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)
Inje University Industry - Academic Cooperation Foundation (Gyeongsangnam-Do, KR)
Na Ri Kim (Busan, KR)
Na Ri Kim (Busan, KR)
Jin Han (Busan, KR)
Jin Han (Busan, KR)
Assignees:
INJE UNIVERSITY INDUSTRY- ACADEMIC COOPERATION FOUNDATION
IPC8 Class: AG01N3368FI
USPC Class:
435 15
Class name: Chemistry: molecular biology and microbiology measuring or testing process involving enzymes or micro-organisms; composition or test strip therefore; processes of forming such composition or test strip involving transferase
Publication date: 2013-08-08
Patent application number: 20130203095
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:
1-6. (canceled)
7. A method of using a marker for early diagnosis and prediction of preeclampsia, comprising: selecting one or more proteins from the protein group consisting of ER-60 protease, 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, proteasome subunit alpha type-2 (PSMA2) protein, glutathione S-transferase, Ig heavy chain v region, and smooth muscle myosin alkali light chain, wherein the one or more proteins are isolated from a placental tissue and the isolated proteins are separated two-dimensionally through 2D electrophoresis; and analyzing the isolated and separated proteins based on scanned gel images and differences in the images against normal placental proteins, wherein the marker for early diagnosis and prediction of preeclampsia shows an increased expression of 140% or more than the normal placental proteins based on scanned gel images and differences in the images against the normal placental proteins.
8. The method of claim 7, wherein the ER-60 protease, 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, and smooth muscle myosin alkali light chain have the sequences of SEQ ID NO:2, 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, respectively.
Description:
CROSS REFERENCE TO A PARENT APPLICATION
[0001] The present application is a divisional application of application Ser. No. 13/154,774 filed on Jun. 7, 2011, which is a divisional application of application Ser. No. 12/218,767 filed on Jul. 16, 2008, now U.S. Pat. No. 7,998,508, 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 Feb. 4, 2013, is named 19325-0003-D2.txt and is 41,671 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 m/) 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 Category Protein change (%) Structural Smooth muscle myosin alkali light 191 chain 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 151 human 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
