Patent application title: METHOD OF SCREENING PLACENTAL PROTEINS RESPONSIBLE FOR PATHOPHYSIOLOGY OF PREECLAMPSIA, AND MARKER FOR EARLY DIAGNOSIS AND PREDICTION OF PREECLAMPSIA
Inventors:
Won Sun Park (Busan, KR)
Won Sun Park (Busan, KR)
Na Ri Kim (Busan, KR)
Na Ri Kim (Busan, KR)
Jin Han (Busan, KR)
Jin Han (Busan, KR)
IPC8 Class: AC12N996FI
USPC Class:
435188
Class name: Chemistry: molecular biology and microbiology enzyme (e.g., ligases (6. ), etc.), proenzyme; compositions thereof; process for preparing, activating, inhibiting, separating, or purifying enzymes stablizing an enzyme by forming a mixture, an adduct or a composition, or formation of an adduct or enzyme conjugate
Publication date: 2011-12-29
Patent application number: 20110318809
Abstract:
The present invention relates to a method of screening placental proteins
responsible for pathophysiology of preeclampsia, and a marker for early
diagnosis and prediction of preeclampsia. In accordance with one aspect
of the present invention, there is provided a method of screening
placental proteins responsible for pathophysiology of preeclampsia by 2D
E-proteomics analysis, comprising: isolating placental proteins from a
placental tissue; separating the isolated proteins two-dimensionally
through 2D electrophoresis; and comparing and analyzing the separated
proteins based on scanned gel images and differences in the images
between normal placental proteins and preeclamptic placental proteins,
wherein the comparison and analysis of the placental proteins based on
the scanned gel images and differences in the images are accomplished by
selecting proteins with differences of 140% or more between two
placentas.Claims:
1-4. (canceled)
5. A marker for early diagnosis and prediction of preeclampsia, comprising one or more proteins selected from the protein group consisting of chaperonin, ER-60 protease, isocitrate dehydrogenase 1, aldehyde reductase 1, fidaresta chain B bonded to human aldose reductase, voltage-dependent anion channel 1, nuclear chloride channel, cathepsin D chain H, phosphoglycerate mutase 1, endoplasmic reticulum protein, PSMA2 protein, glutathione S-transferase, Ig heavy chain v region, smooth muscle myosin alkali light chain, and fatty acid binding protein.
6. The marker of claim 5, wherein the chaperonin, ER-60 protease, isocitrate dehydrogenase 1, aldehyde reductase 1, fidaresta chain B bonded to human aldose reductase, voltage-dependent anion channel 1, nuclear chloride channel, cathepsin D chain H, phosphoglycerate mutase 1, endoplasmic reticulum protein, PSMA2 protein, glutathione S-transferase, Ig heavy chain v region, smooth muscle myosin alkali light chain and fatty acid binding protein have the sequences of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, respectively.
Description:
CROSS REFERENCE TO A PARENT APPLICATION
[0001] The present application is a divisional application of application Ser. No. 12/218,767 filed on Jul. 16, 2008, which claims priority under 35 U.S.C. §119(a) to an application filed in the Korean Intellectual Property Office on Jul. 16, 2007 and assigned Korean Patent Application No. 10-2007-0071058, the contents of which are incorporated herein by reference.
SEQUENCE LISTING
[0002] The instant application contains a Sequence Listing which has been submitted via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Jun. 7, 2011, is named 1029007DIV.txt and is 41,679 bytes in size.
FIELD OF THE INVENTION
[0003] The present invention relates to a method of screening placental proteins responsible for pathophysiology of preeclampsia, and a marker for early diagnosis and prediction of preeclampsia.
BACKGROUND OF THE INVENTION
[0004] Preeclampsia in pregnancy can be a very serious health problem. It can cause fetal growth restriction, fetal death and morbidity, premature deliveries, and death of the mother. The exact cause of preeclampsia is not known, and treatments for efficiently curing or preventing preeclampsia are not also available yet. Preeclampsia is known to cause several problems at the same time, such as high blood pressure (hypertension), pathological edema and leakage of protein into the urine (proteinuria). Further, preeclampsia is one of the pregnancy complications that bring hypertension, proteinuria and traumatism to the mother. It is known that preeclampsia occurs to only about 3-5% of pregnant women, but it can seriously affect both the mother and her unborn (or newborn) baby, and thus, acts as a major cause of increasing perinatal mortality and morbidity rates.
[0005] Globally, at least 200,000 pregnant women die from preeclampsia every year. Its symptoms typically become evident after the 20th week of pregnancy. Preeclampsia is usually diagnosed by detecting high blood pressure of a pregnant woman or by checking her urine for protein. Early diagnosis and timely treatment of preeclampsia can remarkably reduce risks to the mother and her unborn baby, but such a monitoring method by using those symptoms as criteria is not effective for an early diagnosis of preeclampsia. Further, no treatments are currently available to cure preeclampsia. Preeclampsia can be mild, but potentially life-threatening depending on the severity of the disease. Despite such clinical risks, however, it is difficult to find the cause or the pathogenesis of preeclampsia at an early stage, or to make an early diagnosis and prognosis.
[0006] Therefore, if it becomes possible to suggest the pathogenesis of preeclampsia and make an early diagnosis and prognosis based on the same, the mother having preeclampsia and her unborn baby can be protected, and the death rate would be reduced. Even if many researches have been conducted to monitor and predict the occurrence of preeclampsia, they are limited to using a specific protein or substance, which is not sufficient to explain the whole phenomenon about the occurrence of preeclampsia and the pathogenesis thereof.
[0007] While the inventors of the present invention have been trying to discover the pathogenesis of preeclampsia, they checked entire protein expressions in a placenta that plays a key role in the onset of preeclampsia and analyzed any change in the protein expressions in a preeclamptic placenta. Based on this, they devised a method of screening placental proteins responsible for pathophysiology of preeclampsia and a marker for early diagnosis and prediction of preeclampsia and also suggested a comprehensive theory of the pathogenesis of preeclampsia to complete the present invention.
SUMMARY OF THE INVENTION
[0008] It is, therefore, a primary object of the present invention to provide a method of screening placental proteins responsible for pathophysiology of preeclampsia.
[0009] It is another object of the present invention to provide a marker protein for early diagnosis and prediction of preeclampsia.
[0010] In accordance with one aspect of the present invention, there is provided a method of screening placental proteins responsible for pathophysiology of preeclampsia by 2D E-proteomics analysis, comprising: isolating placental proteins from a placental tissue; separating the isolated proteins two-dimensionally through 2D electrophoresis; and comparing and analyzing the separated proteins based on scanned gel images and differences in the images between normal placental proteins and preeclamptic placental proteins, wherein the comparison and analysis of the placental proteins based on the scanned gel images and differences in the images are accomplished by selecting proteins with differences of 140% or more between two placentas.
