtggagag tttcagtgcc 3480 agaatgaatt ttcttgctgc tatgcctttc ttgcctcctt ctatgacaat cctaaaatta 3540 tctcagaaca aattttcctg tattccagaa gcaattttaa atcttccaca cttgcggtct 3600 ttagatatga gcagcaatga tattcagtac ctaccaggtc ccgcacactg gaaatctttg 3660 aacttaaggg aactcttatt tagccataat cagatcagca tcttggactt gagtgaaaaa 3720 gcatatttat ggtctagagt agagaaactg catctttctc acaataaact gaaagagatt 3780 cctcctgaga ttggctgtct tgaaaatctg acatctctgg atgtcagtta caacttggaa 3840 ctaagatcct ttcccaatga aatggggaaa ttaagcaaaa tatgggatct tcctttggat 3900 gaactgcatc ttaactttga ttttaaacat ataggatgta aagccaaaga catcataagg 3960 tttcttcaac agcgattaaa aaaggctgtg ccttataacc gaatgaaact tatgattgtg 4020 ggaaatactg ggagtggtaa aaccacctta ttgcagcaat taatgaaaac caagaaatca 4080 gatcttggaa tgcaaagtgc cacagttggc atagatgtga aagactggcc tatccaaata 4140 agagacaaaa gaaagagaga tctcgtccta aatgtgtggg attttgcagg tcgtgaggaa 4200 ttctatagta ctcatcccca ttttatgacg cagcgagcat tgtaccttgc tgtctatgac 4260 ctcagcaagg gacaggctga agttgatgcc atgaagcctt ggctcttcaa tataaaggct 4320 ggcgcttctt cttcccctgt gattctcgtt ggcacacatt tggatgtttc tgatgagaag 4380 caacgcaaag cctgcatgag taaaatcacc aaggaactcc tgaataagcg agggttccct 4440 gccatacgag attaccactt tgtgaatgcc accgaggaat ctgatgcttt ggcaaaactt 4500 cggaaaacca tcataaacga gagccttaat ttcaagatcc gagatcagct tgttgttgga 4560 cagctgattc cagactgcta tgtagaactt gaaaaaatca ttttatcgga gcgtaaaaat 4620 gtgccaattg aatttcccgt aattgaccgg aaacgattat tacaactagt gagagaaaat 4680 cagctgcagt tagatgaaaa tgagcttcct cacgcagttc actttctaaa tgaatcagga 4740 gtccttcttc attttcaaga cccagcactg cagttaagtg acttgtactt tgtggaaccc 4800 aagtggcttt gtaaaatcat ggcacagatt ttgacagtga aagtggaagg ttgtccaaaa 4860 caccctaagg gcattatttc gcgtagagat gtggaaaaat ttctttcaaa aaaaaggaaa 4920 tttccaaaga actacatgtc acagtatttt aagctcctag aaaaattcca gattgctttg 4980 ccaataggag aagaatattt gctggttcca agcagtttgt ctgaccacag gcctgtgata 5040 gagcttcccc attgtgagaa ctctgaaatt atcatccgac tatatgaaat gccttatttt 5100 ccaatgggat tttggtcaag attaatcaat cgattacttg agatttcacc ttacatgctt 5160 tcagggagag aacgagcact tcgcccaaac agaatgtatt ggcgacaagg catttactta 5220 aattggtctc ctgaagctta ttgtctggta ggatctgaag tcttagacaa tcatccagag 5280 agtttcttaa aaattacagt tccttcttgt agaaaaggct gtattctttt gggccaagtt 5340 gtggaccaca ttgattctct catggaagaa tggtttcctg ggttgctgga gattgatatt 5400 tgtggtgaag gagaaactct gttgaagaaa tgggcattat atagttttaa tgatggcgaa 5460 gaacatcaaa aaatcttact tgatgacttg atgaagaaag cagaggaagg agatctctta 5520 gtaaatccag atcaaccaag gctcaccatt ccaatatctc agattgcccc tgacttgatt 5580 ttggctgacc tgcctagaaa tattatgttg aataatgatg agttggaatt tgaacaagct 5640 ccagagtttc tcctaggtga tggcagtttt ggatcagttt accgagcagc ctatgaagga 5700 gaagaagtgg ctgtgaagat ttttaataaa catacatcac tcaggctgtt aagacaagag 5760 cttgtggtgc tttgccacct ccaccacccc agtttgatat ctttgctggc agctgggatt 5820 cgtccccgga tgttggtgat ggagttagcc tccaagggtt ccttggatcg cctgcttcag 5880 caggacaaag ccagcctcac tagaacccta cagcacagga ttgcactcca cgtagctgat 5940 ggtttgagat acctccactc agccatgatt atataccgag acctgaaacc ccacaatgtg 6000 ctgcttttca cactgtatcc caatgctgcc atcattgcaa agattgctga ctacggcatt 6060 gctcagtact gctgtagaat ggggataaaa acatcagagg gcacaccagg gtttcgtgca 6120 cctgaagttg ccagaggaaa tgtcatttat aaccaacagg ctgatgttta ttcatttggt 6180 ttactactct atgacatttt gacaactgga ggtagaatag tagagggttt gaagtttcca 6240 aatgagtttg atgaattaga aatacaagga aaattacctg atccagttaa agaatatggt 6300 tgtgccccat ggcctatggt tgagaaatta attaaacagt gtttgaaaga aaatcctcaa 6360 gaaaggccta cttctgccca ggtctttgac attttgaatt cagctgaatt agtctgtctg 6420 acgagacgca ttttattacc taaaaacgta attgttgaat gcatggttgc tacacatcac 6480 aacagcagga atgcaagcat ttggctgggc tgtgggcaca ccgacagagg acagctctca 6540 tttcttgact taaatactga aggatacact tctgaggaag ttgctgatag tagaatattg 6600 tgcttagcct tggtgcatct tcctgttgaa aaggaaagct ggattgtgtc tgggacacag 6660 tctggtactc tcctggtcat caataccgaa gatgggaaaa agagacatac cctagaaaag 6720 atgactgatt ctgtcacttg tttgtattgc aattcctttt ccaagcaaag caaacaaaaa 6780 aattttcttt tggttggaac cgctgatggc aagttagcaa tttttgaaga taagactgtt 6840 aagcttaaag gagctgctcc tttgaagata ctaaatatag gaaatgtcag tactccattg 6900 atgtgtttga gtgaatccac aaattcaacg gaaagaaatg taatgtgggg aggatgtggc 6960 acaaagattt tctccttttc taatgatttc accattcaga aactcattga gacaagaaca 7020 agccaactgt tttcttatgc agctttcagt gattccaaca tcataacagt ggtggtagac 7080 actgctctct atattgctaa gcaaaatagc cctgttgtgg aagtgtggga taagaaaact 7140 gaaaaactct gtggactaat agactgcgtg cactttttaa gggaggtaat ggtaaaagaa 7200 aacaaggaat caaaacacaa aatgtcttat tctgggagag tgaaaaccct ctgccttcag 7260 aagaacactg ctctttggat aggaactgga ggaggccata ttttactcct ggatctttca 7320 actcgtcgac ttatacgtgt aatttacaac ttttgtaatt cggtcagagt catgatgaca 7380 gcacagctag gaagccttaa aaatgtcatg ctggtattgg gctacaaccg gaaaaatact 7440 gaaggtacac aaaagcagaa agagatacaa tcttgcttga ccgtttggga catcaatctt 7500 ccacatgaag tgcaaaattt agaaaaacac attgaagtga gaaaagaatt agctgaaaaa 7560 atgagacgaa catctgttga gtaa 7584 <210> 6 <211> 2527 <212> PRT <213> Homo sapiens <400> 6 Met Ala Ser Gly Ser Cys Gln Gly Cys Glu Glu Asp Glu Glu Thr Leu   1 5 10 15 Lys Lys Leu Ile Val Arg Leu Asn Asn Val Gln Glu Gly Lys Gln Ile              20 25 30 Glu Thr Leu Val Gln Ile Leu Glu Asp Leu Leu Val Phe Thr Tyr Ser          35 40 45 Glu His Ala Ser Lys Leu Phe Gln Gly Lys Asn Ile His Val Pro Leu      50 55 60 Leu Ile Val Leu Asp Ser Tyr Met Arg Val Ala Ser Val Gln Gln Val  65 70 75 80 Gly Trp Ser Leu Leu Cys Lys Leu Ile Glu Val Cys Pro Gly Thr Met                  85 90 95 Gln Ser Leu Met Gly Pro Gln Asp Val Gly Asn Asp Trp Glu Val Leu             100 105 110 Gly Val His Gln Leu Ile Leu Lys Met Leu Thr Val His Asn Ala Ser         115 120 125 Val Asn Leu Ser Val Ile Gly Leu Lys Thr Leu Asp Leu Leu Leu Thr     130 135 140 Ser Gly Lys Ile Thr Leu Leu Ile Leu Asp Glu Glu Ser Asp Ile Phe 145 150 155 160 Met Leu Ile Phe Asp Ala Met His Ser Phe Pro Ala Asn Asp Glu Val                 165 170 175 Gln Lys Leu Gly Cys Lys Ala Leu His Val Leu Phe Glu Arg Val Ser             180 185 190 Glu Glu Gln Leu Thr Glu Phe Val Glu Asn Lys Asp Tyr Met Ile Leu         195 200 205 Leu Ser Ala Leu Thr Asn Phe Lys Asp Glu Glu Glu Ile Val Leu His     210 215 220 Val Leu His Cys Leu His Ser Leu Ala Ile Pro Cys Asn Asn Val Glu 225 230 235 240 Val Leu Met Ser Gly Asn Val Arg Cys Tyr Asn Ile Val Val Glu Ala                 245 250 255 Met Lys Ala Phe Pro Met Ser Glu Arg Ile Gln Glu Val Ser Cys Cys             260 265 270 Leu Leu His Arg Leu Thr Leu Gly Asn Phe Phe Asn Ile Leu Val Leu         275 280 285 Asn Glu Val His Glu Phe Val Val Lys Ala Val Gln Gln Tyr Pro Glu     290 295 300 Asn Ala Ala Leu Gln Ile Ser Ala Leu Ser Cys Leu Ala Leu Leu Thr 305 310 315 320 Glu Thr Ile Phe Leu Asn Gln Asp Leu Glu Glu Lys Asn Glu Asn Gln                 325 330 335 Glu Asn Asp Asp Glu Gly Glu Glu Asp Lys Leu Phe Trp Leu Glu Ala             340 345 350 Cys Tyr Lys Ala Leu Thr Trp His Arg Lys Asn Lys His Val Gln Glu         355 360 365 Ala Ala Cys Trp Ala Leu Asn Asn Leu Leu Met Tyr Gln Asn Ser Leu     370 375 380 His Glu Lys Ile Gly Asp Glu Asp Gly His Phe Pro Ala His Arg Glu 385 390 395 400 Val Met Leu Ser Met Leu Met His Ser Ser Ser Lys Glu Val Phe Gln                 405 410 415 Ala Ser Ala Asn Ala Leu Ser Thr Leu Leu Glu Gln Asn Val Asn Phe             420 425 430 Arg Lys Ile Leu Leu Ser Lys Gly Ile His Leu Asn Val Leu Glu Leu         435 440 445 Met Gln Lys His Ile His Ser Pro Glu Val Ala Glu Ser Gly Cys Lys     450 455 460 Met Leu Asn His Leu Phe Glu Gly Ser Asn Thr Ser Leu Asp Ile Met 465 470 475 480 Ala Ala Val Val Pro Lys Ile Leu Thr Val Met Lys Arg His Glu Thr                 485 490 495 Ser Leu Pro Val Gln Leu Glu Ala Leu Arg Ala Ile Leu His Phe Ile             500 505 510 Val Pro Gly Met Pro Glu Glu Ser Arg Glu Asp Thr Glu Phe His His         515 520 525 Lys Leu Asn Met Val Lys Lys Gln Cys Phe Lys Asn Asp Ile His Lys     530 535 540 Leu Val Leu Ala Ala Leu Asn Arg Phe Ile Gly Asn Pro Gly Ile Gln 545 550 555 560 Lys Cys Gly Leu Lys Val Ile Ser Ser Ile Val His Phe Pro Asp Ala                 565 570 575 Leu Glu Met Leu Ser Leu Glu Gly Ala Met Asp Ser Val Leu His Thr             580 585 590 Leu Gln Met Tyr Pro Asp Asp Gln Glu Ile Gln Cys Leu Gly Leu Ser         595 600 605 Leu Ile Gly Tyr Leu Ile Thr Lys Lys Asn Val Phe Ile Gly Thr Gly     610 615 620 His Leu Leu Ala