1
161573PRTMus musculus 1Met Leu Arg Leu Pro Thr Val Phe Arg Gln Met Arg Pro
Val Ser Arg 1 5 10 15
Val Leu Ala Pro His Leu Thr Arg Ala Tyr Ala Lys Asp Val Lys Phe
20 25 30 Gly Ala Asp Ala
Arg Ala Leu Met Leu Gln Gly Val Asp Leu Leu Ala 35
40 45 Asp Ala Val Ala Val Thr Met Gly Pro
Lys Gly Arg Thr Val Ile Ile 50 55
60 Glu Gln Ser Trp Gly Ser Pro Lys Val Thr Lys Asp Gly
Val Thr Val 65 70 75
80 Ala Lys Ser Ile Asp Leu Lys Asp Lys Tyr Lys Asn Ile Gly Ala Lys
85 90 95 Leu Val Gln Asp
Val Ala Asn Asn Thr Asn Glu Glu Ala Gly Asp Gly 100
105 110 Thr Thr Thr Ala Thr Val Leu Ala Arg
Ser Ile Ala Lys Glu Gly Phe 115 120
125 Glu Lys Ile Ser Lys Gly Ala Asn Pro Val Glu Ile Arg Arg
Gly Val 130 135 140
Met Leu Ala Val Asp Ala Val Ile Ala Glu Leu Lys Lys Gln Ser Lys 145
150 155 160 Pro Val Thr Thr Pro
Glu Glu Ile Ala Gln Val Ala Thr Ile Ser Ala 165
170 175 Asn Gly Asp Lys Glu Ile Gly Asn Ile Ile
Ser Asp Ala Met Lys Lys 180 185
190 Val Gly Arg Lys Gly Val Ile Thr Val Lys Asp Gly Lys Thr Leu
Asn 195 200 205 Asp
Glu Leu Glu Ile Ile Glu Gly Met Lys Phe Asp Arg Gly Tyr Ile 210
215 220 Ser Pro Tyr Phe Ile Asn
Thr Ser Lys Gly Gln Lys Cys Glu Phe Gln 225 230
235 240 Asp Ala Tyr Val Leu Leu Ser Glu Lys Lys Ile
Ser Ser Ile Gln Ser 245 250
255 Ile Val Pro Ala Leu Glu Ile Ala Asn Ala His Arg Lys Pro Leu Val
260 265 270 Ile Ile
Ala Glu Asp Val Asp Gly Glu Ala Leu Ser Thr Leu Val Leu 275
280 285 Asn Arg Leu Lys Val Gly Leu
Gln Val Val Ala Val Lys Ala Pro Gly 290 295
300 Phe Gly Asp Asn Arg Lys Asn Gln Leu Lys Asp Met
Ala Ile Ala Thr 305 310 315
320 Gly Gly Ala Val Phe Gly Glu Glu Gly Leu Thr Leu Asn Leu Glu Asp
325 330 335 Val Gln Pro
His Asp Leu Gly Lys Val Gly Glu Val Ile Val Thr Lys 340
345 350 Asp Asp Ala Met Leu Leu Lys Gly
Lys Gly Asp Lys Ala Gln Ile Glu 355 360
365 Lys Arg Ile Gln Glu Ile Ile Glu Gln Leu Asp Val Thr
Thr Ser Glu 370 375 380
Tyr Glu Lys Glu Lys Leu Asn Glu Arg Leu Ala Lys Leu Ser Asp Gly 385
390 395 400 Val Ala Val Leu
Lys Val Gly Gly Thr Ser Asp Val Glu Val Asn Glu 405
410 415 Lys Lys Asp Arg Val Thr Asp Ala Leu
Asn Ala Thr Arg Ala Ala Val 420 425
430 Glu Glu Gly Ile Val Leu Gly Gly Gly Cys Ala Leu Leu Arg
Cys Ile 435 440 445
Pro Ala Leu Asp Ser Leu Thr Pro Ala Asn Glu Asp Gln Lys Ile Gly 450