[0011] In accordance with another aspect of the present invention, there is provided a marker for early diagnosis and prediction of preeclampsia, comprising one or more proteins selected from the protein group consisting of chaperonin, ER-60 protease, isocitrate dehydrogenase 1, aldehyde reductase 1, fidaresta chain B bonded to human aldose reductase, voltage-dependent anion channel 1, nuclear chloride channel, cathepsin D chain H, phosphoglycerate mutase 1, endoplasmic reticulum protein, PSMA2 protein, glutathione S-transferase, Ig heavy chain v region, smooth muscle myosin alkali light chain, and fatty acid binding protein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] The above and other objects and features of the present invention will become apparent from the following description of the preferred examples given in conjunction with the accompanying drawings, in which:
[0013] FIG. 1 shows 2-D gel E-proteomics analysis pictures taken for the identification of changes in placental proteins of a pregnant woman with preeclampsia, in which FIG. 1A is a gel picture of placental proteins in normal pregnancy and FIG. 1B is a gel picture of placental proteins in pregnancy with preeclampsia;
[0014] FIG. 2 presents comparative pictures of 21 proteins which show big differences in expression between normal placenta and preeclamptic placenta (left-hand side: normal cell; right-hand side: gastric cancer cell) in result of the E-proteomics analysis depicted in FIG. 1; and
[0015] FIG. 3 offers a conceptual diagram suggesting the pathogenesis of preeclampsia on the basis of the analysis of proteins exhibiting different expression in preeclamptic placenta.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0016] In the following detailed description, reference is made to the accompanying drawings that show, by way of illustration, specific embodiments in which the invention may be practiced. These embodiments are described in sufficient detail to enable those skilled in the art to practice the invention. It is to be understood that the various embodiments of the invention, although different, are not necessarily mutually exclusive. The following detailed description is, therefore, not to be taken in a limiting sense, and the scope of the present invention is defined only by the appended claims that should be appropriately interpreted along with the full range of equivalents to which the claims are entitled.
[0017] Then, experiments performed for better understanding the present invention will be described in detail as follows, which are set forth to illustrate, but are not to be construed to limit the present invention.
[0018] Hereinafter, the present invention will be described in more detail.
[0019] The present invention is directed to analyzing protein expression in preeclamptic placenta. More specifically, the present invention is directed to analyzing placental proteins that demonstrate more changes in expression in preeclamptic pregnancy than in normal pregnancy, thus identifying proteins responsible for pathophysiology of preeclampsia.
[0020] In order to identify proteins associated with pathophysiology of preeclampsia, the inventors conducted 2D E-proteomics analysis on the expression of placental proteins, and compared protein expression in a normal placenta and in a preeclamptic placenta to verify the differences in protein expression between them. The "2D E-proteomics analysis" perceives cell or tissue proteins in a packet and identifies an overall change, not individual changes, in proteins reflected in electrical and physical natures proved by electrophoresis. This research method is now actively being used worldwide and is largely composed of primary separation of proteins by isoelectric point and secondary gel-based protein separation by molecular mass. Images of proteins that are broadly distributed over the gel through the two-step protein separation technique were analyzed by an image analyzer for comparison of quantitative expression of proteins. Among them, proteins showing big differences were collected, and molecular weight in unit of peptide (a small cut piece of protein) of which were measured by a molecular weight measurement technique called MALDI-TOF MS. Each of the measured peptide masses was again calculated in terms of the mass of amino acids constituting a peptide. The final masses were compared with those in the already known peptide mass database to prove nature of original proteins.
[0021] The present invention suggests, based on the 2D E-proteomics analysis, 21 proteins demonstrating big differences in expression in a preeclamptic placenta. These proteins may be used for explaining abnormal metabolism in a preeclamptic placenta and its pathophysiology. Further, the proteins are expected to be effectively used for early diagnosis and prediction of preeclampsia in pregnant women.
[0022] For the 2D E-proteomics analysis, the inventors obtained normal placenta tissues and preeclamptic placenta tissues and separated placental proteins according to their isoelectric point (the primary separation step) and according to their molecular weight (the secondary separation step). The gel obtained after electrophoresis was stained by silver nitrate. Then, the stained gel was scanned with a flatbed scanner and analyzed through an image analysis program. Proteins showing differences of 140% or more in two groups of placental samples were selected and finally identified. Twenty one proteins were collected and peaks of protein mass spectrometry were searched by MASCOT PMF based on the NCBI database (see Table 1). Seventeen out of those twenty one proteins were analyzed, and most of them were identified as ones associated with placental metabolism (see Table 2). These proteins may be categorized into different types on the basis of their association with antioxidant activities, recombination related to stress, apoptosis, glycolysis, immunomodulation, or remodeling of reduced NADP, such that the pathophysiology of protein-underlying preeclampsia can be presented (see FIG. 3).
[0023] Hereinafter, the present invention will be explained in more detail through examples. However, it will be apparent to those skilled in the art that these examples are only for the purpose of explaining the present invention in detail, but not intended to limit the scope of the invention.
EXAMPLE 1
Separation of Placental Proteins
[0024] Normal placenta and preeclamptic placenta were prepared for 2D E-proteomics analysis. Placental tissues were ground to fine powder in presence of liquid nitrogen, and a buffer (tissue: 0.2 g/10 ml) was added thereto. The samples were then divided into tubes, boiled for five minutes, put into the ice bath for five minutes, and centrifuged at 8,000 rpm and 4° C. for 10 minutes. Each of the upper phases was transferred to a new tube by 800 μl, treated with enzymes (DNase/RNase), and put into the ice bath for 10 minutes. Next, 200 μl of 10% TCA/acetone preparation-50% TCA/acetone was added to each tube. The tubes were placed into the ice bath for a period of 1 hour. The samples were then centrifuged at 12,000 rpm and 4° C. for 10 minutes, and the resulting pallets were washed with acetone. The remaining dry powders were kept at -20° C.
EXAMPLE 2
Separation of Proteins by 2D E-Proteomics
[0025] <2-1> Primary Separation of Proteins by Isoelectric Point
[0026] Proteins are primarily separated based on isoelectric point. Dry immobilized pH gradient (IPG) strips of 13 cm were added with 250 μl isoelectric point marker containing 50 μg protein and rehydrated over 10 hours. The rehydrated IPG strips were subjected to isoelectric point separation in an IPG phore (GE Healthcare, USA). The isoelectric point separation was carried out for 1 hour at 500 V, for 1 hour at 1,000 V, and finally at 8,000 V until the final accumulated voltage becomes 60,000 V. At this time, the highest current was set to 50 μA per strip. The strips separated by isoelectric point were slowly stirred over a period of 15 minutes in presence of a primary phase equilibrium solution (50 mM Tris-HCl containing 6M urea, 30% glycerol, 2% SDS, bromophenol blue and 1% DTT, pH 8.8). These primary phase equilibrated strips were soaked in a secondary phase equilibrium solution (50 mM Tris-HCl containing 6M urea, 30% glycerol, 2% SDS, bromophenol blue and 2.5% iodoaceamide, pH 8.8) and stirred again over a period of 15 minutes.
[0027] <2-2> Secondary Protein Electrophoresis
[0028] Proteins are separated in a polyacrylamide gel depending on their molecular weight. A 12.5% sodium dodecyl sulfate polyacrylamide gel was prepared in size of 13 cm through SE 600 Ruby electrophoresis set (Amersham, USA). Phase equilibrated strips were put on the gel, and the gap between the strip and the gel was filled with a sealing Aga. A running buffer (25 mM Tris, 192 mM glycine, 2.5 mM SDS, pH 8.3) was poured into the set, and proteins of the strips were transferred to the gel within the first 20 minutes at 80V, and electrophoresis was carried out for the next 5 hours at 240V. The electrophoresed gel was stained with silver nitrate. In result, by comparing a gel picture of placental proteins in normal pregnancy by 2D electrophoresis (see FIG. 1A) with a gel picture of placental proteins in pregnancy with preeclampsia by 2D electrophoresis (see FIG. 1B), the inventors could verify changes in placental proteins in pregnancy with preeclampsia.