Lys Ile Leu Val Ser Ser Leu Tyr Arg Phe Lys Asp 625 630 635 640 Val Ala Glu Ile Gln Thr Lys Gly Phe Gln Thr Ile Leu Ala Ile Leu                 645 650 655 Lys Leu Ser Ala Ser Phe Ser Lys Leu Leu Val His His Ser Phe Asp             660 665 670 Leu Val Ile Phe His Gln Met Ser Ser Asn Ile Met Glu Gln Lys Asp         675 680 685 Gln Gln Phe Leu Asn Leu Cys Cys Lys Cys Phe Ala Lys Val Ala Met     690 695 700 Asp Asp Tyr Leu Lys Asn Val Met Leu Glu Arg Ala Cys Asp Gln Asn 705 710 715 720 Asn Ser Ile Met Val Glu Cys Leu Leu Leu Leu Gly Ala Asp Ala Asn                 725 730 735 Gln Ala Lys Glu Gly Ser Ser Leu Ile Cys Gln Val Cys Glu Lys Glu             740 745 750 Ser Ser Pro Lys Leu Val Glu Leu Leu Leu Asn Ser Gly Ser Arg Glu         755 760 765 Gln Asp Val Arg Lys Ala Leu Thr Ile Ser Ile Gly Lys Gly Asp Ser     770 775 780 Gln Ile Ile Ser Leu Leu Leu Arg Arg Leu Ala Leu Asp Val Ala Asn 785 790 795 800 Asn Ser Ile Cys Leu Gly Gly Phe Cys Ile Gly Lys Val Glu Pro Ser                 805 810 815 Trp Leu Gly Pro Leu Phe Pro Asp Lys Thr Ser Asn Leu Arg Lys Gln             820 825 830 Thr Asn Ile Ala Ser Thr Leu Ala Arg Met Val Ile Arg Tyr Gln Met         835 840 845 Lys Ser Ala Val Glu Glu Gly Thr Ala Ser Gly Ser Asp Gly Asn Phe     850 855 860 Ser Glu Asp Val Leu Ser Lys Phe Asp Glu Trp Thr Phe Ile Pro Asp 865 870 875 880 Ser Ser Met Asp Ser Val Phe Ala Gln Ser Asp Asp Leu Asp Ser Glu                 885 890 895 Gly Ser Glu Gly Ser Phe Leu Val Lys Lys Lys Ser Asn Ser Ile Ser             900 905 910 Val Gly Glu Phe Tyr Arg Asp Ala Val Leu Gln Arg Cys Ser Pro Asn         915 920 925 Leu Gln Arg His Ser Asn Ser Leu Gly Pro Ile Phe Asp His Glu Asp     930 935 940 Leu Leu Lys Arg Lys Arg Lys Ile Leu Ser Ser Asp Asp Ser Leu Arg 945 950 955 960 Ser Ser Lys Leu Gln Ser His Met Arg His Ser Asp Ser Ile Ser Ser                 965 970 975 Leu Ala Ser Glu Arg Glu Tyr Ile Thr Ser Leu Asp Leu Ser Ala Asn             980 985 990 Glu Leu Arg Asp Ile Asp Ala Leu Ser Gln Lys Cys Cys Ile Ser Val         995 1000 1005 His Leu Glu His Leu Glu Lys Leu Glu Leu His Gln Asn Ala Leu Thr    1010 1015 1020 Ser Phe Pro Gln Gln Leu Cys Glu Thr Leu Lys Ser Leu Thr His Leu 1025 1030 1035 1040 Asp Leu His Ser Asn Lys Phe Thr Ser Phe Pro Ser Tyr Leu Leu Lys                1045 1050 1055 Met Ser Cys Ile Ala Asn Leu Asp Val Ser Arg Asn Asp Ile Gly Pro            1060 1065 1070 Ser Val Val Leu Asp Pro Thr Val Lys Cys Pro Thr Leu Lys Gln Phe        1075 1080 1085 Asn Leu Ser Tyr Asn Gln Leu Ser Phe Val Pro Glu Asn Leu Thr Asp    1090 1095 1100 Val Val Glu Lys Leu Glu Gln Leu Ile Leu Glu Gly Asn Lys Ile Ser 1105 1110 1115 1120 Gly Ile Cys Ser Pro Leu Arg Leu Lys Glu Leu Lys Ile Leu Asn Leu                1125 1130 1135 Ser Lys Asn His Ile Ser Ser Leu Ser Glu Asn Phe Leu Glu Ala Cys            1140 1145 1150 Pro Lys Val Glu Ser Phe Ser Ala Arg Met Asn Phe Leu Ala Ala Met        1155 1160 1165 Pro Phe Leu Pro Pro Ser Met Thr Ile Leu Lys Leu Ser Gln Asn Lys    1170 1175 1180 Phe Ser Cys Ile Pro Glu Ala Ile Leu Asn Leu Pro His Leu Arg Ser 1185 1190 1195 1200 Leu Asp Met Ser Ser Asn Asp Ile Gln Tyr Leu Pro Gly Pro Ala His                1205 1210 1215 Trp Lys Ser Leu Asn Leu Arg Glu Leu Leu Phe Ser His Asn Gln Ile            1220 1225 1230 Ser Ile Leu Asp Leu Ser Glu Lys Ala Tyr Leu Trp Ser Arg Val Glu        1235 1240 1245 Lys Leu His Leu Ser His Asn Lys Leu Lys Glu Ile Pro Pro Glu Ile    1250 1255 1260 Gly Cys Leu Glu Asn Leu Thr Ser Leu Asp Val Ser Tyr Asn Leu Glu 1265 1270 1275 1280 Leu Arg Ser Phe Pro Asn Glu Met Gly Lys Leu Ser Lys Ile Trp Asp                1285 1290 1295 Leu Pro Leu Asp Glu Leu His Leu Asn Phe Asp Phe Lys His Ile Gly            1300 1305 1310 Cys Lys Ala Lys Asp Ile Ile Arg Phe Leu Gln Gln Arg Leu Lys Lys        1315 1320 1325 Ala Val Pro Tyr Asn Arg Met Lys Leu Met Ile Val Gly Asn Thr Gly    1330 1335 1340 Ser Gly Lys Thr Thr Leu Leu Gln Gln Leu Met Lys Thr Lys Lys Ser 1345 1350 1355 1360 Asp Leu Gly Met Gln Ser Ala Thr Val Gly Ile Asp Val Lys Asp Trp                1365 1370 1375 Pro Ile Gln Ile Arg Asp Lys Arg Lys Arg Asp Leu Val Leu Asn Val            1380 1385 1390 Trp Asp Phe Ala Gly Arg Glu Glu Phe Tyr Ser Thr His Pro His Phe        1395 1400 1405 Met Thr Gln Arg Ala Leu Tyr Leu Ala Val Tyr Asp Leu Ser Lys Gly    1410 1415 1420 Gln Ala Glu Val Asp Ala Met Lys Pro Trp Leu Phe Asn Ile Lys Ala 1425 1430 1435 1440 Gly Ala Ser Ser Ser Pro Val Ile Leu Val Gly Thr His Leu Asp Val                1445 1450 1455 Ser Asp Glu Lys Gln Arg Lys Ala Cys Met Ser Lys Ile Thr Lys Glu            1460 1465 1470 Leu Leu Asn Lys Arg Gly Phe Pro Ala Ile Arg Asp Tyr His Phe Val        1475 1480 1485 Asn Ala Thr Glu Glu Ser Asp Ala Leu Ala Lys Leu Arg Lys Thr Ile    1490 1495 1500 Ile Asn Glu Ser Leu Asn Phe Lys Ile Arg Asp Gln Leu Val Val Gly 1505 1510 1515 1520 Gln Leu Ile Pro Asp Cys Tyr Val Glu Leu Glu Lys Ile Ile Leu Ser                1525 1530 1535 Glu Arg Lys Asn Val Pro Ile Glu Phe Pro Val Ile Asp Arg Lys Arg            1540 1545 1550 Leu Leu Gln Leu Val Arg Glu Asn Gln Leu Gln Leu Asp Glu Asn Glu        1555 1560 1565 Leu Pro His Ala Val His Phe Leu Asn Glu Ser Gly Val Leu Leu His    1570 1575 1580 Phe Gln Asp Pro Ala Leu Gln Leu Ser Asp Leu Tyr Phe Val Glu Pro 1585 1590 1595 1600 Lys Trp Leu Cys Lys Ile Met Ala Gln Ile Leu Thr Val Lys Val Glu                1605 1610 1615 Gly Cys Pro Lys His Pro Lys Gly Ile Ile Ser Arg Arg Asp Val Glu            1620 1625 1630 Lys Phe Leu Ser Lys Lys Arg Lys Phe Pro Lys Asn Tyr Met Ser Gln        1635 1640 1645 Tyr Phe Lys Leu Leu Glu Lys Phe Gln Ile Ala Leu Pro Ile Gly Glu    1650 1655 1660 Glu Tyr Leu Leu Val Pro Ser Ser Leu Ser Asp His Arg Pro Val Ile 1665 1670 1675 1680 Glu Leu Pro His Cys Glu Asn Ser Glu Ile Ile Ile Arg Leu Tyr Glu                1685 1690 1695 Met Pro Tyr Phe Pro Met Gly Phe Trp Ser Arg Leu Ile Asn Arg Leu            1700 1705 1710 Leu Glu Ile Ser Pro Tyr Met Leu Ser Gly Arg Glu Arg Ala Leu Arg        1715 1720 1725 Pro Asn Arg Met Tyr Trp Arg Gln Gly Ile Tyr Leu Asn Trp Ser Pro    1730 1735 1740 Glu Ala Tyr Cys Leu Val Gly Ser Glu Val Leu Asp Asn His Pro Glu 1745 1750 1755 1760 Ser Phe Leu Lys Ile Thr Val Pro Ser Cys Arg Lys Gly Cys Ile Leu                1765 1770 1775 Leu Gly Gln Val Val Asp His Ile Asp Ser Leu Met Glu Glu Trp Phe            1780 1785 1790 Pro Gly Leu Leu Glu Ile Asp Ile Cys Gly Glu Gly Glu Thr Leu Leu        1795 1800 1805 Lys Lys Trp Ala Leu Tyr Ser Phe Asn Asp Gly Glu Glu His Gln Lys    1810 1815 1820 Ile Leu Leu Asp Asp Leu Met Lys Lys Ala Glu Glu Gly Asp Leu Leu 1825 1830 1835 1840 Val Asn Pro Asp Gln Pro Arg Leu Thr Ile Pro Ile Ser Gln Ile Ala                1845 1850 1855 Pro Asp Leu Ile Leu Ala Asp Leu Pro Arg Asn Ile Met Leu Asn Asn            1860 1865 1870 Asp Glu Leu Glu Phe Glu Gln Ala Pro Glu Phe Leu Leu Gly Asp Gly        1875 1880 1885 Ser Phe Gly Ser Val Tyr Arg Ala Ala Tyr Glu Gly Glu Glu Val Ala    1890 1895 1900 Val Lys Ile Phe Asn Lys His Thr Ser Leu Arg Leu Leu Arg Gln Glu 1905 1910 1915 1920 Leu Val Val Leu Cys His Leu His His Pro Ser Leu Ile Ser Leu Leu                1925 1930 1935 Ala Ala Gly Ile Arg Pro Arg Met Leu Val Met Glu Leu Ala Ser Lys            1940 1945 1950 Gly Ser Leu Asp Arg Leu Leu Gln Gln Asp Lys Ala Ser Leu Thr Arg        1955 1960 1965 Thr Leu Gln His Arg Ile Ala Leu His Val Ala Asp Gly Leu Arg Tyr    1970 1975 1980 Leu His Ser Ala Met Ile Ile Tyr Arg Asp Leu Lys Pro His Asn Val 1985 1990 1995 2000 Leu Leu Phe Thr Leu Tyr Pro Asn Ala Ala Ile Ile Ala Lys Ile Ala                2005 2010 2015 Asp Tyr Gly Ile Ala Gln Tyr Cys Cys Arg Met Gly Ile Lys Thr Ser            2020 2025 2030 Glu Gly Thr Pro Gly Phe Arg Ala Pro Glu Val Ala Arg Gly Asn Val        2035 2040 2045 Ile Tyr Asn Gln Gln Ala Asp Val Tyr Ser Phe Gly Leu Leu Leu Tyr    2050 2055 2060 Asp Ile Leu Thr Thr Gly Gly Arg Ile Val Glu Gly Leu Lys Phe Pro 2065 2070 2075 2080 Asn Glu Phe Asp Glu Leu Glu Ile Gln Gly Lys Leu Pro Asp Pro Val                2085 2090 2095 Lys Glu Tyr Gly Cys Ala Pro Trp Pro Met Val Glu Lys Leu Ile Lys            2100 2105 2110 Gln Cys Leu Lys Glu Asn Pro Gln Glu Arg Pro Thr Ser Ala Gln Val        2115 2120 2125 Phe Asp Ile Leu Asn Ser Ala Glu Leu Val Cys Leu Thr Arg Arg Ile    2130 2135 2140 Leu Leu Pro Lys Asn Val