455 460 Ile Glu Ile Ile Lys
Arg Thr Leu Lys Ile Pro Ala Met Thr Ile Ala 465 470
475 480 Lys Asn Ala Gly Val Glu Gly Ser Leu Ile
Val Glu Lys Ile Met Gln 485 490
495 Ser Ser Ser Glu Val Gly Tyr Asp Ala Met Ala Gly Asp Phe Val
Asn 500 505 510 Met
Val Glu Lys Gly Ile Ile Asp Pro Thr Lys Val Val Arg Thr Ala 515
520 525 Leu Leu Asp Ala Ala Gly
Val Ala Ser Leu Leu Thr Thr Ala Glu Val 530 535
540 Val Val Thr Glu Ile Pro Lys Glu Glu Lys Asp
Pro Gly Met Gly Ala 545 550 555
560 Met Gly Gly Met Gly Gly Gly Met Gly Gly Gly Met Phe
565 570 2505PRTHomo sapiens 2Met Arg Leu
Arg Arg Leu Ala Leu Phe Pro Gly Val Ala Leu Leu Leu 1 5
10 15 Ala Ala Gly Arg Leu Val Ala Ala
Ser Asp Val Leu Glu Leu Thr Asp 20 25
30 Asp Asn Phe Glu Ser Arg Ile Ser Asp Thr Gly Ser Ala
Gly Leu Met 35 40 45
Leu Val Glu Phe Phe Ala Pro Trp Cys Gly His Cys Lys Arg Leu Ala 50
55 60 Pro Glu Tyr Glu
Ala Ala Ala Thr Arg Leu Lys Gly Ile Val Pro Leu 65 70
75 80 Ala Lys Val Asp Cys Thr Ala Asn Thr
Asn Thr Cys Asn Lys Tyr Gly 85 90
95 Val Ser Gly Tyr Pro Thr Leu Lys Ile Phe Arg Asp Gly Glu
Glu Ala 100 105 110
Gly Ala Tyr Asp Gly Pro Arg Thr Ala Asp Gly Ile Val Ser His Leu
115 120 125 Lys Lys Gln Ala
Gly Pro Ala Ser Val Pro Leu Arg Thr Glu Glu Glu 130
135 140 Phe Lys Lys Phe Ile Ser Asp Lys
Asp Ala Ser Ile Val Gly Phe Phe 145 150
155 160 Asp Asp Ser Phe Ser Glu Ala His Ser Glu Phe Leu
Lys Ala Ala Ser 165 170
175 Asn Leu Arg Asp Asn Tyr Arg Phe Ala His Thr Asn Val Glu Ser Leu
180 185 190 Val Asn Glu
Tyr Asp Asp Asn Gly Glu Gly Ile Ile Leu Phe Arg Pro 195
200 205 Ser His Leu Thr Asn Lys Phe Glu
Asp Lys Thr Val Ala Tyr Thr Glu 210 215
220 Gln Lys Met Thr Ser Gly Lys Ile Lys Lys Phe Ile Gln
Glu Asn Ile 225 230 235
240 Phe Gly Ile Cys Pro His Met Thr Glu Asp Asn Lys Asp Leu Ile Gln
245 250 255 Gly Lys Asp Leu
Leu Ile Ala Tyr Tyr Asp Val Asp Tyr Glu Lys Asn 260
265 270 Ala Lys Gly Ser Asn Tyr Trp Arg Asn
Arg Val Met Met Val Ala Lys 275 280
285 Lys Phe Leu Asp Ala Gly His Lys Leu Asn Phe Ala Val Ala
Ser Arg 290 295 300
Lys Thr Phe Ser His Glu Leu Ser Asp Phe Gly Leu Glu Ser Thr Ala 305
310 315 320 Gly Glu Ile Pro Val
Val Ala Ile Arg Thr Ala Lys Gly Glu Lys Phe 325
330 335 Val Met Gln Glu Glu Phe Ser Arg Asp Gly
Lys Ala Leu Glu Arg Phe 340 345
350 Leu Gln Asp Tyr Phe Asp Gly Asn Leu Lys Arg Tyr Leu Lys Ser
Glu 355 360 365 Pro
Ile Pro Glu Ser Asn Asp Gly Pro Val Lys Val Val Val Ala Glu 370