EXAMPLE 3
Gel Scanning and Gel Image Analysis
[0029] The stained gel was scanned through a flatbed scanner (UMAX PowerLook 1100, USA). During scanning, the option of a transmissive type with 300 dpi resolution was chosen. The scanned gel images were analyzed through an image analysis program (Image Master 2D Platinum, GE Healthcare, USA). Based on the image analysis result, proteins showing differences up to 140% or more in two groups of placental samples were selected and finally identified. In result, the inventors checked proteins showing big differences between normal placenta and preeclamptic placenta by electrophoresis shown in FIG. 1 (In FIG. 2, left-hand side: normal cell; right-hand side: gastric cancer cell), and identified 21 proteins with differences in expression between normal placenta and preeclamptic placenta.
EXAMPLE 4
Protein Identification
[0030] The 21 proteins with differences in expression between normal placenta and preeclamptic placenta used were collected and sent to IN2GEN Co., Ltd. for protein mass analysis based on MALDI-TOF MS technique. Peaks of protein mass spectrometry analyzed were searched by MASCOT PMF based on the NCBI database and listed with GeneBank IDs in Table 1 below.
TABLE-US-00001 TABLE 1 NCBI Spot accession NOs NOs SEQ ID NOs protein identification 1 49522865 SEQ ID NO: 1 chaperonin 2 1208427 SEQ ID NO: 2 ER-60 protease 3 1167843 SEQ ID NO: 3 alpha-enolase 4 28178825 SEQ ID NO: 4 Isocitrate dehydrogenase 1 5 1633300 SEQ ID NO: 5 Aldehyde reductase 6 493797 SEQ ID NO: 6 chain B, Fidarestat Bonded to human Aldose reductase 7 14250132 SEQ ID NO: 7 Voltage-dependent anion channel 1 8 4588526 SEQ ID NO: 8 Nuclear chloride channel 9 5822091 SEQ ID NO: 9 Chain H, Cathepsin D 10 56081766 SEQ ID NO: 10 Phosphoglycerate mutase 1 11 5803013 SEQ ID NO: 11 Endoplasmic reticulum protein 12 50881968 SEQ ID NO: 12 PSMA2 protein 13 2204207 SEQ ID NO: 13 Glutathione S-transferase 14 8249777 SEQ ID NO: 14 Ig heavy chain v region 15 16924329 SEQ ID NO: 15 Smooth muscle myosin alkali light chain 16 4557581 SEQ ID NO: 16 Fatty acid binding protein
[0031] The above Table 1 presents the analysis result on the 21 proteins obtained by MALDI-TOF MS technique, verifying that all of the 21 proteins except one were expressed remarkably high in the preeclamptic placenta compared with the normal placenta.
EXAMPLE 5
Protein Analysis and Suggestion of Pathophysiology
[0032] The inventors analyzed 17 out of the 21 proteins and confirmed that most of the proteins were associated with placenta metabolism. To be more specific, the inventors analyzed not only functions of those 21 proteins, but also changes in protein expression detected in the preeclamptic placenta compared with that of the normal placenta, wherein the analysis result is listed in Table 2 below.
TABLE-US-00002 TABLE 2 Relative change Category Protein (%) Structural Smooth muscle myosin alkali light chain 191 Antioxidant and Glutathione S-transferase 177 detoxicant Isocitrate dehydrogenase 155 Stress-related Chaperonin (heat shock protein 60) 223 protein remodeling Apoptosis Voltage-dependent anion channel 185 Nuclear chloride channel 208 Chain H, Cathepsin D at pH 7.5 245 Reduced NADP.sup.+ - Aldehyde reductase 142 regeneration Chain B, Fidarestat bound to human 151 aldose Glycolysis Phosphoglycerate mutase 267 Alpha enolase 149 Immunoremodeling ER-60 protease 179 Other Endoplasmic reticulum protein 29 242 PSMA2 protein 156 Ig heavy chain v region 216 Fatty acid binding protein 5 220
[0033] The proteins were categorized into different types based on their association with antioxidant activities, recombination related to stress, apoptosis, glycolysis, immunomodulation, or remodeling of reduced NADP such that the pathophysiology of protein-underlying preeclampsia can be presented as shown in FIG. 3.
[0034] As discussed above, according to the present invention, the variation in certain protein expression in a preeclamptic placenta can be identified by a 2-D E-proteomics analysis, thus making it possible to present a theory on the pathogenesis of preeclampsia. Further, the screening method and marker of the present invention can screen placental proteins of different expressions in the placenta of a pregnant woman with preeclampsia, and those proteins can be used as a marker for prevention and early treatment of preeclampsia.
[0035] While the invention has been shown and described with respect to the preferred embodiments, it will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and the scope of the invention as defined in the following claims.