Ile Val Glu Cys Met Val Ala Thr His His 2145 2150 2155 2160 Asn Ser Arg Asn Ala Ser Ile Trp Leu Gly Cys Gly His Thr Asp Arg                2165 2170 2175 Gly Gln Leu Ser Phe Leu Asp Leu Asn Thr Glu Gly Tyr Thr Ser Glu            2180 2185 2190 Glu Val Ala Asp Ser Arg Ile Leu Cys Leu Ala Leu Val His Leu Pro        2195 2200 2205 Val Glu Lys Glu Ser Trp Ile Val Ser Gly Thr Gln Ser Gly Thr Leu    2210 2215 2220 Leu Val Ile Asn Thr Glu Asp Gly Lys Lys Arg His Thr Leu Glu Lys 2225 2230 2235 2240 Met Thr Asp Ser Val Thr Cys Leu Tyr Cys Asn Ser Phe Ser Lys Gln                2245 2250 2255 Ser Lys Gln Lys Asn Phe Leu Leu Val Gly Thr Ala Asp Gly Lys Leu            2260 2265 2270 Ala Ile Phe Glu Asp Lys Thr Val Lys Leu Lys Gly Ala Ala Pro Leu        2275 2280 2285 Lys Ile Leu Asn Ile Gly Asn Val Ser Thr Pro Leu Met Cys Leu Ser    2290 2295 2300 Glu Ser Thr Asn Ser Thr Glu Arg Asn Val Met Trp Gly Gly Cys Gly 2305 2310 2315 2320 Thr Lys Ile Phe Ser Phe Ser Asn Asp Phe Thr Ile Gln Lys Leu Ile                2325 2330 2335 Glu Thr Arg Thr Ser Gln Leu Phe Ser Tyr Ala Ala Phe Ser Asp Ser            2340 2345 2350 Asn Ile Ile Thr Val Val Val Asp Thr Ala Leu Tyr Ile Ala Lys Gln        2355 2360 2365 Asn Ser Pro Val Val Glu Val Trp Asp Lys Lys Thr Glu Lys Leu Cys    2370 2375 2380 Gly Leu Ile Asp Cys Val His Phe Leu Arg Glu Val Met Val Lys Glu 2385 2390 2395 2400 Asn Lys Glu Ser Lys His Lys Met Ser Tyr Ser Gly Arg Val Lys Thr                2405 2410 2415 Leu Cys Leu Gln Lys Asn Thr Ala Leu Trp Ile Gly Thr Gly Gly Gly            2420 2425 2430 His Ile Leu Leu Leu Asp Leu Ser Thr Arg Arg Leu Ile Arg Val Ile        2435 2440 2445 Tyr Asn Phe Cys Asn Ser Val Arg Val Met Met Thr Ala Gln Leu Gly    2450 2455 2460 Ser Leu Lys Asn Val Met Leu Val Leu Gly Tyr Asn Arg Lys Asn Thr 2465 2470 2475 2480 Glu Gly Thr Gln Lys Gln Lys Glu Ile Gln Ser Cys Leu Thr Val Trp                2485 2490 2495 Asp Ile Asn Leu Pro His Glu Val Gln Asn Leu Glu Lys His Ile Glu            2500 2505 2510 Val Arg Lys Glu Leu Ala Glu Lys Met Arg Arg Thr Ser Val Glu        2515 2520 2525 <210> 7 <211> 7584 <212> DNA <213> Homo sapiens <400> 7 atggctagtg gcagctgtca ggggtgcgaa gaggacgagg aaactctgaa gaagttgata 60 gtcaggctga acaatgtcca ggaaggaaaa cagatagaaa cgctggtcca aatcctggag 120 gatctgctgg tgttcacgta ctccgagcac gcctccaagt tatttcaagg caaaaatatc 180 catgtgcctc tgttgatcgt cttggactcc tatatgagag tcgcgagtgt gcagcaggtg 240 ggttggtcac ttctgtgcaa attaatagaa gtctgtccag gtacaatgca aagcttaatg 300 ggaccccagg atgttggaaa tgattgggaa gtccttggtg ttcaccaatt gattcttaaa 360 atgctaacag ttcataatgc cagtgtaaac ttgtcagtga ttggactgaa gaccttagat 420 ctcctcctaa cttcaggtaa aatcaccttg ctgatactgg atgaagaaag tgatattttc 480 atgttaattt ttgatgccat gcactcattt ccagccaatg atgaagtcca gaaacttgga 540 tgcaaagctt tacatgtgct gtttgagaga gtctcagagg agcaactgac tgaatttgtt 600 gagaacaaag attatatgat attgttaagt gcgtcaacaa attttaaaga tgaagaggaa 660 attgtgcttc atgtgctgca ttgtttacat tccctagcga ttccttgcaa taatgtggaa 720 gtcctcatga gtggcaatgt caggtgttat aatattgtgg tggaagctat gaaagcattc 780 cctatgagtg aaagaattca agaagtgagt tgctgtttgc tccataggct tacattaggt 840 aattttttca atatcctggt attaaacgaa gtccatgagt ttgtggtgaa agctgtgcag 900 cagtacccag agaatgcagc attgcagatc tcagcgctca gctgtttggc cctcctcact 960 gagactattt tcttaaatca agatttagag gaaaagaatg agaatcaaga gaatgatgat 1020 gagggggaag aagataaatt gttttggctg gaagcctgtt acaaagcatt aacgtggcat 1080 agaaagaaca agcacgtgca ggaggccgca tgctgggcac taaataatct ccttatgtac 1140 caaaacagtt tacatgagaa gattggagat gaagatggcc atttcccagc tcatagggaa 1200 gtgatgctct ccatgctgat gcattcttca tcaaaggaag ttttccaggc atctgcgaat 1260 gcattgtcaa ctctcttaga acaaaatgtt aatttcagaa aaatactgtt atcaaaagga 1320 atacacctga atgttttgga gttaatgcag aagcatatac attctcctga agtggctgaa 1380 agtggctgta aaatgctaaa tcatcttttt gaaggaagca acacttccct ggatataatg 1440 gcagcagtgg tccccaaaat actaacagtt atgaaacgtc atgagacatc attaccagtg 1500 cagctggagg cgcttcgagc tattttacat tttatagtgc ctggcatgcc agaagaatcc 1560 agggaggata cagaatttca tcataagcta aatatggtta aaaaacagtg tttcaagaat 1620 gatattcaca aactggtcct agcagctttg aacaggttca ttggaaatcc tgggattcag 1680 aaatgtggat taaaagtaat ttcttctatt gtacattttc ctgatgcatt agagatgtta 1740 tccctggaag gtgctatgga ttcagtgctt cacacactgc agatgtatcc agatgaccaa 1800 gaaattcagt gtctgggttt aagtcttata ggatacttga ttacaaagaa gaatgtgttc 1860 ataggaactg gacatctgct ggcaaaaatt ctggtttcca gcttataccg atttaaggat 1920 gttgctgaaa tacagactaa aggatttcag acaatcttag caatcctcaa attgtcagca 1980 tctttttcta agctgctggt gcatcattca tttgacttag taatattcca tcaaatgtct 2040 tccaatatca tggaacaaaa ggatcaacag tttctaaacc tctgttgcaa gtgttttgca 2100 aaagtagcta tggatgatta cttaaaaaat gtgatgctag agagagcgtg tgatcagaat 2160 aacagcatca tggttgaatg cttgcttcta ttgggagcag atgccaatca agcaaaggag 2220 ggatcttctt taatttgtca ggtatgtgag aaagagagca gtcccaaatt ggtggaactc 2280 ttactgaata gtggatctcg tgaacaagat gtacgaaaag cgttgacgat aagcattggg 2340 aaaggtgaca gccagatcat cagcttgctc ttaaggaggc tggccctgga tgtggccaac 2400 aatagcattt gccttggagg attttgtata ggaaaagttg aaccttcttg gcttggtcct 2460 ttatttccag ataagacttc taatttaagg aaacaaacaa atatagcatc tacactagca 2520 agaatggtga tcagatatca gatgaaaagt gctgtggaag aaggaacagc ctcaggcagc 2580 gatggaaatt tttctgaaga tgtgctgtct aaatttgatg aatggacctt tattcctgac 2640 tcttctatgg acagtgtgtt tgctcaaagt gatgacctgg atagtgaagg aagtgaaggc 2700 tcatttcttg tgaaaaagaa atctaattca attagtgtag gagaatttta ccgagatgcc 2760 gtattacagc gttgctcacc aaatttgcaa agacattcca attccttggg gcccattttt 2820 gatcatgaag atttactgaa gcgaaaaaga aaaatactat cttcagatga ttcactcagg 2880 tcatcaaaac ttcaatccca tatgaggcat tcagacagca tttcttctct ggcttctgag 2940 agagaatata ttacatcact agacctttca gcaaatgaac taagagatat tgatgcccta 3000 agccagaaat gctgtataag tgttcatttg gagcatcttg aaaagctgga gcttcaccag 3060 aatgcactca cgagctttcc acaacagcta tgtgaaactc tgaagagttt gacacatttg 3120 gacttgcaca gtaataaatt tacatcattt ccttcttatt tgttgaaaat gagttgtatt 3180 gctaatcttg atgtctctcg aaatgacatt ggaccctcag tggttttaga tcctacagtg 3240 aaatgtccaa ctctgaaaca gtttaacctg tcatataacc agctgtcttt tgtacctgag 3300 aacctcactg atgtggtaga gaaactggag cagctcattt tagaaggaaa taaaatatca 3360 gggatatgct cccccttgag actgaaggaa ctgaagattt taaaccttag taagaaccac 3420 atttcatccc tatcagagaa ctttcttgag gcttgtccta aagtggagag tttcagtgcc 3480 agaatgaatt ttcttgctgc tatgcctttc ttgcctcctt ctatgacaat cctaaaatta 3540 tctcagaaca aattttcctg tattccagaa gcaattttaa atcttccaca cttgcggtct 3600 ttagatatga gcagcaatga tattcagtac ctaccaggtc ccgcacactg gaaatctttg 3660 aacttaaggg aactcttatt tagccataat cagatcagca tcttggactt gagtgaaaaa 3720 gcatatttat ggtctagagt agagaaactg catctttctc acaataaact gaaagagatt 3780 cctcctgaga ttggctgtct tgaaaatctg acatctctgg atgtcagtta caacttggaa 3840 ctaagatcct ttcccaatga aatggggaaa ttaagcaaaa tatgggatct tcctttggat 3900 gaactgcatc ttaactttga ttttaaacat ataggatgta aagccaaaga catcataagg 3960 tttcttcaac agcgattaaa aaaggctgtg ccttataacc gaatgaaact tatgattgtg 4020 ggaaatactg ggagtggtaa aaccacctta ttgcagcaat taatgaaaac caagaaatca 4080 gatcttggaa tgcaaagtgc cacagttggc atagatgtga aagactggcc tatccaaata 4140 agagacaaaa gaaagagaga tctcgtccta aatgtgtggg attttgcagg tcgtgaggaa 4200 ttctatagta ctcatcccca ttttatgacg cagcgagcat tgtaccttgc tgtctatgac 4260 ctcagcaagg gacaggctga agttgatgcc atgaagcctt ggctcttcaa tataaaggct 4320 cgcgcttctt cttcccctgt gattctcgtt ggcacacatt tggatgtttc tgatgagaag 4380 caacgcaaag cctgcatgag taaaatcacc aaggaactcc tgaataagcg agggttccct 4440 gccatacgag attaccactt tgtgaatgcc accgaggaat ctgatgcttt ggcaaaactt 4500 cggaaaacca tcataaacga gagccttaat ttcaagatcc gagatcagct tgttgttgga 4560 cagctgattc cagactgcta tgtagaactt gaaaaaatca ttttatcgga gcgtaaaaat 4620 gtgccaattg aatttcccgt aattgaccgg aaacgattat tacaactagt gagagaaaat 4680 cagctgcagt tagatgaaaa tgagcttcct cacgcagttc actttctaaa tgaatcagga 4740 gtccttcttc attttcaaga cccagcactg cagttaagtg acttgtactt tgtggaaccc 4800 aagtggcttt gtaaaatcat ggcacagatt ttgacagtga aagtggaagg ttgtccaaaa 4860 caccctaagg gcattatttc gcgtagagat gtggaaaaat ttctttcaaa aaaaaggaaa 4920 tttccaaaga actacatgtc acagtatttt aagctcctag aaaaattcca gattgctttg 4980 ccaataggag aagaatattt gctggttcca agcagtttgt ctgaccacag gcctgtgata 5040 gagcttcccc attgtgagaa ctctgaaatt atcatccgac tatatgaaat gccttgtttt 5100 ccaatgggat tttggtcaag attaatcaat cgattacttg agatttcacc ttacatgctt 5160 tcagggagag aacgagcact