375 380 Asn Phe Asp Glu Ile Val
Asn Asn Glu Asn Lys Asp Val Leu Ile Glu 385 390
395 400 Phe Tyr Ala Pro Trp Cys Gly His Cys Lys Asn
Leu Glu Pro Lys Tyr 405 410
415 Lys Glu Leu Gly Glu Lys Leu Ser Lys Asp Pro Asn Ile Val Ile Ala
420 425 430 Lys Met
Asp Ala Thr Ala Asn Asp Val Pro Ser Pro Tyr Glu Val Arg 435
440 445 Gly Phe Pro Thr Ile Tyr Phe
Ser Pro Ala Asn Lys Lys Leu Asn Pro 450 455
460 Lys Lys Tyr Glu Gly Gly Arg Glu Leu Ser Asp Phe
Ile Ser Tyr Leu 465 470 475
480 Gln Arg Glu Ala Thr Asn Pro Pro Val Ile Gln Glu Glu Lys Pro Lys
485 490 495 Lys Lys Lys
Lys Ala Gln Glu Asp Leu 500 505 3434PRTHomo
sapiens 3Met Ser Ile Leu Lys Ile His Ala Arg Glu Ile Phe Asp Ser Arg Gly
1 5 10 15 Asn Pro
Thr Val Glu Val Asp Leu Phe Thr Ser Lys Gly Leu Phe Arg 20
25 30 Ala Ala Val Pro Ser Gly Ala
Ser Thr Gly Ile Tyr Glu Ala Leu Glu 35 40
45 Leu Arg Asp Asn Asp Lys Thr Arg Tyr Met Gly Lys
Gly Val Ser Lys 50 55 60
Ala Val Glu His Ile Asn Lys Thr Ile Ala Pro Ala Leu Val Ser Lys 65
70 75 80 Lys Leu Asn
Val Thr Glu Gln Glu Lys Ile Asp Lys Leu Met Ile Glu 85
90 95 Met Asp Gly Thr Glu Asn Lys Ser
Lys Phe Gly Ala Asn Ala Ile Leu 100 105
110 Gly Val Ser Leu Ala Val Cys Lys Ala Gly Ala Val Glu
Lys Gly Val 115 120 125
Pro Leu Tyr Arg His Ile Ala Asp Leu Ala Gly Asn Ser Glu Val Ile 130
135 140 Leu Pro Val Pro
Ala Phe Asn Val Ile Asn Gly Gly Ser His Ala Gly 145 150
155 160 Asn Lys Leu Ala Met Gln Glu Phe Met
Ile Leu Pro Val Gly Ala Ala 165 170
175 Asn Phe Arg Glu Ala Met Arg Ile Gly Ala Glu Val Tyr His
Asn Leu 180 185 190
Lys Asn Val Ile Lys Glu Lys Tyr Gly Lys Asp Ala Thr Asn Val Gly
195 200 205 Asp Glu Gly Gly
Phe Ala Pro Asn Ile Leu Glu Asn Lys Glu Gly Leu 210
215 220 Glu Leu Leu Lys Thr Ala Ile Gly
Lys Ala Gly Tyr Thr Asp Lys Val 225 230
235 240 Val Ile Gly Met Asp Val Ala Ala Ser Glu Phe Phe
Arg Ser Gly Lys 245 250
255 Tyr Asp Leu Asp Phe Lys Ser Pro Asp Asp Pro Ser Arg Tyr Ile Ser
260 265 270 Pro Asp Gln
Leu Ala Asp Leu Tyr Lys Ser Phe Ile Lys Asp Tyr Pro 275
280 285 Val Val Ser Ile Glu Asp Pro Phe
Asp Gln Asp Asp Trp Gly Ala Trp 290 295
300 Gln Lys Phe Thr Ala Ser Ala Gly Ile Gln Val Val Gly
Asp Asp Leu 305 310 315
320 Thr Val Thr Asn Pro Lys Arg Ile Ala Lys Ala Val Asn Glu Lys Ser
325 330 335 Cys Asn Cys Leu
Leu Leu Lys Val Asn Gln Ile Gly Ser Val Thr Glu 340
345 350 Ser Leu Gln Ala Cys Lys Leu Ala Gln
Ala Asn Gly Trp Gly Val Met 355 360
365 Val Ser His Arg Ser Gly Glu Thr Glu Asp Thr Phe Ile Ala