Sequence CWU
1
161573PRTMus musculus 1Met Leu Arg Leu Pro Thr Val Phe Arg Gln Met Arg Pro
Val Ser Arg1 5 10 15Val
Leu Ala Pro His Leu Thr Arg Ala Tyr Ala Lys Asp Val Lys Phe 20
25 30Gly Ala Asp Ala Arg Ala Leu Met
Leu Gln Gly Val Asp Leu Leu Ala 35 40
45Asp Ala Val Ala Val Thr Met Gly Pro Lys Gly Arg Thr Val Ile Ile
50 55 60Glu Gln Ser Trp Gly Ser Pro Lys
Val Thr Lys Asp Gly Val Thr Val65 70 75
80Ala Lys Ser Ile Asp Leu Lys Asp Lys Tyr Lys Asn Ile
Gly Ala Lys 85 90 95Leu
Val Gln Asp Val Ala Asn Asn Thr Asn Glu Glu Ala Gly Asp Gly
100 105 110Thr Thr Thr Ala Thr Val Leu
Ala Arg Ser Ile Ala Lys Glu Gly Phe 115 120
125Glu Lys Ile Ser Lys Gly Ala Asn Pro Val Glu Ile Arg Arg Gly
Val 130 135 140Met Leu Ala Val Asp Ala
Val Ile Ala Glu Leu Lys Lys Gln Ser Lys145 150
155 160Pro Val Thr Thr Pro Glu Glu Ile Ala Gln Val
Ala Thr Ile Ser Ala 165 170
175Asn Gly Asp Lys Glu Ile Gly Asn Ile Ile Ser Asp Ala Met Lys Lys
180 185 190Val Gly Arg Lys Gly Val
Ile Thr Val Lys Asp Gly Lys Thr Leu Asn 195 200
205Asp Glu Leu Glu Ile Ile Glu Gly Met Lys Phe Asp Arg Gly
Tyr Ile 210 215 220Ser Pro Tyr Phe Ile
Asn Thr Ser Lys Gly Gln Lys Cys Glu Phe Gln225 230
235 240Asp Ala Tyr Val Leu Leu Ser Glu Lys Lys
Ile Ser Ser Ile Gln Ser 245 250
255Ile Val Pro Ala Leu Glu Ile Ala Asn Ala His Arg Lys Pro Leu Val
260 265 270Ile Ile Ala Glu Asp
Val Asp Gly Glu Ala Leu Ser Thr Leu Val Leu 275
280 285Asn Arg Leu Lys Val Gly Leu Gln Val Val Ala Val
Lys Ala Pro Gly 290 295 300Phe Gly Asp
Asn Arg Lys Asn Gln Leu Lys Asp Met Ala Ile Ala Thr305
310 315 320Gly Gly Ala Val Phe Gly Glu
Glu Gly Leu Thr Leu Asn Leu Glu Asp 325
330 335Val Gln Pro His Asp Leu Gly Lys Val Gly Glu Val
Ile Val Thr Lys 340 345 350Asp
Asp Ala Met Leu Leu Lys Gly Lys Gly Asp Lys Ala Gln Ile Glu 355
360 365Lys Arg Ile Gln Glu Ile Ile Glu Gln
Leu Asp Val Thr Thr Ser Glu 370 375
380Tyr Glu Lys Glu Lys Leu Asn Glu Arg Leu Ala Lys Leu Ser Asp Gly385
390 395 400Val Ala Val Leu
Lys Val Gly Gly Thr Ser Asp Val Glu Val Asn Glu 405
410 415Lys Lys Asp Arg Val Thr Asp Ala Leu Asn
Ala Thr Arg Ala Ala Val 420 425
430Glu Glu Gly Ile Val Leu Gly Gly Gly Cys Ala Leu Leu Arg Cys Ile
435 440 445Pro Ala Leu Asp Ser Leu Thr
Pro Ala Asn Glu Asp Gln Lys Ile Gly 450 455
460Ile Glu Ile Ile Lys Arg Thr Leu Lys Ile Pro Ala Met Thr Ile
Ala465 470 475 480Lys Asn
Ala Gly Val Glu Gly Ser Leu Ile Val Glu Lys Ile Met Gln
485 490 495Ser Ser Ser Glu Val Gly Tyr
Asp Ala Met Ala Gly Asp Phe Val Asn 500 505
510Met Val Glu Lys Gly Ile Ile Asp Pro Thr Lys Val Val Arg
Thr Ala 515 520 525Leu Leu Asp Ala
Ala Gly Val Ala Ser Leu Leu Thr Thr Ala Glu Val 530
535 540Val Val Thr Glu Ile Pro Lys Glu Glu Lys Asp Pro
Gly Met Gly Ala545 550 555
560Met Gly Gly Met Gly Gly Gly Met Gly Gly Gly Met Phe
565 5702505PRTHomo sapiens 2Met Arg Leu Arg Arg Leu Ala
Leu Phe Pro Gly Val Ala Leu Leu Leu1 5 10
15Ala Ala Gly Arg Leu Val Ala Ala Ser Asp Val Leu Glu
Leu Thr Asp 20 25 30Asp Asn
Phe Glu Ser Arg Ile Ser Asp Thr Gly Ser Ala Gly Leu Met 35
40 45Leu Val Glu Phe Phe Ala Pro Trp Cys Gly
His Cys Lys Arg Leu Ala 50 55 60Pro
Glu Tyr Glu Ala Ala Ala Thr Arg Leu Lys Gly Ile Val Pro Leu65
70 75 80Ala Lys Val Asp Cys Thr
Ala Asn Thr Asn Thr Cys Asn Lys Tyr Gly 85
90 95Val Ser Gly Tyr Pro Thr Leu Lys Ile Phe Arg Asp
Gly Glu Glu Ala 100 105 110Gly
Ala Tyr Asp Gly Pro Arg Thr Ala Asp Gly Ile Val Ser His Leu 115
120 125Lys Lys Gln Ala Gly Pro Ala Ser Val
Pro Leu Arg Thr Glu Glu Glu 130 135
140Phe Lys Lys Phe Ile Ser Asp Lys Asp Ala Ser Ile Val Gly Phe Phe145
150 155 160Asp Asp Ser Phe
Ser Glu Ala His Ser Glu Phe Leu Lys Ala Ala Ser 165
170 175Asn Leu Arg Asp Asn Tyr Arg Phe Ala His
Thr Asn Val Glu Ser Leu 180 185
190Val Asn Glu Tyr Asp Asp Asn Gly Glu Gly Ile Ile Leu Phe Arg Pro
195 200 205Ser His Leu Thr Asn Lys Phe
Glu Asp Lys Thr Val Ala Tyr Thr Glu 210 215
220Gln Lys Met Thr Ser Gly Lys Ile Lys Lys Phe Ile Gln Glu Asn
Ile225 230 235 240Phe Gly
Ile Cys Pro His Met Thr Glu Asp Asn Lys Asp Leu Ile Gln
245 250 255Gly Lys Asp Leu Leu Ile Ala
Tyr Tyr Asp Val Asp Tyr Glu Lys Asn 260 265
270Ala Lys Gly Ser Asn Tyr Trp Arg Asn Arg Val Met Met Val
Ala Lys 275 280 285Lys Phe Leu Asp
Ala Gly His Lys Leu Asn Phe Ala Val Ala Ser Arg 290
295 300Lys Thr Phe Ser His Glu Leu Ser Asp Phe Gly Leu
Glu Ser Thr Ala305 310 315
320Gly Glu Ile Pro Val Val Ala Ile Arg Thr Ala Lys Gly Glu Lys Phe
325 330 335Val Met Gln Glu Glu
Phe Ser Arg Asp Gly Lys Ala Leu Glu Arg Phe 340