tcgcccaaac agaatgtatt ggcgacaagg catttactta 5220 aattggtctc ctgaagctta ttgtctggta ggatctgaag tcttagacaa tcatccagag 5280 agtttcttaa aaattacagt tccttcttgt agaaaaggct gtattctttt gggccaagtt 5340 gtggaccaca ttgattctct catggaagaa tggtttcctg ggttgctgga gattgatatt 5400 tgtggtgaag gagaaactct gttgaagaaa tgggcattat atagttttaa tgatggcgaa 5460 gaacatcaaa aaatcttact tgatgacttg atgaagaaag cagaggaagg agatctctta 5520 gtaaatccag atcaaccaag gctcaccatt ccaatatctc agattgcccc tgacttgatt 5580 ttggctgacc tgcctagaaa tattatgttg aataatgatg agttggaatt tgaacaagct 5640 ccagagtttc tcctaggtga tggcagtttt ggatcagttt accgagcagc ctatgaagga 5700 gaagaagtgg ctgtgaagat ttttaataaa catacatcac tcaggctgtt aagacaagag 5760 cttgtggtgc tttgccacct ccaccacccc agtttgatat ctttgctggc agctgggatt 5820 cgtccccgga tgttggtgat ggagttagcc tccaagggtt ccttggatcg cctgcttcag 5880 caggacaaag ccagcctcac tagaacccta cagcacagga ttgcactcca cgtagctgat 5940 ggtttgagat acctccactc agccatgatt atataccgag acctgaaacc ccacaatgtg 6000 ctgcttttca cactgtatcc caatgctgcc atcattgcaa agattgctga ctacggcatt 6060 gctcagtact gctgtagaat ggggataaaa acatcagagg gcacaccagg gtttcgtgca 6120 cctgaagttg ccagaggaaa tgtcatttat aaccaacagg ctgatgttta ttcatttggt 6180 ttactactct atgacatttt gacaactgga ggtagaatag tagagggttt gaagtttcca 6240 aatgagtttg atgaattaga aatacaagga aaattacctg atccagttaa agaatatggt 6300 tgtgccccat ggcctatggt tgagaaatta attaaacagt gtttgaaaga aaatcctcaa 6360 gaaaggccta cttctgccca ggtctttgac attttgaatt cagctgaatt agtctgtctg 6420 acgagacgca ttttattacc taaaaacgta attgttgaat gcatggttgc tacacatcac 6480 aacagcagga atgcaagcat ttggctgggc tgtgggcaca ccgacagagg acagctctca 6540 tttcttgact taaatactga aggatacact tctgaggaag ttgctgatag tagaatattg 6600 tgcttagcct tggtgcatct tcctgttgaa aaggaaagct ggattgtgtc tgggacacag 6660 tctggtactc tcctggtcat caataccgaa gatgggaaaa agagacatac cctagaaaag 6720 atgactgatt ctgtcacttg tttgtattgc aattcctttt ccaagcaaag caaacaaaaa 6780 aattttcttt tggttggaac cgctgatggc aagttagcaa tttttgaaga taagactgtt 6840 aagcttaaag gagctgctcc tttgaagata ctaaatatag gaaatgtcag tactccattg 6900 atgtgtttga gtgaatccac aaattcaacg gaaagaaatg taatgtgggg aggatgtggc 6960 acaaagattt tctccttttc taatgatttc accattcaga aactcattga gacaagaaca 7020 agccaactgt tttcttatgc agctttcagt gattccaaca tcataacagt ggtggtagac 7080 actgctctct atattgctaa gcaaaatagc cctgttgtgg aagtgtggga taagaaaact 7140 gaaaaactct gtggactaat agactgcgtg cactttttaa gggaggtaat ggtaaaagaa 7200 aacaaggaat caaaacacaa aatgtcttat tctgggagag tgaaaaccct ctgccttcag 7260 aagaacactg ctctttggat aggaactgga ggaggccata ttttactcct ggatctttca 7320 actcgtcgac ttatacgtgt aatttacaac ttttgtaatt cggtcagagt catgatgaca 7380 gcacagctag gaagccttaa aaatgtcatg ctggtattgg gctacaaccg gaaaaatact 7440 gaaggtacac aaaagcagaa agagatacaa tcttgcttga ccgtttggga catcaatctt 7500 ccacatgaag tgcaaaattt agaaaaacac attgaagtga gaaaagaatt agctgaaaaa 7560 atgagacgaa catctgttga gtaa 7584 <210> 8 <211> 2527 <212> PRT <213> Homo sapiens <400> 8 Met Ala Ser Gly Ser Cys Gln Gly Cys Glu Glu Asp Glu Glu Thr Leu   1 5 10 15 Lys Lys Leu Ile Val Arg Leu Asn Asn Val Gln Glu Gly Lys Gln Ile              20 25 30 Glu Thr Leu Val Gln Ile Leu Glu Asp Leu Leu Val Phe Thr Tyr Ser          35 40 45 Glu His Ala Ser Lys Leu Phe Gln Gly Lys Asn Ile His Val Pro Leu      50 55 60 Leu Ile Val Leu Asp Ser Tyr Met Arg Val Ala Ser Val Gln Gln Val  65 70 75 80 Gly Trp Ser Leu Leu Cys Lys Leu Ile Glu Val Cys Pro Gly Thr Met                  85 90 95 Gln Ser Leu Met Gly Pro Gln Asp Val Gly Asn Asp Trp Glu Val Leu             100 105 110 Gly Val His Gln Leu Ile Leu Lys Met Leu Thr Val His Asn Ala Ser         115 120 125 Val Asn Leu Ser Val Ile Gly Leu Lys Thr Leu Asp Leu Leu Leu Thr     130 135 140 Ser Gly Lys Ile Thr Leu Leu Ile Leu Asp Glu Glu Ser Asp Ile Phe 145 150 155 160 Met Leu Ile Phe Asp Ala Met His Ser Phe Pro Ala Asn Asp Glu Val                 165 170 175 Gln Lys Leu Gly Cys Lys Ala Leu His Val Leu Phe Glu Arg Val Ser             180 185 190 Glu Glu Gln Leu Thr Glu Phe Val Glu Asn Lys Asp Tyr Met Ile Leu         195 200 205 Leu Ser Ala Leu Thr Asn Phe Lys Asp Glu Glu Glu Ile Val Leu His     210 215 220 Val Leu His Cys Leu His Ser Leu Ala Ile Pro Cys Asn Asn Val Glu 225 230 235 240 Val Leu Met Ser Gly Asn Val Arg Cys Tyr Asn Ile Val Val Glu Ala                 245 250 255 Met Lys Ala Phe Pro Met Ser Glu Arg Ile Gln Glu Val Ser Cys Cys             260 265 270 Leu Leu His Arg Leu Thr Leu Gly Asn Phe Phe Asn Ile Leu Val Leu         275 280 285 Asn Glu Val His Glu Phe Val Val Lys Ala Val Gln Gln Tyr Pro Glu     290 295 300 Asn Ala Ala Leu Gln Ile Ser Ala Leu Ser Cys Leu Ala Leu Leu Thr 305 310 315 320 Glu Thr Ile Phe Leu Asn Gln Asp Leu Glu Glu Lys Asn Glu Asn Gln                 325 330 335 Glu Asn Asp Asp Glu Gly Glu Glu Asp Lys Leu Phe Trp Leu Glu Ala             340 345 350 Cys Tyr Lys Ala Leu Thr Trp His Arg Lys Asn Lys His Val Gln Glu         355 360 365 Ala Ala Cys Trp Ala Leu Asn Asn Leu Leu Met Tyr Gln Asn Ser Leu     370 375 380 His Glu Lys Ile Gly Asp Glu Asp Gly His Phe Pro Ala His Arg Glu 385 390 395 400 Val Met Leu Ser Met Leu Met His Ser Ser Ser Lys Glu Val Phe Gln                 405 410 415 Ala Ser Ala Asn Ala Leu Ser Thr Leu Leu Glu Gln Asn Val Asn Phe             420 425 430 Arg Lys Ile Leu Leu Ser Lys Gly Ile His Leu Asn Val Leu Glu Leu         435 440 445 Met Gln Lys His Ile His Ser Pro Glu Val Ala Glu Ser Gly Cys Lys     450 455 460 Met Leu Asn His Leu Phe Glu Gly Ser Asn Thr Ser Leu Asp Ile Met 465 470 475 480 Ala Ala Val Val Pro Lys Ile Leu Thr Val Met Lys Arg His Glu Thr                 485 490 495 Ser Leu Pro Val Gln Leu Glu Ala Leu Arg Ala Ile Leu His Phe Ile             500 505 510 Val Pro Gly Met Pro Glu Glu Ser Arg Glu Asp Thr Glu Phe His His         515 520 525 Lys Leu Asn Met Val Lys Lys Gln Cys Phe Lys Asn Asp Ile His Lys     530 535 540 Leu Val Leu Ala Ala Leu Asn Arg Phe Ile Gly Asn Pro Gly Ile Gln 545 550 555 560 Lys Cys Gly Leu Lys Val Ile Ser Ser Ile Val His Phe Pro Asp Ala                 565 570 575 Leu Glu Met Leu Ser Leu Glu Gly Ala Met Asp Ser Val Leu His Thr             580 585 590 Leu Gln Met Tyr Pro Asp Asp Gln Glu Ile Gln Cys Leu Gly Leu Ser         595 600 605 Leu Ile Gly Tyr Leu Ile Thr Lys Lys Asn Val Phe Ile Gly Thr Gly     610 615 620 His Leu Leu Ala Lys Ile Leu Val Ser Ser Leu Tyr Arg Phe Lys Asp 625 630 635 640 Val Ala Glu Ile Gln Thr Lys Gly Phe Gln Thr Ile Leu Ala Ile Leu                 645 650 655 Lys Leu Ser Ala Ser Phe Ser Lys Leu Leu Val His His Ser Phe Asp             660 665 670 Leu Val Ile Phe His Gln Met Ser Ser Asn Ile Met Glu Gln Lys Asp         675 680 685 Gln Gln Phe Leu Asn Leu Cys Cys Lys Cys Phe Ala Lys Val Ala Met     690 695 700 Asp Asp Tyr Leu Lys Asn Val Met Leu Glu Arg Ala Cys Asp Gln Asn 705 710 715 720 Asn Ser Ile Met Val Glu Cys Leu Leu Leu Leu Gly Ala Asp Ala Asn                 725 730 735 Gln Ala Lys Glu Gly Ser Ser Leu Ile Cys Gln Val Cys Glu Lys Glu             740 745 750 Ser Ser Pro Lys Leu Val Glu Leu Leu Leu Asn Ser Gly Ser Arg Glu         755 760 765 Gln Asp Val Arg Lys Ala Leu Thr Ile Ser Ile Gly Lys Gly Asp Ser     770 775 780 Gln Ile Ile Ser Leu Leu Leu Arg Arg Leu Ala Leu Asp Val Ala Asn 785 790 795 800 Asn Ser Ile Cys Leu Gly Gly Phe Cys Ile Gly Lys Val Glu Pro Ser                 805 810 815 Trp Leu Gly Pro Leu Phe Pro Asp Lys Thr Ser Asn Leu Arg Lys Gln             820 825 830 Thr Asn Ile Ala Ser Thr Leu Ala Arg Met Val Ile Arg Tyr Gln Met         835 840 845 Lys Ser Ala Val Glu Glu Gly Thr Ala Ser Gly Ser Asp Gly Asn Phe     850 855 860 Ser Glu Asp Val Leu Ser Lys Phe Asp Glu Trp Thr Phe Ile Pro Asp 865 870 875 880 Ser Ser Met Asp Ser Val Phe Ala Gln Ser Asp Asp Leu Asp Ser Glu                 885 890 895 Gly Ser Glu Gly Ser Phe Leu Val Lys Lys Lys Ser Asn Ser Ile Ser             900 905 910 Val Gly Glu Phe Tyr Arg Asp Ala Val Leu Gln Arg Cys Ser Pro Asn         915 920 925 Leu Gln Arg His Ser Asn Ser Leu Gly Pro Ile Phe Asp His Glu Asp     930 935 940 Leu Leu Lys Arg Lys Arg Lys Ile Leu Ser Ser Asp Asp Ser Leu Arg 945 950 955 960 Ser Ser Lys Leu Gln Ser His Met Arg His Ser Asp Ser Ile Ser Ser                 965 970 975 Leu Ala Ser Glu Arg Glu Tyr Ile Thr Ser Leu Asp Leu Ser Ala Asn             980 985 990 Glu Leu Arg Asp Ile Asp Ala Leu Ser Gln Lys Cys Cys Ile Ser Val         995 1000 1005 His Leu Glu