Asp Leu 370 375 380
Val Val Gly Leu Cys Thr Gly Gln Ile Lys Thr Gly Ala Pro Cys Arg 385
390 395 400 Ser Glu Arg Leu Ala
Lys Tyr Asn Gln Leu Leu Arg Ile Glu Glu Glu 405
410 415 Leu Gly Ser Lys Ala Lys Phe Ala Gly Arg
Asn Phe Arg Asn Pro Leu 420 425
430 Ala Lys 4414PRTHomo sapiens 4Met Ser Lys Lys Ile Ser Gly
Gly Ser Val Val Glu Met Gln Gly Asp 1 5
10 15 Glu Met Thr Arg Ile Ile Trp Glu Leu Ile Lys
Glu Lys Leu Ile Phe 20 25
30 Pro Tyr Val Glu Leu Asp Leu His Ser Tyr Asp Leu Gly Ile Glu
Asn 35 40 45 Arg
Asp Ala Thr Asn Asp Gln Val Thr Lys Asp Ala Ala Glu Ala Ile 50
55 60 Lys Lys His Asn Val Gly
Val Lys Cys Ala Thr Ile Thr Pro Asp Glu 65 70
75 80 Lys Arg Val Glu Glu Phe Lys Leu Lys Gln Met
Trp Lys Ser Pro Asn 85 90
95 Gly Thr Ile Arg Asn Ile Leu Gly Gly Thr Val Phe Arg Glu Ala Ile
100 105 110 Ile Cys
Lys Asn Ile Pro Arg Leu Val Ser Gly Trp Val Lys Pro Ile 115
120 125 Ile Ile Gly Arg His Ala Tyr
Gly Asp Gln Tyr Arg Ala Thr Asp Phe 130 135
140 Val Val Pro Gly Pro Gly Lys Val Glu Ile Thr Tyr
Thr Pro Ser Asp 145 150 155
160 Gly Thr Gln Lys Val Thr Tyr Leu Val His Asn Phe Glu Glu Gly Gly
165 170 175 Gly Val Ala
Met Gly Met Tyr Asn Gln Asp Lys Ser Ile Glu Asp Phe 180
185 190 Ala His Ser Ser Phe Gln Met Ala
Leu Ser Lys Gly Trp Pro Leu Tyr 195 200
205 Leu Ser Thr Lys Asn Thr Ile Leu Lys Lys Tyr Asp Gly
Arg Phe Lys 210 215 220
Asp Ile Phe Gln Glu Ile Tyr Asp Lys Gln Tyr Lys Ser Gln Phe Glu 225
230 235 240 Ala Gln Lys Ile
Trp Tyr Glu His Arg Leu Ile Asp Asp Met Val Ala 245
250 255 Gln Ala Met Lys Ser Glu Gly Gly Phe
Ile Trp Ala Cys Lys Asn Tyr 260 265
270 Asp Gly Asp Val Gln Ser Asp Ser Val Ala Gln Gly Tyr Gly
Ser Leu 275 280 285
Gly Met Met Thr Ser Val Leu Val Cys Pro Asp Gly Lys Thr Val Glu 290
295 300 Ala Glu Ala Ala His
Gly Thr Val Thr Arg His Tyr Arg Met Tyr Gln 305 310
315 320 Lys Gly Gln Glu Thr Ser Thr Asn Pro Ile
Ala Ser Ile Phe Ala Trp 325 330
335 Thr Arg Gly Leu Ala His Arg Ala Lys Leu Asp Asn Asn Lys Glu
Leu 340 345 350 Ala
Phe Phe Ala Asn Ala Leu Glu Glu Val Ser Ile Glu Thr Ile Glu 355
360 365 Ala Gly Phe Met Thr Lys
Asp Leu Ala Ala Cys Ile Lys Gly Leu Pro 370 375
380 Asn Val Gln Arg Ser Asp Tyr Leu Asn Thr Phe
Glu Phe Met Asp Lys 385 390 395
400 Leu Gly Glu Asn Leu Lys Ile Lys Leu Ala Gln Ala Lys Leu
405 410 5324PRTHomo sapiens 5Ala
Ala Ser Cys Val Leu Leu His Thr Gly Gln Lys Met Pro Leu Ile 1
5 10 15 Gly Leu Gly Thr Trp Lys
Ser Glu Pro Gly Gln Val Lys Ala Ala Val 20