345 350Leu Gln Asp Tyr Phe Asp Gly Asn Leu Lys Arg Tyr
Leu Lys Ser Glu 355 360 365Pro Ile
Pro Glu Ser Asn Asp Gly Pro Val Lys Val Val Val Ala Glu 370
375 380Asn Phe Asp Glu Ile Val Asn Asn Glu Asn Lys
Asp Val Leu Ile Glu385 390 395
400Phe Tyr Ala Pro Trp Cys Gly His Cys Lys Asn Leu Glu Pro Lys Tyr
405 410 415Lys Glu Leu Gly
Glu Lys Leu Ser Lys Asp Pro Asn Ile Val Ile Ala 420
425 430Lys Met Asp Ala Thr Ala Asn Asp Val Pro Ser
Pro Tyr Glu Val Arg 435 440 445Gly
Phe Pro Thr Ile Tyr Phe Ser Pro Ala Asn Lys Lys Leu Asn Pro 450
455 460Lys Lys Tyr Glu Gly Gly Arg Glu Leu Ser
Asp Phe Ile Ser Tyr Leu465 470 475
480Gln Arg Glu Ala Thr Asn Pro Pro Val Ile Gln Glu Glu Lys Pro
Lys 485 490 495Lys Lys Lys
Lys Ala Gln Glu Asp Leu 500 5053434PRTHomo
sapiens 3Met Ser Ile Leu Lys Ile His Ala Arg Glu Ile Phe Asp Ser Arg Gly1
5 10 15Asn Pro Thr Val
Glu Val Asp Leu Phe Thr Ser Lys Gly Leu Phe Arg 20
25 30Ala Ala Val Pro Ser Gly Ala Ser Thr Gly Ile
Tyr Glu Ala Leu Glu 35 40 45Leu
Arg Asp Asn Asp Lys Thr Arg Tyr Met Gly Lys Gly Val Ser Lys 50
55 60Ala Val Glu His Ile Asn Lys Thr Ile Ala
Pro Ala Leu Val Ser Lys65 70 75
80Lys Leu Asn Val Thr Glu Gln Glu Lys Ile Asp Lys Leu Met Ile
Glu 85 90 95Met Asp Gly
Thr Glu Asn Lys Ser Lys Phe Gly Ala Asn Ala Ile Leu 100
105 110Gly Val Ser Leu Ala Val Cys Lys Ala Gly
Ala Val Glu Lys Gly Val 115 120
125Pro Leu Tyr Arg His Ile Ala Asp Leu Ala Gly Asn Ser Glu Val Ile 130
135 140Leu Pro Val Pro Ala Phe Asn Val
Ile Asn Gly Gly Ser His Ala Gly145 150
155 160Asn Lys Leu Ala Met Gln Glu Phe Met Ile Leu Pro
Val Gly Ala Ala 165 170
175Asn Phe Arg Glu Ala Met Arg Ile Gly Ala Glu Val Tyr His Asn Leu
180 185 190Lys Asn Val Ile Lys Glu
Lys Tyr Gly Lys Asp Ala Thr Asn Val Gly 195 200
205Asp Glu Gly Gly Phe Ala Pro Asn Ile Leu Glu Asn Lys Glu
Gly Leu 210 215 220Glu Leu Leu Lys Thr
Ala Ile Gly Lys Ala Gly Tyr Thr Asp Lys Val225 230
235 240Val Ile Gly Met Asp Val Ala Ala Ser Glu
Phe Phe Arg Ser Gly Lys 245 250
255Tyr Asp Leu Asp Phe Lys Ser Pro Asp Asp Pro Ser Arg Tyr Ile Ser
260 265 270Pro Asp Gln Leu Ala
Asp Leu Tyr Lys Ser Phe Ile Lys Asp Tyr Pro 275
280 285Val Val Ser Ile Glu Asp Pro Phe Asp Gln Asp Asp
Trp Gly Ala Trp 290 295 300Gln Lys Phe
Thr Ala Ser Ala Gly Ile Gln Val Val Gly Asp Asp Leu305
310 315 320Thr Val Thr Asn Pro Lys Arg
Ile Ala Lys Ala Val Asn Glu Lys Ser 325
330 335Cys Asn Cys Leu Leu Leu Lys Val Asn Gln Ile Gly
Ser Val Thr Glu 340 345 350Ser
Leu Gln Ala Cys Lys Leu Ala Gln Ala Asn Gly Trp Gly Val Met 355
360 365Val Ser His Arg Ser Gly Glu Thr Glu
Asp Thr Phe Ile Ala Asp Leu 370 375
380Val Val Gly Leu Cys Thr Gly Gln Ile Lys Thr Gly Ala Pro Cys Arg385
390 395 400Ser Glu Arg Leu
Ala Lys Tyr Asn Gln Leu Leu Arg Ile Glu Glu Glu 405
410 415Leu Gly Ser Lys Ala Lys Phe Ala Gly Arg
Asn Phe Arg Asn Pro Leu 420 425
430Ala Lys4414PRTHomo sapiens 4Met Ser Lys Lys Ile Ser Gly Gly Ser Val
Val Glu Met Gln Gly Asp1 5 10
15Glu Met Thr Arg Ile Ile Trp Glu Leu Ile Lys Glu Lys Leu Ile Phe
20 25 30Pro Tyr Val Glu Leu Asp
Leu His Ser Tyr Asp Leu Gly Ile Glu Asn 35 40
45Arg Asp Ala Thr Asn Asp Gln Val Thr Lys Asp Ala Ala Glu
Ala Ile 50 55 60Lys Lys His Asn Val
Gly Val Lys Cys Ala Thr Ile Thr Pro Asp Glu65 70
75 80Lys Arg Val Glu Glu Phe Lys Leu Lys Gln
Met Trp Lys Ser Pro Asn 85 90
95Gly Thr Ile Arg Asn Ile Leu Gly Gly Thr Val Phe Arg Glu Ala Ile
100 105 110Ile Cys Lys Asn Ile
Pro Arg Leu Val Ser Gly Trp Val Lys Pro Ile 115
120 125Ile Ile Gly Arg His Ala Tyr Gly Asp Gln Tyr Arg
Ala Thr Asp Phe 130 135 140Val Val Pro
Gly Pro Gly Lys Val Glu Ile Thr Tyr Thr Pro Ser Asp145
150 155 160Gly Thr Gln Lys Val Thr Tyr
Leu Val His Asn Phe Glu Glu Gly Gly 165
170 175Gly Val Ala Met Gly Met Tyr Asn Gln Asp Lys Ser
Ile Glu Asp Phe 180 185 190Ala
His Ser Ser Phe Gln Met Ala Leu Ser Lys Gly Trp Pro Leu Tyr 195
200 205Leu Ser Thr Lys Asn Thr Ile Leu Lys
Lys Tyr Asp Gly Arg Phe Lys 210 215
220Asp Ile Phe Gln Glu Ile Tyr Asp Lys Gln Tyr Lys Ser Gln Phe Glu225
230 235 240Ala Gln Lys Ile
Trp Tyr Glu His Arg Leu Ile Asp Asp Met Val Ala 245
250 255Gln Ala Met Lys Ser Glu Gly Gly Phe Ile
Trp Ala Cys Lys Asn Tyr 260 265
270Asp Gly Asp Val Gln Ser Asp Ser Val Ala Gln Gly Tyr Gly Ser Leu
275 280 285Gly Met Met Thr Ser Val Leu
Val Cys Pro Asp Gly Lys Thr Val Glu 290 295
300Ala Glu Ala Ala His Gly Thr Val Thr Arg His Tyr Arg Met Tyr
Gln305 310 315 320Lys Gly
Gln Glu Thr Ser Thr Asn Pro Ile Ala Ser Ile Phe Ala Trp
325 330 335Thr Arg Gly Leu Ala His Arg
Ala Lys Leu Asp Asn Asn Lys Glu Leu 340 345
350Ala Phe Phe Ala Asn Ala Leu Glu Glu Val Ser Ile Glu Thr
Ile Glu 355 360 365Ala Gly Phe Met