His Leu Glu Lys Leu Glu Leu His Gln Asn Ala Leu Thr    1010 1015 1020 Ser Phe Pro Gln Gln Leu Cys Glu Thr Leu Lys Ser Leu Thr His Leu 1025 1030 1035 1040 Asp Leu His Ser Asn Lys Phe Thr Ser Phe Pro Ser Tyr Leu Leu Lys                1045 1050 1055 Met Ser Cys Ile Ala Asn Leu Asp Val Ser Arg Asn Asp Ile Gly Pro            1060 1065 1070 Ser Val Val Leu Asp Pro Thr Val Lys Cys Pro Thr Leu Lys Gln Phe        1075 1080 1085 Asn Leu Ser Tyr Asn Gln Leu Ser Phe Val Pro Glu Asn Leu Thr Asp    1090 1095 1100 Val Val Glu Lys Leu Glu Gln Leu Ile Leu Glu Gly Asn Lys Ile Ser 1105 1110 1115 1120 Gly Ile Cys Ser Pro Leu Arg Leu Lys Glu Leu Lys Ile Leu Asn Leu                1125 1130 1135 Ser Lys Asn His Ile Ser Ser Leu Ser Glu Asn Phe Leu Glu Ala Cys            1140 1145 1150 Pro Lys Val Glu Ser Phe Ser Ala Arg Met Asn Phe Leu Ala Ala Met        1155 1160 1165 Pro Phe Leu Pro Pro Ser Met Thr Ile Leu Lys Leu Ser Gln Asn Lys    1170 1175 1180 Phe Ser Cys Ile Pro Glu Ala Ile Leu Asn Leu Pro His Leu Arg Ser 1185 1190 1195 1200 Leu Asp Met Ser Ser Asn Asp Ile Gln Tyr Leu Pro Gly Pro Ala His                1205 1210 1215 Trp Lys Ser Leu Asn Leu Arg Glu Leu Leu Phe Ser His Asn Gln Ile            1220 1225 1230 Ser Ile Leu Asp Leu Ser Glu Lys Ala Tyr Leu Trp Ser Arg Val Glu        1235 1240 1245 Lys Leu His Leu Ser His Asn Lys Leu Lys Glu Ile Pro Pro Glu Ile    1250 1255 1260 Gly Cys Leu Glu Asn Leu Thr Ser Leu Asp Val Ser Tyr Asn Leu Glu 1265 1270 1275 1280 Leu Arg Ser Phe Pro Asn Glu Met Gly Lys Leu Ser Lys Ile Trp Asp                1285 1290 1295 Leu Pro Leu Asp Glu Leu His Leu Asn Phe Asp Phe Lys His Ile Gly            1300 1305 1310 Cys Lys Ala Lys Asp Ile Ile Arg Phe Leu Gln Gln Arg Leu Lys Lys        1315 1320 1325 Ala Val Pro Tyr Asn Arg Met Lys Leu Met Ile Val Gly Asn Thr Gly    1330 1335 1340 Ser Gly Lys Thr Thr Leu Leu Gln Gln Leu Met Lys Thr Lys Lys Ser 1345 1350 1355 1360 Asp Leu Gly Met Gln Ser Ala Thr Val Gly Ile Asp Val Lys Asp Trp                1365 1370 1375 Pro Ile Gln Ile Arg Asp Lys Arg Lys Arg Asp Leu Val Leu Asn Val            1380 1385 1390 Trp Asp Phe Ala Gly Arg Glu Glu Phe Tyr Ser Thr His Pro His Phe        1395 1400 1405 Met Thr Gln Arg Ala Leu Tyr Leu Ala Val Tyr Asp Leu Ser Lys Gly    1410 1415 1420 Gln Ala Glu Val Asp Ala Met Lys Pro Trp Leu Phe Asn Ile Lys Ala 1425 1430 1435 1440 Arg Ala Ser Ser Ser Pro Val Ile Leu Val Gly Thr His Leu Asp Val                1445 1450 1455 Ser Asp Glu Lys Gln Arg Lys Ala Cys Met Ser Lys Ile Thr Lys Glu            1460 1465 1470 Leu Leu Asn Lys Arg Gly Phe Pro Ala Ile Arg Asp Tyr His Phe Val        1475 1480 1485 Asn Ala Thr Glu Glu Ser Asp Ala Leu Ala Lys Leu Arg Lys Thr Ile    1490 1495 1500 Ile Asn Glu Ser Leu Asn Phe Lys Ile Arg Asp Gln Leu Val Val Gly 1505 1510 1515 1520 Gln Leu Ile Pro Asp Cys Tyr Val Glu Leu Glu Lys Ile Ile Leu Ser                1525 1530 1535 Glu Arg Lys Asn Val Pro Ile Glu Phe Pro Val Ile Asp Arg Lys Arg            1540 1545 1550 Leu Leu Gln Leu Val Arg Glu Asn Gln Leu Gln Leu Asp Glu Asn Glu        1555 1560 1565 Leu Pro His Ala Val His Phe Leu Asn Glu Ser Gly Val Leu Leu His    1570 1575 1580 Phe Gln Asp Pro Ala Leu Gln Leu Ser Asp Leu Tyr Phe Val Glu Pro 1585 1590 1595 1600 Lys Trp Leu Cys Lys Ile Met Ala Gln Ile Leu Thr Val Lys Val Glu                1605 1610 1615 Gly Cys Pro Lys His Pro Lys Gly Ile Ile Ser Arg Arg Asp Val Glu            1620 1625 1630 Lys Phe Leu Ser Lys Lys Arg Lys Phe Pro Lys Asn Tyr Met Ser Gln        1635 1640 1645 Tyr Phe Lys Leu Leu Glu Lys Phe Gln Ile Ala Leu Pro Ile Gly Glu    1650 1655 1660 Glu Tyr Leu Leu Val Pro Ser Ser Leu Ser Asp His Arg Pro Val Ile 1665 1670 1675 1680 Glu Leu Pro His Cys Glu Asn Ser Glu Ile Ile Ile Arg Leu Tyr Glu                1685 1690 1695 Met Pro Cys Phe Pro Met Gly Phe Trp Ser Arg Leu Ile Asn Arg Leu            1700 1705 1710 Leu Glu Ile Ser Pro Tyr Met Leu Ser Gly Arg Glu Arg Ala Leu Arg        1715 1720 1725 Pro Asn Arg Met Tyr Trp Arg Gln Gly Ile Tyr Leu Asn Trp Ser Pro    1730 1735 1740 Glu Ala Tyr Cys Leu Val Gly Ser Glu Val Leu Asp Asn His Pro Glu 1745 1750 1755 1760 Ser Phe Leu Lys Ile Thr Val Pro Ser Cys Arg Lys Gly Cys Ile Leu                1765 1770 1775 Leu Gly Gln Val Val Asp His Ile Asp Ser Leu Met Glu Glu Trp Phe            1780 1785 1790 Pro Gly Leu Leu Glu Ile Asp Ile Cys Gly Glu Gly Glu Thr Leu Leu        1795 1800 1805 Lys Lys Trp Ala Leu Tyr Ser Phe Asn Asp Gly Glu Glu His Gln Lys    1810 1815 1820 Ile Leu Leu Asp Asp Leu Met Lys Lys Ala Glu Glu Gly Asp Leu Leu 1825 1830 1835 1840 Val Asn Pro Asp Gln Pro Arg Leu Thr Ile Pro Ile Ser Gln Ile Ala                1845 1850 1855 Pro Asp Leu Ile Leu Ala Asp Leu Pro Arg Asn Ile Met Leu Asn Asn            1860 1865 1870 Asp Glu Leu Glu Phe Glu Gln Ala Pro Glu Phe Leu Leu Gly Asp Gly        1875 1880 1885 Ser Phe Gly Ser Val Tyr Arg Ala Ala Tyr Glu Gly Glu Glu Val Ala    1890 1895 1900 Val Lys Ile Phe Asn Lys His Thr Ser Leu Arg Leu Leu Arg Gln Glu 1905 1910 1915 1920 Leu Val Val Leu Cys His Leu His His Pro Ser Leu Ile Ser Leu Leu                1925 1930 1935 Ala Ala Gly Ile Arg Pro Arg Met Leu Val Met Glu Leu Ala Ser Lys            1940 1945 1950 Gly Ser Leu Asp Arg Leu Leu Gln Gln Asp Lys Ala Ser Leu Thr Arg        1955 1960 1965 Thr Leu Gln His Arg Ile Ala Leu His Val Ala Asp Gly Leu Arg Tyr    1970 1975 1980 Leu His Ser Ala Met Ile Ile Tyr Arg Asp Leu Lys Pro His Asn Val 1985 1990 1995 2000 Leu Leu Phe Thr Leu Tyr Pro Asn Ala Ala Ile Ile Ala Lys Ile Ala                2005 2010 2015 Asp Tyr Gly Ile Ala Gln Tyr Cys Cys Arg Met Gly Ile Lys Thr Ser            2020 2025 2030 Glu Gly Thr Pro Gly Phe Arg Ala Pro Glu Val Ala Arg Gly Asn Val        2035 2040 2045 Ile Tyr Asn Gln Gln Ala Asp Val Tyr Ser Phe Gly Leu Leu Leu Tyr    2050 2055 2060 Asp Ile Leu Thr Thr Gly Gly Arg Ile Val Glu Gly Leu Lys Phe Pro 2065 2070 2075 2080 Asn Glu Phe Asp Glu Leu Glu Ile Gln Gly Lys Leu Pro Asp Pro Val                2085 2090 2095 Lys Glu Tyr Gly Cys Ala Pro Trp Pro Met Val Glu Lys Leu Ile Lys            2100 2105 2110 Gln Cys Leu Lys Glu Asn Pro Gln Glu Arg Pro Thr Ser Ala Gln Val        2115 2120 2125 Phe Asp Ile Leu Asn Ser Ala Glu Leu Val Cys Leu Thr Arg Arg Ile    2130 2135 2140 Leu Leu Pro Lys Asn Val Ile Val Glu Cys Met Val Ala Thr His His 2145 2150 2155 2160 Asn Ser Arg Asn Ala Ser Ile Trp Leu Gly Cys Gly His Thr Asp Arg                2165 2170 2175 Gly Gln Leu Ser Phe Leu Asp Leu Asn Thr Glu Gly Tyr Thr Ser Glu            2180 2185 2190 Glu Val Ala Asp Ser Arg Ile Leu Cys Leu Ala Leu Val His Leu Pro        2195 2200 2205 Val Glu Lys Glu Ser Trp Ile Val Ser Gly Thr Gln Ser Gly Thr Leu    2210 2215 2220 Leu Val Ile Asn Thr Glu Asp Gly Lys Lys Arg His Thr Leu Glu Lys 2225 2230 2235 2240 Met Thr Asp Ser Val Thr Cys Leu Tyr Cys Asn Ser Phe Ser Lys Gln                2245 2250 2255 Ser Lys Gln Lys Asn Phe Leu Leu Val Gly Thr Ala Asp Gly Lys Leu            2260 2265 2270 Ala Ile Phe Glu Asp Lys Thr Val Lys Leu Lys Gly Ala Ala Pro Leu        2275 2280 2285 Lys Ile Leu Asn Ile Gly Asn Val Ser Thr Pro Leu Met Cys Leu Ser    2290 2295 2300 Glu Ser Thr Asn Ser Thr Glu Arg Asn Val Met Trp Gly Gly Cys Gly 2305 2310 2315 2320 Thr Lys Ile Phe Ser Phe Ser Asn Asp Phe Thr Ile Gln Lys Leu Ile                2325 2330 2335 Glu Thr Arg Thr Ser Gln Leu Phe Ser Tyr Ala Ala Phe Ser Asp Ser            2340 2345 2350 Asn Ile Ile Thr Val Val Val Asp Thr Ala Leu Tyr Ile Ala Lys Gln        2355 2360 2365 Asn Ser Pro Val Val Glu Val Trp Asp Lys Lys Thr Glu Lys Leu Cys    2370 2375 2380 Gly Leu Ile Asp Cys Val His Phe Leu Arg Glu Val Met Val Lys Glu 2385 2390 2395 2400 Asn Lys Glu Ser Lys His Lys Met Ser Tyr Ser Gly Arg Val Lys Thr                2405 2410 2415 Leu Cys Leu Gln Lys Asn Thr Ala Leu Trp Ile Gly Thr Gly Gly Gly            2420 2425 2430 His Ile Leu Leu Leu Asp Leu Ser Thr Arg Arg Leu Ile Arg Val Ile        2435 2440 2445 Tyr Asn Phe Cys Asn Ser Val Arg Val Met Met Thr Ala Gln Leu Gly    2450 2455 2460 Ser Leu Lys Asn Val Met Leu Val Leu Gly Tyr Asn Arg Lys Asn Thr 2465 2470 2475 2480 Glu Gly Thr Gln Lys Gln Lys Glu Ile Gln Ser Cys Leu Thr Val Trp                2485 2490 2495 Asp Ile Asn Leu Pro His Glu Val Gln Asn Leu Glu Lys His Ile Glu            2500 2505 2510 Val Arg Lys Glu Leu Ala Glu Lys Met Arg Arg Thr Ser