25 30 Lys Tyr Ala Leu Ser Val Gly Tyr Arg His
Ile Asp Cys Ala Ala Ile 35 40
45 Tyr Gly Asn Glu Pro Glu Ile Gly Glu Ala Leu Lys Glu Asp
Val Gly 50 55 60
Pro Gly Lys Ala Val Pro Arg Glu Glu Leu Phe Val Thr Ser Lys Leu 65
70 75 80 Trp Asn Thr Lys His
His Pro Glu Asp Val Glu Pro Ala Leu Arg Lys 85
90 95 Thr Leu Ala Asp Leu Gln Leu Glu Tyr Leu
Asp Leu Tyr Leu Met His 100 105
110 Trp Pro Tyr Ala Phe Glu Arg Gly Asp Asn Pro Phe Pro Lys Asn
Ala 115 120 125 Asp
Gly Thr Ile Cys Tyr Asp Ser Thr His Tyr Lys Glu Thr Trp Lys 130
135 140 Ala Leu Glu Ala Leu Val
Ala Lys Gly Leu Val Gln Ala Leu Gly Leu 145 150
155 160 Ser Asn Phe Asn Ser Arg Gln Ile Asp Asp Ile
Leu Ser Val Ala Ser 165 170
175 Val Arg Pro Ala Val Leu Gln Val Glu Cys His Pro Tyr Leu Ala Gln
180 185 190 Asn Glu
Leu Ile Ala His Cys Gln Ala Arg Gly Leu Glu Val Thr Ala 195
200 205 Tyr Ser Pro Leu Gly Ser Ser
Asp Arg Ala Trp Arg Asp Pro Asp Glu 210 215
220 Pro Val Leu Leu Glu Glu Pro Val Val Leu Ala Leu
Ala Glu Lys Tyr 225 230 235
240 Gly Arg Ser Pro Ala Gln Ile Leu Leu Arg Trp Gln Val Gln Arg Lys
245 250 255 Val Ile Cys
Ile Pro Lys Ser Ile Thr Pro Ser Arg Ile Leu Gln Asn 260
265 270 Ile Lys Val Phe Asp Phe Thr Phe
Ser Pro Glu Glu Met Lys Gln Leu 275 280
285 Asn Ala Leu Asn Lys Asn Trp Arg Tyr Ile Val Pro Met
Leu Thr Val 290 295 300
Asp Gly Lys Arg Val Pro Arg Asp Ala Gly His Pro Leu Tyr Pro Phe 305
310 315 320 Asn Asp Pro Tyr
6315PRTHomo sapiens 6Ala Ser Arg Leu Leu Leu Asn Asn Gly Ala Lys Met Pro
Ile Leu Gly 1 5 10 15
Leu Gly Thr Trp Lys Ser Pro Pro Gly Gln Val Thr Glu Ala Val Lys
20 25 30 Val Ala Ile Asp
Val Gly Tyr Arg His Ile Asp Cys Ala His Val Tyr 35
40 45 Gln Asn Glu Asn Glu Val Gly Val Ala
Ile Gln Glu Lys Leu Arg Glu 50 55
60 Gln Val Val Lys Arg Glu Glu Leu Phe Ile Val Ser Lys
Leu Trp Cys 65 70 75
80 Thr Tyr His Glu Lys Gly Leu Val Lys Gly Ala Cys Gln Lys Thr Leu
85 90 95 Ser Asp Leu Lys
Leu Asp Tyr Leu Asp Leu Tyr Leu Ile His Trp Pro 100
105 110 Thr Gly Phe Lys Pro Gly Lys Glu Phe
Phe Pro Leu Asp Glu Ser Gly 115 120
125 Asn Val Val Pro Ser Asp Thr Asn Ile Leu Asp Thr Trp Ala
Ala Met 130 135 140
Glu Glu Leu Val Asp Glu Gly Leu Val Lys Ala Ile Gly Ile Ser Asn 145
150 155 160 Phe Asn His Leu Gln
Val Glu Met Ile Leu Asn Lys Pro Gly Leu Lys 165
170 175 Tyr Lys Pro Ala Val Asn Gln Ile Glu Cys
His Pro Tyr Leu Thr Gln 180 185
190 Glu Lys Leu Ile Gln Tyr Cys Gln Ser Lys Gly Ile Val Val Thr