Thr Lys Asp Leu Ala Ala Cys Ile Lys Gly Leu Pro 370
375 380Asn Val Gln Arg Ser Asp Tyr Leu Asn Thr Phe Glu
Phe Met Asp Lys385 390 395
400Leu Gly Glu Asn Leu Lys Ile Lys Leu Ala Gln Ala Lys Leu
405 4105324PRTHomo sapiens 5Ala Ala Ser Cys Val Leu Leu
His Thr Gly Gln Lys Met Pro Leu Ile1 5 10
15Gly Leu Gly Thr Trp Lys Ser Glu Pro Gly Gln Val Lys
Ala Ala Val 20 25 30Lys Tyr
Ala Leu Ser Val Gly Tyr Arg His Ile Asp Cys Ala Ala Ile 35
40 45Tyr Gly Asn Glu Pro Glu Ile Gly Glu Ala
Leu Lys Glu Asp Val Gly 50 55 60Pro
Gly Lys Ala Val Pro Arg Glu Glu Leu Phe Val Thr Ser Lys Leu65
70 75 80Trp Asn Thr Lys His His
Pro Glu Asp Val Glu Pro Ala Leu Arg Lys 85
90 95Thr Leu Ala Asp Leu Gln Leu Glu Tyr Leu Asp Leu
Tyr Leu Met His 100 105 110Trp
Pro Tyr Ala Phe Glu Arg Gly Asp Asn Pro Phe Pro Lys Asn Ala 115
120 125Asp Gly Thr Ile Cys Tyr Asp Ser Thr
His Tyr Lys Glu Thr Trp Lys 130 135
140Ala Leu Glu Ala Leu Val Ala Lys Gly Leu Val Gln Ala Leu Gly Leu145
150 155 160Ser Asn Phe Asn
Ser Arg Gln Ile Asp Asp Ile Leu Ser Val Ala Ser 165
170 175Val Arg Pro Ala Val Leu Gln Val Glu Cys
His Pro Tyr Leu Ala Gln 180 185
190Asn Glu Leu Ile Ala His Cys Gln Ala Arg Gly Leu Glu Val Thr Ala
195 200 205Tyr Ser Pro Leu Gly Ser Ser
Asp Arg Ala Trp Arg Asp Pro Asp Glu 210 215
220Pro Val Leu Leu Glu Glu Pro Val Val Leu Ala Leu Ala Glu Lys
Tyr225 230 235 240Gly Arg
Ser Pro Ala Gln Ile Leu Leu Arg Trp Gln Val Gln Arg Lys
245 250 255Val Ile Cys Ile Pro Lys Ser
Ile Thr Pro Ser Arg Ile Leu Gln Asn 260 265
270Ile Lys Val Phe Asp Phe Thr Phe Ser Pro Glu Glu Met Lys
Gln Leu 275 280 285Asn Ala Leu Asn
Lys Asn Trp Arg Tyr Ile Val Pro Met Leu Thr Val 290
295 300Asp Gly Lys Arg Val Pro Arg Asp Ala Gly His Pro
Leu Tyr Pro Phe305 310 315
320Asn Asp Pro Tyr6315PRTHomo sapiens 6Ala Ser Arg Leu Leu Leu Asn Asn
Gly Ala Lys Met Pro Ile Leu Gly1 5 10
15Leu Gly Thr Trp Lys Ser Pro Pro Gly Gln Val Thr Glu Ala
Val Lys 20 25 30Val Ala Ile
Asp Val Gly Tyr Arg His Ile Asp Cys Ala His Val Tyr 35
40 45Gln Asn Glu Asn Glu Val Gly Val Ala Ile Gln
Glu Lys Leu Arg Glu 50 55 60Gln Val
Val Lys Arg Glu Glu Leu Phe Ile Val Ser Lys Leu Trp Cys65
70 75 80Thr Tyr His Glu Lys Gly Leu
Val Lys Gly Ala Cys Gln Lys Thr Leu 85 90
95Ser Asp Leu Lys Leu Asp Tyr Leu Asp Leu Tyr Leu Ile
His Trp Pro 100 105 110Thr Gly
Phe Lys Pro Gly Lys Glu Phe Phe Pro Leu Asp Glu Ser Gly 115
120 125Asn Val Val Pro Ser Asp Thr Asn Ile Leu
Asp Thr Trp Ala Ala Met 130 135 140Glu
Glu Leu Val Asp Glu Gly Leu Val Lys Ala Ile Gly Ile Ser Asn145
150 155 160Phe Asn His Leu Gln Val
Glu Met Ile Leu Asn Lys Pro Gly Leu Lys 165
170 175Tyr Lys Pro Ala Val Asn Gln Ile Glu Cys His Pro
Tyr Leu Thr Gln 180 185 190Glu
Lys Leu Ile Gln Tyr Cys Gln Ser Lys Gly Ile Val Val Thr Ala 195
200 205Tyr Ser Pro Leu Gly Ser Pro Asp Arg
Pro Trp Ala Lys Pro Glu Asp 210 215
220Pro Ser Leu Leu Glu Asp Pro Arg Ile Lys Ala Ile Ala Ala Lys His225
230 235 240Asn Lys Thr Thr
Ala Gln Val Leu Ile Arg Phe Pro Met Gln Arg Asn 245
250 255Leu Val Val Ile Pro Lys Ser Val Thr Pro
Glu Arg Ile Ala Glu Asn 260 265
270Phe Lys Val Phe Asp Phe Glu Leu Ser Ser Gln Asp Met Thr Thr Leu
275 280 285Leu Ser Tyr Asn Arg Asn Trp
Arg Val Ser Ala Leu Leu Ser Cys Thr 290 295
300Ser His Lys Asp Tyr Pro Phe His Glu Glu Phe305
310 3157315PRTGallus gallus 7Ala Ser Arg Leu Leu Leu Asn
Asn Gly Ala Lys Met Pro Ile Leu Gly1 5 10
15Leu Gly Thr Trp Lys Ser Pro Pro Gly Gln Val Thr Glu
Ala Val Lys 20 25 30Val Ala
Ile Asp Val Gly Tyr Arg His Ile Asp Cys Ala His Val Tyr 35
40 45Gln Asn Glu Asn Glu Val Gly Val Ala Ile
Gln Glu Lys Leu Arg Glu 50 55 60Gln
Val Val Lys Arg Glu Glu Leu Phe Ile Val Ser Lys Leu Trp Cys65
70 75 80Thr Tyr His Glu Lys Gly
Leu Val Lys Gly Ala Cys Gln Lys Thr Leu 85
90 95Ser Asp Leu Lys Leu Asp Tyr Leu Asp Leu Tyr Leu
Ile His Trp Pro 100 105 110Thr
Gly Phe Lys Pro Gly Lys Glu Phe Phe Pro Leu Asp Glu Ser Gly 115
120 125Asn Val Val Pro Ser Asp Thr Asn Ile
Leu Asp Thr Trp Ala Ala Met 130 135
140Glu Glu Leu Val Asp Glu Gly Leu Val Lys Ala Ile Gly Ile Ser Asn145
150 155 160Phe Asn His Leu
Gln Val Glu Met Ile Leu Asn Lys Pro Gly Leu Lys 165
170 175Tyr Lys Pro Ala Val Asn Gln Ile Glu Cys
His Pro Tyr Leu Thr Gln 180 185
190Glu Lys Leu Ile Gln Tyr Cys Gln Ser Lys Gly Ile Val Val Thr Ala
195 200 205Tyr Ser Pro Leu Gly Ser Pro
Asp Arg Pro Trp Ala Lys Pro Glu Asp 210 215
220Pro Ser Leu Leu Glu Asp Pro Arg Ile Lys Ala Ile Ala Ala Lys
His225 230 235 240Asn Lys
Thr Thr Ala Gln Val Leu Ile Arg Phe Pro Met Gln Arg Asn
245 250 255Leu Val Val Ile Pro Lys Ser
Val Thr Pro Glu Arg Ile Ala Glu Asn 260 265