Val Glu        2515 2520 2525 <210> 9 <211> 7584 <212> DNA <213> Homo sapiens <400> 9 atggctagtg gcagctgtca ggggtgcgaa gaggacgagg aaactctgaa gaagttgata 60 gtcaggctga acaatgtcca ggaaggaaaa cagatagaaa cgctggtcca aatcctggag 120 gatctgctgg tgttcacgta ctccgagcac gcctccaagt tatttcaagg caaaaatatc 180 catgtgcctc tgttgatcgt cttggactcc tatatgagag tcgcgagtgt gcagcaggtg 240 ggttggtcac ttctgtgcaa attaatagaa gtctgtccag gtacaatgca aagcttaatg 300 ggaccccagg atgttggaaa tgattgggaa gtccttggtg ttcaccaatt gattcttaaa 360 atgctaacag ttcataatgc cagtgtaaac ttgtcagtga ttggactgaa gaccttagat 420 ctcctcctaa cttcaggtaa aatcaccttg ctgatactgg atgaagaaag tgatattttc 480 atgttaattt ttgatgccat gcactcattt ccagccaatg atgaagtcca gaaacttgga 540 tgcaaagctt tacatgtgct gtttgagaga gtctcagagg agcaactgac tgaatttgtt 600 gagaacaaag attatatgat attgttaagt gcgtcaacaa attttaaaga tgaagaggaa 660 attgtgcttc atgtgctgca ttgtttacat tccctagcga ttccttgcaa taatgtggaa 720 gtcctcatga gtggcaatgt caggtgttat aatattgtgg tggaagctat gaaagcattc 780 cctatgagtg aaagaattca agaagtgagt tgctgtttgc tccataggct tacattaggt 840 aattttttca atatcctggt attaaacgaa gtccatgagt ttgtggtgaa agctgtgcag 900 cagtacccag agaatgcagc attgcagatc tcagcgctca gctgtttggc cctcctcact 960 gagactattt tcttaaatca agatttagag gaaaagaatg agaatcaaga gaatgatgat 1020 gagggggaag aagataaatt gttttggctg gaagcctgtt acaaagcatt aacgtggcat 1080 agaaagaaca agcacgtgca ggaggccgca tgctgggcac taaataatct ccttatgtac 1140 caaaacagtt tacatgagaa gattggagat gaagatggcc atttcccagc tcatagggaa 1200 gtgatgctct ccatgctgat gcattcttca tcaaaggaag ttttccaggc atctgcgaat 1260 gcattgtcaa ctctcttaga acaaaatgtt aatttcagaa aaatactgtt atcaaaagga 1320 atacacctga atgttttgga gttaatgcag aagcatatac attctcctga agtggctgaa 1380 agtggctgta aaatgctaaa tcatcttttt gaaggaagca acacttccct ggatataatg 1440 gcagcagtgg tccccaaaat actaacagtt atgaaacgtc atgagacatc attaccagtg 1500 cagctggagg cgcttcgagc tattttacat tttatagtgc ctggcatgcc agaagaatcc 1560 agggaggata cagaatttca tcataagcta aatatggtta aaaaacagtg tttcaagaat 1620 gatattcaca aactggtcct agcagctttg aacaggttca ttggaaatcc tgggattcag 1680 aaatgtggat taaaagtaat ttcttctatt gtacattttc ctgatgcatt agagatgtta 1740 tccctggaag gtgctatgga ttcagtgctt cacacactgc agatgtatcc agatgaccaa 1800 gaaattcagt gtctgggttt aagtcttata ggatacttga ttacaaagaa gaatgtgttc 1860 ataggaactg gacatctgct ggcaaaaatt ctggtttcca gcttataccg atttaaggat 1920 gttgctgaaa tacagactaa aggatttcag acaatcttag caatcctcaa attgtcagca 1980 tctttttcta agctgctggt gcatcattca tttgacttag taatattcca tcaaatgtct 2040 tccaatatca tggaacaaaa ggatcaacag tttctaaacc tctgttgcaa gtgttttgca 2100 aaagtagcta tggatgatta cttaaaaaat gtgatgctag agagagcgtg tgatcagaat 2160 aacagcatca tggttgaatg cttgcttcta ttgggagcag atgccaatca agcaaaggag 2220 ggatcttctt taatttgtca ggtatgtgag aaagagagca gtcccaaatt ggtggaactc 2280 ttactgaata gtggatctcg tgaacaagat gtacgaaaag cgttgacgat aagcattggg 2340 aaaggtgaca gccagatcat cagcttgctc ttaaggaggc tggccctgga tgtggccaac 2400 aatagcattt gccttggagg attttgtata ggaaaagttg aaccttcttg gcttggtcct 2460 ttatttccag ataagacttc taatttaagg aaacaaacaa atatagcatc tacactagca 2520 agaatggtga tcagatatca gatgaaaagt gctgtggaag aaggaacagc ctcaggcagc 2580 gatggaaatt tttctgaaga tgtgctgtct aaatttgatg aatggacctt tattcctgac 2640 tcttctatgg acagtgtgtt tgctcaaagt gatgacctgg atagtgaagg aagtgaaggc 2700 tcatttcttg tgaaaaagaa atctaattca attagtgtag gagaatttta ccgagatgcc 2760 gtattacagc gttgctcacc aaatttgcaa agacattcca attccttggg gcccattttt 2820 gatcatgaag atttactgaa gcgaaaaaga aaaatactat cttcagatga ttcactcagg 2880 tcatcaaaac ttcaatccca tatgaggcat tcagacagca tttcttctct ggcttctgag 2940 agagaatata ttacatcact agacctttca gcaaatgaac taagagatat tgatgcccta 3000 agccagaaat gctgtataag tgttcatttg gagcatcttg aaaagctgga gcttcaccag 3060 aatgcactca cgagctttcc acaacagcta tgtgaaactc tgaagagttt gacacatttg 3120 gacttgcaca gtaataaatt tacatcattt ccttcttatt tgttgaaaat gagttgtatt 3180 gctaatcttg atgtctctcg aaatgacatt ggaccctcag tggttttaga tcctacagtg 3240 aaatgtccaa ctctgaaaca gtttaacctg tcatataacc agctgtcttt tgtacctgag 3300 aacctcactg atgtggtaga gaaactggag cagctcattt tagaaggaaa taaaatatca 3360 gggatatgct cccccttgag actgaaggaa ctgaagattt taaaccttag taagaaccac 3420 atttcatccc tatcagagaa ctttcttgag gcttgtccta aagtggagag tttcagtgcc 3480 agaatgaatt ttcttgctgc tatgcctttc ttgcctcctt ctatgacaat cctaaaatta 3540 tctcagaaca aattttcctg tattccagaa gcaattttaa atcttccaca cttgcggtct 3600 ttagatatga gcagcaatga tattcagtac ctaccaggtc ccgcacactg gaaatctttg 3660 aacttaaggg aactcttatt tagccataat cagatcagca tcttggactt gagtgaaaaa 3720 gcatatttat ggtctagagt agagaaactg catctttctc acaataaact gaaagagatt 3780 cctcctgaga ttggctgtct tgaaaatctg acatctctgg atgtcagtta caacttggaa 3840 ctaagatcct ttcccaatga aatggggaaa ttaagcaaaa tatgggatct tcctttggat 3900 gaactgcatc ttaactttga ttttaaacat ataggatgta aagccaaaga catcataagg 3960 tttcttcaac agcgattaaa aaaggctgtg ccttataacc gaatgaaact tatgattgtg 4020 ggaaatactg ggagtggtaa aaccacctta ttgcagcaat taatgaaaac caagaaatca 4080 gatcttggaa tgcaaagtgc cacagttggc atagatgtga aagactggcc tatccaaata 4140 agagacaaaa gaaagagaga tctcgtccta aatgtgtggg attttgcagg tcgtgaggaa 4200 ttctatagta ctcatcccca ttttatgacg cagcgagcat tgtaccttgc tgtctatgac 4260 ctcagcaagg gacaggctga agttgatgcc atgaagcctt ggctcttcaa tataaaggct 4320 cgcgcttctt cttcccctgt gattctcgtt ggcacacatt tggatgtttc tgatgagaag 4380 caacgcaaag cctgcatgag taaaatcacc aaggaactcc tgaataagcg agggttccct 4440 gccatacgag attaccactt tgtgaatgcc accgaggaat ctgatgcttt ggcaaaactt 4500 cggaaaacca tcataaacga gagccttaat ttcaagatcc gagatcagct tgttgttgga 4560 cagctgattc cagactgcta tgtagaactt gaaaaaatca ttttatcgga gcgtaaaaat 4620 gtgccaattg aatttcccgt aattgaccgg aaacgattat tacaactagt gagagaaaat 4680 cagctgcagt tagatgaaaa tgagcttcct cacgcagttc actttctaaa tgaatcagga 4740 gtccttcttc attttcaaga cccagcactg cagttaagtg acttgtactt tgtggaaccc 4800 aagtggcttt gtaaaatcat ggcacagatt ttgacagtga aagtggaagg ttgtccaaaa 4860 caccctaagg gcattatttc gcgtagagat gtggaaaaat ttctttcaaa aaaaaggaaa 4920 tttccaaaga actacatgtc acagtatttt aagctcctag aaaaattcca gattgctttg 4980 ccaataggag aagaatattt gctggttcca agcagtttgt ctgaccacag gcctgtgata 5040 gagcttcccc attgtgagaa ctctgaaatt atcatccgac tatatgaaat gccttatttt 5100 ccaatgggat tttggtcaag attaatcaat cgattacttg agatttcacc ttacatgctt 5160 tcagggagag aacgagcact tcgcccaaac agaatgtatt ggcgacaagg catttactta 5220 aattggtctc ctgaagctta ttgtctggta ggatctgaag tcttagacaa tcatccagag 5280 agtttcttaa aaattacagt tccttcttgt agaaaaggct gtattctttt gggccaagtt 5340 gtggaccaca ttgattctct catggaagaa tggtttcctg ggttgctgga gattgatatt 5400 tgtggtgaag gagaaactct gttgaagaaa tgggcattat atagttttaa tgatggcgaa 5460 gaacatcaaa aaatcttact tgatgacttg atgaagaaag cagaggaagg agatctctta 5520 gtaaatccag atcaaccaag gctcaccatt ccaatatctc agattgcccc tgacttgatt 5580 ttggctgacc tgcctagaaa tattatgttg aataatgatg agttggaatt tgaacaagct 5640 ccagagtttc tcctaggtga tggcagtttt ggatcagttt accgagcagc ctatgaagga 5700 gaagaagtgg ctgtgaagat ttttaataaa catacatcac tcaggctgtt aagacaagag 5760 cttgtggtgc tttgccacct ccaccacccc agtttgatat ctttgctggc agctgggatt 5820 cgtccccgga tgttggtgat ggagttagcc tccaagggtt ccttggatcg cctgcttcag 5880 caggacaaag ccagcctcac tagaacccta cagcacagga ttgcactcca cgtagctgat 5940 ggtttgagat acctccactc agccatgatt atataccgag acctgaaacc ccacaatgtg 6000 ctgcttttca cactgtatcc caatgctgcc atcattgcaa agattgctga ctacggcact 6060 gctcagtact gctgtagaat ggggataaaa acatcagagg gcacaccagg gtttcgtgca 6120 cctgaagttg ccagaggaaa tgtcatttat aaccaacagg ctgatgttta ttcatttggt 6180 ttactactct atgacatttt gacaactgga ggtagaatag tagagggttt gaagtttcca 6240 aatgagtttg atgaattaga aatacaagga aaattacctg atccagttaa agaatatggt 6300 tgtgccccat ggcctatggt tgagaaatta attaaacagt gtttgaaaga aaatcctcaa 6360 gaaaggccta cttctgccca ggtctttgac attttgaatt cagctgaatt agtctgtctg 6420 acgagacgca ttttattacc taaaaacgta attgttgaat gcatggttgc tacacatcac 6480 aacagcagga atgcaagcat ttggctgggc tgtgggcaca ccgacagagg acagctctca 6540 tttcttgact taaatactga aggatacact tctgaggaag ttgctgatag tagaatattg 6600 tgcttagcct tggtgcatct tcctgttgaa aaggaaagct ggattgtgtc tgggacacag 6660 tctggtactc tcctggtcat caataccgaa gatgggaaaa agagacatac cctagaaaag 6720 atgactgatt ctgtcacttg tttgtattgc aattcctttt ccaagcaaag caaacaaaaa 6780 aattttcttt tggttggaac cgctgatggc aagttagcaa tttttgaaga taagactgtt 6840 aagcttaaag gagctgctcc tttgaagata ctaaatatag gaaatgtcag tactccattg 6900 