Ala 195 200 205 Tyr
Ser Pro Leu Gly Ser Pro Asp Arg Pro Trp Ala Lys Pro Glu Asp 210
215 220 Pro Ser Leu Leu Glu Asp
Pro Arg Ile Lys Ala Ile Ala Ala Lys His 225 230
235 240 Asn Lys Thr Thr Ala Gln Val Leu Ile Arg Phe
Pro Met Gln Arg Asn 245 250
255 Leu Val Val Ile Pro Lys Ser Val Thr Pro Glu Arg Ile Ala Glu Asn
260 265 270 Phe Lys
Val Phe Asp Phe Glu Leu Ser Ser Gln Asp Met Thr Thr Leu 275
280 285 Leu Ser Tyr Asn Arg Asn Trp
Arg Val Ser Ala Leu Leu Ser Cys Thr 290 295
300 Ser His Lys Asp Tyr Pro Phe His Glu Glu Phe 305
310 315 7315PRTGallus gallus 7Ala Ser Arg
Leu Leu Leu Asn Asn Gly Ala Lys Met Pro Ile Leu Gly 1 5
10 15 Leu Gly Thr Trp Lys Ser Pro Pro
Gly Gln Val Thr Glu Ala Val Lys 20 25
30 Val Ala Ile Asp Val Gly Tyr Arg His Ile Asp Cys Ala
His Val Tyr 35 40 45
Gln Asn Glu Asn Glu Val Gly Val Ala Ile Gln Glu Lys Leu Arg Glu 50
55 60 Gln Val Val Lys
Arg Glu Glu Leu Phe Ile Val Ser Lys Leu Trp Cys 65 70
75 80 Thr Tyr His Glu Lys Gly Leu Val Lys
Gly Ala Cys Gln Lys Thr Leu 85 90
95 Ser Asp Leu Lys Leu Asp Tyr Leu Asp Leu Tyr Leu Ile His
Trp Pro 100 105 110
Thr Gly Phe Lys Pro Gly Lys Glu Phe Phe Pro Leu Asp Glu Ser Gly
115 120 125 Asn Val Val Pro
Ser Asp Thr Asn Ile Leu Asp Thr Trp Ala Ala Met 130
135 140 Glu Glu Leu Val Asp Glu Gly Leu
Val Lys Ala Ile Gly Ile Ser Asn 145 150
155 160 Phe Asn His Leu Gln Val Glu Met Ile Leu Asn Lys
Pro Gly Leu Lys 165 170
175 Tyr Lys Pro Ala Val Asn Gln Ile Glu Cys His Pro Tyr Leu Thr Gln
180 185 190 Glu Lys Leu
Ile Gln Tyr Cys Gln Ser Lys Gly Ile Val Val Thr Ala 195
200 205 Tyr Ser Pro Leu Gly Ser Pro Asp
Arg Pro Trp Ala Lys Pro Glu Asp 210 215
220 Pro Ser Leu Leu Glu Asp Pro Arg Ile Lys Ala Ile Ala
Ala Lys His 225 230 235
240 Asn Lys Thr Thr Ala Gln Val Leu Ile Arg Phe Pro Met Gln Arg Asn
245 250 255 Leu Val Val Ile
Pro Lys Ser Val Thr Pro Glu Arg Ile Ala Glu Asn 260
265 270 Phe Lys Val Phe Asp Phe Glu Leu Ser
Ser Gln Asp Met Thr Thr Leu 275 280
285 Leu Ser Tyr Asn Arg Asn Trp Arg Val Ser Ala Leu Leu Ser
Cys Thr 290 295 300
Ser His Lys Asp Tyr Pro Phe His Glu Glu Phe 305 310
315 8241PRTHomo sapiens 8Met Ala Glu Glu Gln Pro Gln Val Glu
Leu Phe Val Lys Ala Gly Ser 1 5 10
15 Asp Gly Ala Lys Ile Gly Asn Cys Pro Phe Ser Gln Arg Leu
Phe Met 20 25 30
Val Leu Trp Leu Lys Gly Val Thr Phe Asn Val Thr Thr Val Asp Thr
35 40 45 Lys Arg Arg Thr
Glu Thr Val Gln Lys Leu Cys Pro Gly Gly Glu Leu 50
55 60 Pro Phe Leu Leu Tyr Gly Thr Glu