270Phe Lys Val Phe Asp Phe Glu Leu Ser Ser Gln Asp Met Thr
Thr Leu 275 280 285Leu Ser Tyr Asn
Arg Asn Trp Arg Val Ser Ala Leu Leu Ser Cys Thr 290
295 300Ser His Lys Asp Tyr Pro Phe His Glu Glu Phe305
310 3158241PRTHomo sapiens 8Met Ala Glu Glu
Gln Pro Gln Val Glu Leu Phe Val Lys Ala Gly Ser1 5
10 15Asp Gly Ala Lys Ile Gly Asn Cys Pro Phe
Ser Gln Arg Leu Phe Met 20 25
30Val Leu Trp Leu Lys Gly Val Thr Phe Asn Val Thr Thr Val Asp Thr
35 40 45Lys Arg Arg Thr Glu Thr Val Gln
Lys Leu Cys Pro Gly Gly Glu Leu 50 55
60Pro Phe Leu Leu Tyr Gly Thr Glu Val His Thr Asp Thr Asn Lys Ile65
70 75 80Glu Glu Phe Leu Glu
Ala Val Leu Cys Pro Pro Arg Tyr Pro Lys Leu 85
90 95Ala Ala Leu Asn Pro Glu Ser Asn Thr Ala Gly
Leu Asp Ile Phe Ala 100 105
110Lys Phe Ser Ala Tyr Ile Lys Asn Ser Asn Pro Ala Leu Asn Asp Asn
115 120 125Leu Glu Lys Gly Leu Leu Lys
Ala Leu Lys Val Leu Asp Asn Tyr Leu 130 135
140Thr Ser Pro Leu Pro Glu Glu Val Asp Glu Thr Ser Ala Glu Asp
Glu145 150 155 160Gly Val
Ser Gln Arg Lys Phe Leu Asp Gly Asn Glu Leu Thr Leu Ala
165 170 175Asp Cys Asn Leu Leu Pro Lys
Leu His Ile Val Gln Val Val Cys Lys 180 185
190Lys Tyr Arg Gly Phe Thr Ile Pro Glu Ala Phe Arg Gly Val
His Arg 195 200 205Tyr Leu Ser Asn
Ala Tyr Ala Arg Glu Glu Phe Ala Ser Thr Cys Pro 210
215 220Asp Asp Glu Glu Ile Glu Leu Ala Tyr Glu Gln Val
Ala Lys Ala Leu225 230 235
240Lys9241PRTHomo sapiensMOD_RES(1)..(1)Any amino acid 9Xaa Gly Val Lys
Val Glu Arg Gln Val Phe Gly Glu Ala Thr Lys Gln1 5
10 15Pro Gly Ile Thr Phe Ile Ala Ala Lys Phe
Asp Gly Ile Leu Gly Met 20 25
30Ala Tyr Pro Arg Ile Ser Val Asn Asn Val Leu Pro Val Phe Asp Asn
35 40 45Leu Met Gln Gln Lys Leu Val Asp
Gln Asn Ile Phe Ser Phe Tyr Leu 50 55
60Ser Arg Asp Pro Asp Ala Gln Pro Gly Gly Glu Leu Met Leu Gly Gly65
70 75 80Thr Asp Ser Lys Tyr
Tyr Lys Gly Ser Leu Ser Tyr Leu Asn Val Thr 85
90 95Arg Lys Ala Tyr Trp Gln Val His Leu Asp Gln
Val Glu Val Ala Ser 100 105
110Gly Leu Thr Leu Cys Lys Glu Gly Cys Glu Ala Ile Val Asp Thr Gly
115 120 125Thr Ser Leu Met Val Gly Pro
Val Asp Glu Val Arg Glu Leu Gln Lys 130 135
140Ala Ile Gly Ala Val Pro Leu Ile Gln Gly Glu Tyr Met Ile Pro
Cys145 150 155 160Glu Lys
Val Ser Thr Leu Pro Ala Ile Thr Leu Lys Leu Gly Gly Lys
165 170 175Gly Tyr Lys Leu Ser Pro Glu
Asp Tyr Thr Leu Lys Val Ser Gln Ala 180 185
190Gly Lys Thr Leu Cys Leu Ser Gly Phe Met Gly Met Asp Ile
Pro Pro 195 200 205Pro Ser Gly Pro
Leu Trp Ile Leu Gly Asp Val Phe Ile Gly Arg Tyr 210
215 220Tyr Thr Val Phe Asp Arg Asp Asn Asn Arg Val Gly
Phe Ala Glu Ala225 230 235
240Ala10254PRTHomo sapiens 10Met Ala Ala Tyr Lys Leu Val Leu Ile Arg His
Gly Glu Ser Ala Trp1 5 10
15Asn Leu Glu Asn Arg Phe Ser Gly Trp Tyr Asp Ala Asp Leu Ser Pro
20 25 30Ala Gly His Glu Glu Ala Lys
Arg Gly Gly Gln Ala Leu Arg Asp Ala 35 40
45Gly Tyr Glu Phe Asp Ile Cys Phe Thr Ser Val Gln Lys Arg Ala
Ile 50 55 60Arg Thr Leu Trp Thr Val
Leu Asp Ala Ile Asp Gln Met Trp Leu Pro65 70
75 80Val Val Arg Thr Trp Arg Leu Asn Glu Arg His
Tyr Gly Gly Leu Thr 85 90
95Gly Leu Asn Lys Ala Glu Thr Ala Ala Lys His Gly Glu Ala Gln Val
100 105 110Lys Ile Trp Arg Arg Ser
Tyr Asp Val Pro Pro Pro Pro Met Glu Pro 115 120
125Asp His Pro Phe Tyr Ser Asn Ile Ser Lys Asp Arg Arg Tyr
Ala Asp 130 135 140Leu Thr Glu Asp Gln
Leu Pro Ser Cys Glu Ser Leu Lys Asp Thr Ile145 150
155 160Ala Arg Ala Leu Pro Phe Trp Asn Glu Glu
Ile Val Pro Gln Ile Lys 165 170
175Glu Gly Lys Arg Val Leu Ile Ala Ala His Gly Asn Ser Leu Arg Gly
180 185 190Ile Val Lys His Leu
Glu Gly Leu Ser Glu Glu Ala Ile Met Glu Leu 195
200 205Asn Leu Pro Thr Gly Ile Pro Ile Val Tyr Glu Leu
Asp Lys Asn Leu 210 215 220Lys Pro Ile
Lys Pro Met Gln Phe Leu Gly Asp Glu Glu Thr Val Arg225
230 235 240Lys Ala Met Glu Ala Val Ala
Ala Gln Gly Lys Ala Lys Lys 245
25011261PRTHomo sapiens 11Met Ala Ala Ala Val Pro Arg Ala Ala Phe Leu Ser
Pro Leu Leu Pro1 5 10
15Leu Leu Leu Gly Phe Leu Leu Leu Ser Ala Pro His Gly Gly Ser Gly
20 25 30Leu His Thr Lys Gly Ala Leu
Pro Leu Asp Thr Val Thr Phe Tyr Lys 35 40
45Val Ile Pro Lys Ser Lys Phe Val Leu Val Lys Phe Asp Thr Gln
Tyr 50 55 60Pro Tyr Gly Glu Lys Gln
Asp Glu Phe Lys Arg Leu Ala Glu Asn Ser65 70
75 80Ala Ser Ser Asp Asp Leu Leu Val Ala Glu Val
Gly Ile Ser Asp Tyr 85 90
95Gly Asp Lys Leu Asn Met Glu Leu Ser Glu Lys Tyr Lys Leu Asp Lys
100 105 110Glu Ser Tyr Pro Val Phe
Tyr Leu Phe Arg Asp Gly Asp Phe Glu Asn 115 120
125Pro Val Pro Tyr Thr Gly Ala Val Lys Val Gly Ala Ile Gln
Arg Trp 130 135 140Leu Lys Gly Gln Gly
Val Tyr Leu Gly Met Pro Gly Cys Leu Pro Val145 150
155 160Tyr Asp Ala Leu Ala Gly Glu Phe Ile Arg