atgtgtttga gtgaatccac aaattcaacg gaaagaaatg taatgtgggg aggatgtggc 6960 acaaagattt tctccttttc taatgatttc accattcaga aactcattga gacaagaaca 7020 agccaactgt tttcttatgc agctttcagt gattccaaca tcataacagt ggtggtagac 7080 actgctctct atattgctaa gcaaaatagc cctgttgtgg aagtgtggga taagaaaact 7140 gaaaaactct gtggactaat agactgcgtg cactttttaa gggaggtaat ggtaaaagaa 7200 aacaaggaat caaaacacaa aatgtcttat tctgggagag tgaaaaccct ctgccttcag 7260 aagaacactg ctctttggat aggaactgga ggaggccata ttttactcct ggatctttca 7320 actcgtcgac ttatacgtgt aatttacaac ttttgtaatt cggtcagagt catgatgaca 7380 gcacagctag gaagccttaa aaatgtcatg ctggtattgg gctacaaccg gaaaaatact 7440 gaaggtacac aaaagcagaa agagatacaa tcttgcttga ccgtttggga catcaatctt 7500 ccacatgaag tgcaaaattt agaaaaacac attgaagtga gaaaagaatt agctgaaaaa 7560 atgagacgaa catctgttga gtaa 7584 <210> 10 <211> 2527 <212> PRT <213> Homo sapiens <400> 10 Met Ala Ser Gly Ser Cys Gln Gly Cys Glu Glu Asp Glu Glu Thr Leu   1 5 10 15 Lys Lys Leu Ile Val Arg Leu Asn Asn Val Gln Glu Gly Lys Gln Ile              20 25 30 Glu Thr Leu Val Gln Ile Leu Glu Asp Leu Leu Val Phe Thr Tyr Ser          35 40 45 Glu His Ala Ser Lys Leu Phe Gln Gly Lys Asn Ile His Val Pro Leu      50 55 60 Leu Ile Val Leu Asp Ser Tyr Met Arg Val Ala Ser Val Gln Gln Val  65 70 75 80 Gly Trp Ser Leu Leu Cys Lys Leu Ile Glu Val Cys Pro Gly Thr Met                  85 90 95 Gln Ser Leu Met Gly Pro Gln Asp Val Gly Asn Asp Trp Glu Val Leu             100 105 110 Gly Val His Gln Leu Ile Leu Lys Met Leu Thr Val His Asn Ala Ser         115 120 125 Val Asn Leu Ser Val Ile Gly Leu Lys Thr Leu Asp Leu Leu Leu Thr     130 135 140 Ser Gly Lys Ile Thr Leu Leu Ile Leu Asp Glu Glu Ser Asp Ile Phe 145 150 155 160 Met Leu Ile Phe Asp Ala Met His Ser Phe Pro Ala Asn Asp Glu Val                 165 170 175 Gln Lys Leu Gly Cys Lys Ala Leu His Val Leu Phe Glu Arg Val Ser             180 185 190 Glu Glu Gln Leu Thr Glu Phe Val Glu Asn Lys Asp Tyr Met Ile Leu         195 200 205 Leu Ser Ala Leu Thr Asn Phe Lys Asp Glu Glu Glu Ile Val Leu His     210 215 220 Val Leu His Cys Leu His Ser Leu Ala Ile Pro Cys Asn Asn Val Glu 225 230 235 240 Val Leu Met Ser Gly Asn Val Arg Cys Tyr Asn Ile Val Val Glu Ala                 245 250 255 Met Lys Ala Phe Pro Met Ser Glu Arg Ile Gln Glu Val Ser Cys Cys             260 265 270 Leu Leu His Arg Leu Thr Leu Gly Asn Phe Phe Asn Ile Leu Val Leu         275 280 285 Asn Glu Val His Glu Phe Val Val Lys Ala Val Gln Gln Tyr Pro Glu     290 295 300 Asn Ala Ala Leu Gln Ile Ser Ala Leu Ser Cys Leu Ala Leu Leu Thr 305 310 315 320 Glu Thr Ile Phe Leu Asn Gln Asp Leu Glu Glu Lys Asn Glu Asn Gln                 325 330 335 Glu Asn Asp Asp Glu Gly Glu Glu Asp Lys Leu Phe Trp Leu Glu Ala             340 345 350 Cys Tyr Lys Ala Leu Thr Trp His Arg Lys Asn Lys His Val Gln Glu         355 360 365 Ala Ala Cys Trp Ala Leu Asn Asn Leu Leu Met Tyr Gln Asn Ser Leu     370 375 380 His Glu Lys Ile Gly Asp Glu Asp Gly His Phe Pro Ala His Arg Glu 385 390 395 400 Val Met Leu Ser Met Leu Met His Ser Ser Ser Lys Glu Val Phe Gln                 405 410 415 Ala Ser Ala Asn Ala Leu Ser Thr Leu Leu Glu Gln Asn Val Asn Phe             420 425 430 Arg Lys Ile Leu Leu Ser Lys Gly Ile His Leu Asn Val Leu Glu Leu         435 440 445 Met Gln Lys His Ile His Ser Pro Glu Val Ala Glu Ser Gly Cys Lys     450 455 460 Met Leu Asn His Leu Phe Glu Gly Ser Asn Thr Ser Leu Asp Ile Met 465 470 475 480 Ala Ala Val Val Pro Lys Ile Leu Thr Val Met Lys Arg His Glu Thr                 485 490 495 Ser Leu Pro Val Gln Leu Glu Ala Leu Arg Ala Ile Leu His Phe Ile             500 505 510 Val Pro Gly Met Pro Glu Glu Ser Arg Glu Asp Thr Glu Phe His His         515 520 525 Lys Leu Asn Met Val Lys Lys Gln Cys Phe Lys Asn Asp Ile His Lys     530 535 540 Leu Val Leu Ala Ala Leu Asn Arg Phe Ile Gly Asn Pro Gly Ile Gln 545 550 555 560 Lys Cys Gly Leu Lys Val Ile Ser Ser Ile Val His Phe Pro Asp Ala                 565 570 575 Leu Glu Met Leu Ser Leu Glu Gly Ala Met Asp Ser Val Leu His Thr             580 585 590 Leu Gln Met Tyr Pro Asp Asp Gln Glu Ile Gln Cys Leu Gly Leu Ser         595 600 605 Leu Ile Gly Tyr Leu Ile Thr Lys Lys Asn Val Phe Ile Gly Thr Gly     610 615 620 His Leu Leu Ala Lys Ile Leu Val Ser Ser Leu Tyr Arg Phe Lys Asp 625 630 635 640 Val Ala Glu Ile Gln Thr Lys Gly Phe Gln Thr Ile Leu Ala Ile Leu                 645 650 655 Lys Leu Ser Ala Ser Phe Ser Lys Leu Leu Val His His Ser Phe Asp             660 665 670 Leu Val Ile Phe His Gln Met Ser Ser Asn Ile Met Glu Gln Lys Asp         675 680 685 Gln Gln Phe Leu Asn Leu Cys Cys Lys Cys Phe Ala Lys Val Ala Met     690 695 700 Asp Asp Tyr Leu Lys Asn Val Met Leu Glu Arg Ala Cys Asp Gln Asn 705 710 715 720 Asn Ser Ile Met Val Glu Cys Leu Leu Leu Leu Gly Ala Asp Ala Asn                 725 730 735 Gln Ala Lys Glu Gly Ser Ser Leu Ile Cys Gln Val Cys Glu Lys Glu             740 745 750 Ser Ser Pro Lys Leu Val Glu Leu Leu Leu Asn Ser Gly Ser Arg Glu         755 760 765 Gln Asp Val Arg Lys Ala Leu Thr Ile Ser Ile Gly Lys Gly Asp Ser     770 775 780 Gln Ile Ile Ser Leu Leu Leu Arg Arg Leu Ala Leu Asp Val Ala Asn 785 790 795 800 Asn Ser Ile Cys Leu Gly Gly Phe Cys Ile Gly Lys Val Glu Pro Ser                 805 810 815 Trp Leu Gly Pro Leu Phe Pro Asp Lys Thr Ser Asn Leu Arg Lys Gln             820 825 830 Thr Asn Ile Ala Ser Thr Leu Ala Arg Met Val Ile Arg Tyr Gln Met         835 840 845 Lys Ser Ala Val Glu Glu Gly Thr Ala Ser Gly Ser Asp Gly Asn Phe     850 855 860 Ser Glu Asp Val Leu Ser Lys Phe Asp Glu Trp Thr Phe Ile Pro Asp 865 870 875 880 Ser Ser Met Asp Ser Val Phe Ala Gln Ser Asp Asp Leu Asp Ser Glu                 885 890 895 Gly Ser Glu Gly Ser Phe Leu Val Lys Lys Lys Ser Asn Ser Ile Ser             900 905 910 Val Gly Glu Phe Tyr Arg Asp Ala Val Leu Gln Arg Cys Ser Pro Asn         915 920 925 Leu Gln Arg His Ser Asn Ser Leu Gly Pro Ile Phe Asp His Glu Asp     930 935 940 Leu Leu Lys Arg Lys Arg Lys Ile Leu Ser Ser Asp Asp Ser Leu Arg 945 950 955 960 Ser Ser Lys Leu Gln Ser His Met Arg His Ser Asp Ser Ile Ser Ser                 965 970 975 Leu Ala Ser Glu Arg Glu Tyr Ile Thr Ser Leu Asp Leu Ser Ala Asn             980 985 990 Glu Leu Arg Asp Ile Asp Ala Leu Ser Gln Lys Cys Cys Ile Ser Val         995 1000 1005 His Leu Glu His Leu Glu Lys Leu Glu Leu His Gln Asn Ala Leu Thr    1010 1015 1020 Ser Phe Pro Gln Gln Leu Cys Glu Thr Leu Lys Ser Leu Thr His Leu 1025 1030 1035 1040 Asp Leu His Ser Asn Lys Phe Thr Ser Phe Pro Ser Tyr Leu Leu Lys                1045 1050 1055 Met Ser Cys Ile Ala Asn Leu Asp Val Ser Arg Asn Asp Ile Gly Pro            1060 1065 1070 Ser Val Val Leu Asp Pro Thr Val Lys Cys Pro Thr Leu Lys Gln Phe        1075 1080 1085 Asn Leu Ser Tyr Asn Gln Leu Ser Phe Val Pro Glu Asn Leu Thr Asp    1090 1095 1100 Val Val Glu Lys Leu Glu Gln Leu Ile Leu Glu Gly Asn Lys Ile Ser 1105 1110 1115 1120 Gly Ile Cys Ser Pro Leu Arg Leu Lys Glu Leu Lys Ile Leu Asn Leu                1125 1130 1135 Ser Lys Asn His Ile Ser Ser Leu Ser Glu Asn Phe Leu Glu Ala Cys            1140 1145 1150 Pro Lys Val Glu Ser Phe Ser Ala Arg Met Asn Phe Leu Ala Ala Met        1155 1160 1165 Pro Phe Leu Pro Pro Ser Met Thr Ile Leu Lys Leu Ser Gln Asn Lys    1170 1175 1180 Phe Ser Cys Ile Pro Glu Ala Ile Leu Asn Leu Pro His Leu Arg Ser 1185 1190 1195 1200 Leu Asp Met Ser Ser Asn Asp Ile Gln Tyr Leu Pro Gly Pro Ala His                1205 1210 1215 Trp Lys Ser Leu Asn Leu Arg Glu Leu Leu Phe Ser His Asn Gln Ile            1220 1225 1230 Ser Ile Leu Asp Leu Ser Glu Lys Ala Tyr Leu Trp Ser Arg Val Glu        1235 1240 1245 Lys Leu His Leu Ser His Asn Lys Leu Lys Glu Ile Pro Pro Glu Ile    1250 1255 1260 Gly Cys Leu Glu Asn Leu Thr Ser Leu Asp Val Ser Tyr Asn Leu Glu 1265 1270 1275 1280 Leu Arg Ser Phe Pro Asn Glu Met Gly Lys Leu Ser Lys Ile Trp Asp                1285 1290 1295 Leu Pro Leu Asp Glu Leu His Leu Asn Phe Asp Phe Lys His Ile Gly            1300 1305 1310 Cys Lys Ala Lys Asp Ile Ile Arg Phe Leu Gln Gln Arg Leu Lys Lys        1315 1320 1325 Ala Val Pro Tyr Asn Arg Met Lys Leu Met Ile Val Gly Asn Thr Gly    1330 1335 1340 Ser Gly Lys Thr Thr Leu Leu Gln Gln Leu Met Lys Thr Lys Lys Ser 1345 1350 1355 1360 Asp Leu Gly Met Gln Ser Ala Thr Val Gly Ile Asp Val Lys Asp Trp                1365 1370 1375 Pro Ile Gln Ile Arg Asp Lys Arg Lys Arg Asp Leu Val Leu Asn Val            1380 1385 1390 Trp Asp Phe Ala Gly Arg Glu Glu Phe Tyr Ser Thr His Pro His Phe        1395 1400 1405 Met Thr Gln Arg Ala Leu Tyr Leu Ala Val Tyr Asp Leu Ser Lys Gly    1410 1415 1420 Gln Ala Glu Val Asp Ala Met Lys Pro Trp Leu Phe Asn Ile Lys Ala 1425 1430 1435 1440 Arg Ala Ser Ser Ser Pro Val Ile Leu Val Gly Thr His Leu Asp Val                1445 1450 1455 Ser Asp Glu Lys Gln Arg Lys Ala Cys Met Ser Lys Ile Thr Lys Glu            1460 1465 1470 Leu Leu Asn Lys Arg Gly Phe Pro Ala Ile Arg Asp Tyr His Phe Val        1475 1480 1485 Asn Ala Thr Glu Glu Ser Asp Ala Leu Ala Lys Leu Arg Lys Thr Ile    1490 1495 1500 Ile Asn Glu Ser Leu Asn Phe Lys Ile Arg Asp Gln Leu Val Val Gly 1505 1510 1515 1520 Gln Leu Ile Pro Asp Cys Tyr Val Glu Leu Glu Lys Ile Ile Leu Ser                1525 1530 1535 Glu Arg Lys Asn Val Pro Ile Glu Phe Pro Val Ile Asp Arg Lys Arg            1540 1545 1550 Leu Leu Gln Leu Val Arg Glu Asn Gln Leu Gln Leu Asp Glu Asn Glu        1555 1560 1565 Leu Pro His Ala Val His Phe Leu Asn Glu Ser Gly Val Leu Leu His    1570 1575 1580 Phe Gln Asp Pro Ala Leu Gln Leu Ser Asp Leu Tyr Phe Val Glu Pro 1585 1590 1595 1600 Lys Trp Leu Cys Lys Ile Met Ala Gln Ile Leu Thr Val Lys Val Glu                1605 1610 1615 Gly Cys Pro Lys His Pro Lys Gly Ile Ile Ser Arg Arg Asp Val Glu            1620 1625 1630 Lys Phe Leu Ser Lys Lys Arg Lys Phe Pro Lys Asn Tyr Met Ser Gln        1635 1640 1645 Tyr Phe Lys Leu Leu Glu Lys Phe Gln Ile Ala Leu Pro Ile Gly Glu    1650 1655 1660 Glu Tyr Leu Leu Val Pro Ser Ser Leu Ser Asp His Arg Pro Val Ile 1665 1670 1675 1680 Glu Leu Pro His Cys Glu Asn Ser Glu Ile Ile Ile Arg Leu Tyr Glu                1685 1690 1695 Met Pro Tyr Phe Pro Met Gly Phe Trp Ser Arg Leu Ile Asn Arg Leu            1700 1705 1710 Leu Glu Ile Ser Pro Tyr Met Leu Ser Gly Arg Glu Arg Ala Leu Arg        1715 1720 1725 Pro Asn Arg Met Tyr Trp Arg Gln Gly Ile Tyr Leu Asn Trp Ser Pro    1730 1735 1740 Glu Ala Tyr Cys Leu Val Gly Ser Glu Val Leu Asp Asn His Pro Glu 1745 1750 1755 1760 Ser Phe Leu Lys Ile Thr Val Pro Ser Cys Arg Lys Gly Cys Ile Leu                1765 1770 1775 Leu Gly Gln Val Val Asp His Ile Asp Ser Leu Met Glu Glu Trp Phe            1780 1785 1790 Pro Gly Leu Leu Glu Ile Asp Ile Cys Gly Glu Gly Glu Thr Leu Leu        1795 1800 1805 Lys Lys Trp Ala Leu Tyr Ser Phe Asn Asp Gly Glu Glu His Gln Lys    1810 1815 1820 Ile Leu Leu Asp Asp Leu Met Lys Lys Ala Glu Glu Gly Asp Leu Leu 1825 1830 1835 1840 Val Asn Pro Asp Gln Pro Arg Leu Thr Ile Pro Ile Ser Gln Ile Ala                1845 1850 1855 Pro Asp Leu Ile Leu Ala Asp Leu Pro Arg Asn Ile Met Leu Asn Asn            1860 1865 1870 Asp Glu Leu Glu Phe Glu Gln Ala Pro Glu Phe Leu Leu Gly Asp Gly        1875 1880 1885 Ser Phe Gly Ser Val Tyr Arg Ala Ala Tyr Glu Gly Glu Glu Val Ala    1890 1895 1900 Val Lys Ile Phe Asn Lys His Thr Ser Leu Arg Leu Leu Arg Gln Glu 1905 1910 1915 1920 Leu Val Val Leu Cys His Leu His His Pro Ser Leu Ile Ser Leu Leu                1925 1930 1935 Ala Ala Gly Ile Arg Pro Arg Met Leu Val Met Glu Leu Ala Ser Lys            1940 1945 1950 Gly Ser Leu Asp Arg Leu Leu Gln Gln Asp Lys Ala Ser Leu Thr Arg        1955 1960 1965 Thr Leu Gln His Arg Ile Ala Leu His Val Ala Asp Gly Leu Arg Tyr    1970 1975 1980 Leu His Ser Ala Met Ile Ile Tyr Arg Asp Leu Lys Pro His Asn Val 1985 1990 1995 2000 Leu Leu Phe Thr Leu Tyr Pro Asn Ala Ala Ile Ile Ala Lys Ile Ala                2005 2010 2015 Asp Tyr Gly Thr Ala Gln Tyr Cys Cys Arg Met Gly Ile Lys Thr Ser            2020 2025 2030 Glu Gly Thr Pro Gly Phe Arg Ala Pro Glu Val Ala Arg Gly Asn Val        2035 2040 2045 Ile Tyr Asn Gln Gln Ala Asp Val Tyr Ser Phe Gly Leu Leu Leu Tyr    2050 2055 2060 Asp Ile Leu Thr Thr Gly Gly Arg Ile Val Glu Gly Leu Lys Phe Pro 2065 2070 2075 2080 Asn Glu Phe Asp Glu Leu Glu Ile Gln Gly Lys Leu Pro Asp Pro Val                2085 2090 2095 Lys Glu Tyr Gly Cys Ala Pro Trp Pro Met Val Glu Lys Leu Ile Lys            2100 2105 2110 Gln Cys Leu Lys Glu Asn Pro Gln Glu Arg Pro Thr Ser Ala Gln Val        2115 2120 2125 Phe Asp Ile Leu Asn Ser Ala Glu Leu Val Cys Leu Thr Arg Arg Ile    2130 2135 2140 Leu Leu Pro Lys Asn Val Ile Val Glu Cys Met Val Ala Thr His His 2145 2150 2155 2160 Asn Ser Arg Asn Ala Ser Ile Trp Leu Gly Cys Gly His Thr Asp Arg                2165 2170 2175 Gly Gln Leu Ser Phe Leu Asp Leu Asn Thr Glu Gly Tyr Thr Ser Glu            2180 2185 2190 Glu Val Ala Asp Ser Arg Ile Leu Cys Leu Ala Leu Val His Leu Pro        2195 2200 2205 Val Glu Lys Glu Ser Trp Ile Val Ser Gly Thr Gln Ser Gly Thr Leu    2210 2215 2220 Leu Val Ile Asn Thr Glu Asp Gly Lys Lys Arg His Thr Leu Glu Lys 2225 2230 2235 2240 Met Thr Asp Ser Val Thr Cys Leu Tyr Cys Asn Ser Phe Ser Lys Gln                2245 2250 2255 Ser Lys Gln Lys Asn Phe Leu Leu Val Gly Thr Ala Asp Gly Lys Leu            2260 2265 2270 Ala Ile Phe Glu Asp Lys Thr Val Lys Leu Lys Gly Ala Ala Pro Leu        2275 2280 2285 Lys Ile Leu Asn Ile Gly Asn Val Ser Thr Pro Leu Met Cys Leu Ser    2290 2295 2300 Glu Ser Thr Asn Ser Thr Glu Arg Asn Val Met Trp Gly Gly Cys Gly 2305 2310 2315 2320 Thr Lys Ile Phe Ser Phe Ser Asn Asp Phe Thr Ile Gln Lys Leu Ile                2325 2330 2335 Glu Thr Arg Thr Ser Gln Leu Phe Ser Tyr Ala Ala Phe Ser Asp Ser            2340 2345 2350 Asn Ile Ile Thr Val Val Val Asp Thr Ala Leu Tyr Ile Ala Lys Gln        2355 2360 2365 Asn Ser Pro Val Val Glu Val Trp Asp Lys Lys Thr Glu Lys Leu Cys    2370 2375 2380 Gly Leu Ile Asp Cys Val His Phe Leu Arg Glu Val Met Val Lys Glu 2385 2390 2395 2400 Asn Lys Glu Ser Lys His Lys Met Ser Tyr Ser Gly Arg Val Lys Thr                2405 2410 2415 Leu Cys Leu Gln Lys Asn Thr Ala Leu Trp Ile Gly Thr Gly Gly Gly            2420 2425 2430 His Ile Leu Leu Leu Asp Leu Ser Thr Arg Arg Leu Ile Arg Val Ile        2435 2440 2445 Tyr Asn Phe Cys Asn Ser Val Arg Val Met Met Thr Ala Gln Leu Gly    2450 2455 2460 Ser Leu Lys Asn Val Met Leu Val Leu Gly Tyr Asn Arg Lys Asn Thr 2465 2470 2475 2480 Glu Gly Thr Gln Lys Gln Lys Glu Ile Gln Ser Cys Leu Thr Val Trp                2485 2490 2495 Asp Ile Asn Leu Pro His Glu Val Gln Asn Leu Glu Lys His Ile Glu            2500 2505 2510 Val Arg Lys Glu Leu Ala Glu Lys Met Arg Arg Thr Ser Val Glu        2515 2520 2525  

Claims (7)

Expressing a leucine rich repeat kinase 2 (LRRK2) mutant protein in a cell; Treating the cells with oxidative stress or mitochondrial toxic substances; Contacting the test substance with the cell; Comparing cells in contact with the test substance with cells not in contact with the test substance; And A method for screening a Parkinson's disease therapeutic agent comprising the step of determining whether the cell death by contact with the test substance is reduced. Expressing the LRRK2 mutant protein in the cell; Adding an oxidative stress or mitochondrial toxic substance to the cells; Transforming said cell with a test gene; Comparing the cells transformed with the test gene with the cells not transformed with the test gene; And A method for screening a Parkinson's disease therapeutic agent comprising the step of measuring whether or not to reduce cell death by transformation of the test gene. According to claim 1 or 2, wherein the LRRK2 mutant protein is G2019S represented by SEQ ID NO: 2, R1441C represented by SEQ ID NO: 4, R1441G represented by SEQ ID NO: 6, Y1699C represented by SEQ ID NO: 8, SEQ ID NO: 10 Method for screening a Parkinson's disease therapeutic agent, characterized in that at least one protein selected from the group consisting of I2020T. The method according to claim 1 or 2, wherein the cell is a cell group secreting dopamine consisting of MN9D, SN4741, SH-SY5Y, SK-N-BE2C, and PC12 or dopamine composed of HEK293T, HeLa, and COS-7 cells. A method for screening a therapeutic agent for Parkinson's disease, characterized in that it is at least one cell selected from the non-secreting cell group. The method of claim 1 or 2, wherein the oxidative stress is induced by hydrogen peroxide. The method of claim 1 or 2, wherein the mitochondrial toxicity-inducing substance is paraquat. Parkin's disease screening kit comprising a cell expressing the LRRK2 mutant protein, a cell death reduction.

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