Ala Ser Gly Val Glu Ala 165 170
175Arg Gln Ala Leu Leu Lys Gln Gly Gln Asp Asn Leu Ser Ser Val Lys
180 185 190Glu Thr Gln Lys Lys
Trp Ala Glu Gln Tyr Leu Lys Ile Met Gly Lys 195
200 205Ile Leu Asp Gln Gly Glu Asp Phe Pro Ala Ser Glu
Met Thr Arg Ile 210 215 220Ala Arg Leu
Ile Glu Lys Asn Lys Met Ser Asp Gly Lys Lys Glu Glu225
230 235 240Leu Gln Lys Ser Leu Asn Ile
Leu Thr Ala Phe Gln Lys Lys Gly Ala 245
250 255Glu Lys Glu Glu Leu 26012234PRTMus
musculus 12Met Ala Glu Arg Gly Tyr Ser Phe Ser Leu Thr Thr Phe Ser Pro
Ser1 5 10 15Gly Lys Leu
Val Gln Ile Glu Tyr Ala Leu Ala Ala Val Ala Gly Gly 20
25 30Ala Pro Ser Val Gly Ile Lys Ala Ala Asn
Gly Val Val Leu Ala Thr 35 40
45Glu Lys Lys Gln Lys Ser Ile Leu Tyr Asp Glu Arg Ser Val His Lys 50
55 60Val Glu Pro Ile Thr Lys His Ile Gly
Leu Val Tyr Ser Gly Met Gly65 70 75
80Pro Asp Tyr Arg Val Leu Val His Arg Ala Arg Lys Leu Ala
Gln Gln 85 90 95Tyr Tyr
Leu Val Tyr Gln Glu Pro Ile Pro Thr Ala Gln Leu Val Gln 100
105 110Arg Val Ala Ser Val Met Gln Glu Tyr
Thr Gln Ser Gly Gly Val Arg 115 120
125Pro Phe Gly Val Ser Leu Leu Ile Cys Gly Trp Asn Glu Gly Arg Pro
130 135 140Tyr Leu Phe Gln Ser Asp Pro
Ser Gly Ala Tyr Phe Ala Trp Lys Ala145 150
155 160Thr Ala Met Gly Lys Asn Tyr Val Asn Gly Lys Thr
Phe Leu Glu Lys 165 170
175Arg Tyr Asn Glu Asp Leu Glu Leu Glu Asp Ala Ile His Thr Ala Ile
180 185 190Leu Thr Leu Lys Glu Ser
Phe Glu Gly Gln Met Thr Glu Asp Asn Ile 195 200
205Glu Val Gly Ile Cys Asn Glu Ala Gly Phe Arg Arg Leu Thr
Pro Thr 210 215 220Glu Val Lys Asp Tyr
Leu Ala Ala Ile Ala225 23013210PRTHomo sapiens 13Met Pro
Pro Tyr Thr Val Val Tyr Phe Pro Val Arg Gly Arg Cys Ala1 5
10 15Ala Leu Arg Met Leu Leu Ala Asp
Gln Gly Gln Ser Trp Lys Glu Glu 20 25
30Val Val Thr Val Glu Thr Trp Gln Glu Gly Ser Leu Lys Ala Ser
Cys 35 40 45Leu Tyr Gly Gln Leu
Pro Lys Phe Gln Asp Gly Asp Leu Thr Leu Tyr 50 55
60Gln Ser Asn Thr Ile Leu Arg His Leu Gly Arg Thr Leu Gly
Leu Tyr65 70 75 80Gly
Lys Asp Gln Gln Glu Ala Ala Leu Val Asp Met Val Asn Asp Gly
85 90 95Val Glu Asp Leu Arg Cys Lys
Tyr Ile Ser Leu Ile Tyr Thr Asn Tyr 100 105
110Glu Ala Gly Lys Asp Asp Tyr Val Lys Ala Leu Pro Gly Gln
Leu Lys 115 120 125Pro Phe Glu Thr
Leu Leu Ser Gln Asn Gln Gly Gly Lys Thr Phe Ile 130
135 140Val Gly Asp Gln Ile Ser Phe Ala Asp Tyr Asn Leu
Leu Asp Leu Leu145 150 155
160Leu Ile His Glu Val Leu Ala Pro Gly Cys Leu Asp Ala Phe Pro Leu
165 170 175Leu Ser Ala Tyr Val
Gly Arg Leu Ser Pro Arg Pro Lys Leu Lys Ala 180
185 190Phe Leu Ala Ser Pro Glu Tyr Val Asn Leu Pro Ile
Asn Gly Asn Gly 195 200 205Lys Gln
21014111PRTMus musculus 14Val Asp Gly Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe1 5 10
15Ser His Tyr Ala Val His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
20 25 30Glu Trp Leu Ala Phe Ile Ser
Ala Asp Gly Ser Asp Thr Asp His Ala 35 40
45Pro Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Arg
Asn 50 55 60Met Leu Phe Leu Gln Met
Asn Asn Val Arg Val Asp Asp Thr Ala Val65 70
75 80Tyr Tyr Cys Ala Arg Glu Tyr Gly Arg Asp Tyr
Asp Asp Tyr Gly Thr 85 90
95Tyr Tyr Tyr Asp Ser Trp Gly Arg Gly Thr Leu Val Thr Val Asp
100 105 11015151PRTHomo sapiens 15Met Cys
Asp Phe Thr Glu Asp Gln Thr Ala Glu Phe Lys Glu Ala Phe1 5
10 15Gln Leu Phe Asp Arg Thr Gly Asp
Gly Lys Ile Leu Tyr Ser Gln Cys 20 25
30Gly Asp Val Met Arg Ala Leu Gly Gln Asn Pro Thr Asn Ala Glu
Val 35 40 45Leu Lys Val Leu Gly
Asn Pro Lys Ser Asp Glu Met Asn Val Lys Val 50 55
60Leu Asp Phe Glu His Phe Leu Pro Met Leu Gln Thr Val Ala
Lys Asn65 70 75 80Lys
Asp Gln Gly Thr Tyr Glu Asp Tyr Val Glu Gly Leu Arg Val Phe
85 90 95Asp Lys Glu Gly Asn Gly Thr
Val Met Gly Ala Glu Ile Arg His Val 100 105
110Leu Val Thr Leu Gly Glu Lys Met Thr Glu Glu Glu Val Glu
Met Leu 115 120 125Val Ala Gly His
Glu Asp Ser Asn Gly Cys Ile Asn Tyr Glu Ala Phe 130
135 140Val Arg His Ile Leu Ser Gly145
15016135PRTHomo sapiens 16Met Ala Thr Val Gln Gln Leu Glu Gly Arg Trp Arg
Leu Val Asp Ser1 5 10
15Lys Gly Phe Asp Glu Tyr Met Lys Glu Leu Gly Val Gly Ile Ala Leu
20 25 30Arg Lys Met Gly Ala Met Ala
Lys Pro Asp Cys Ile Ile Thr Cys Asp 35 40
45Gly Lys Asn Leu Thr Ile Lys Thr Glu Ser Thr Leu Lys Thr Thr
Gln 50 55 60Phe Ser Cys Thr Leu Gly
Glu Lys Phe Glu Glu Thr Thr Ala Asp Gly65 70
75 80Arg Lys Thr Gln Thr Val Cys Asn Phe Thr Asp
Gly Ala Leu Val Gln 85 90
95His Gln Glu Trp Asp Gly Lys Glu Ser Thr Ile Thr Arg Lys Leu Lys
100 105 110Asp Gly Lys Leu Val Val
Glu Cys Val Met Asn Asn Val Thr Cys Thr 115 120
125Arg Ile Tyr Glu Lys Val Glu 130 135
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