Val His Thr Asp Thr Asn Lys Ile 65 70
75 80 Glu Glu Phe Leu Glu Ala Val Leu Cys Pro Pro Arg
Tyr Pro Lys Leu 85 90
95 Ala Ala Leu Asn Pro Glu Ser Asn Thr Ala Gly Leu Asp Ile Phe Ala
100 105 110 Lys Phe Ser
Ala Tyr Ile Lys Asn Ser Asn Pro Ala Leu Asn Asp Asn 115
120 125 Leu Glu Lys Gly Leu Leu Lys Ala
Leu Lys Val Leu Asp Asn Tyr Leu 130 135
140 Thr Ser Pro Leu Pro Glu Glu Val Asp Glu Thr Ser Ala
Glu Asp Glu 145 150 155
160 Gly Val Ser Gln Arg Lys Phe Leu Asp Gly Asn Glu Leu Thr Leu Ala
165 170 175 Asp Cys Asn Leu
Leu Pro Lys Leu His Ile Val Gln Val Val Cys Lys 180
185 190 Lys Tyr Arg Gly Phe Thr Ile Pro Glu
Ala Phe Arg Gly Val His Arg 195 200
205 Tyr Leu Ser Asn Ala Tyr Ala Arg Glu Glu Phe Ala Ser Thr
Cys Pro 210 215 220
Asp Asp Glu Glu Ile Glu Leu Ala Tyr Glu Gln Val Ala Lys Ala Leu 225
230 235 240 Lys 9241PRTHomo
sapiensMOD_RES(1)..(1)Any amino acid 9Xaa Gly Val Lys Val Glu Arg Gln Val
Phe Gly Glu Ala Thr Lys Gln 1 5 10
15 Pro Gly Ile Thr Phe Ile Ala Ala Lys Phe Asp Gly Ile Leu
Gly Met 20 25 30
Ala Tyr Pro Arg Ile Ser Val Asn Asn Val Leu Pro Val Phe Asp Asn
35 40 45 Leu Met Gln Gln
Lys Leu Val Asp Gln Asn Ile Phe Ser Phe Tyr Leu 50
55 60 Ser Arg Asp Pro Asp Ala Gln Pro
Gly Gly Glu Leu Met Leu Gly Gly 65 70
75 80 Thr Asp Ser Lys Tyr Tyr Lys Gly Ser Leu Ser Tyr
Leu Asn Val Thr 85 90
95 Arg Lys Ala Tyr Trp Gln Val His Leu Asp Gln Val Glu Val Ala Ser
100 105 110 Gly Leu Thr
Leu Cys Lys Glu Gly Cys Glu Ala Ile Val Asp Thr Gly 115
120 125 Thr Ser Leu Met Val Gly Pro Val
Asp Glu Val Arg Glu Leu Gln Lys 130 135
140 Ala Ile Gly Ala Val Pro Leu Ile Gln Gly Glu Tyr Met
Ile Pro Cys 145 150 155
160 Glu Lys Val Ser Thr Leu Pro Ala Ile Thr Leu Lys Leu Gly Gly Lys
165 170 175 Gly Tyr Lys Leu
Ser Pro Glu Asp Tyr Thr Leu Lys Val Ser Gln Ala 180
185 190 Gly Lys Thr Leu Cys Leu Ser Gly Phe
Met Gly Met Asp Ile Pro Pro 195 200
205 Pro Ser Gly Pro Leu Trp Ile Leu Gly Asp Val Phe Ile Gly
Arg Tyr 210 215 220
Tyr Thr Val Phe Asp Arg Asp Asn Asn Arg Val Gly Phe Ala Glu Ala 225
230 235 240 Ala 10254PRTHomo
sapiens 10Met Ala Ala Tyr Lys Leu Val Leu Ile Arg His Gly Glu Ser Ala Trp
1 5 10 15 Asn Leu
Glu Asn Arg Phe Ser Gly Trp Tyr Asp Ala Asp Leu Ser Pro 20
25 30 Ala Gly His Glu Glu Ala Lys
Arg Gly Gly Gln Ala Leu Arg Asp Ala 35 40
45 Gly Tyr Glu Phe Asp Ile Cys Phe Thr Ser Val Gln
Lys Arg Ala Ile 50 55 60
Arg Thr Leu Trp Thr Val Leu Asp Ala Ile Asp Gln Met Trp Leu Pro 65
70 75 80 Val Val Arg
Thr Trp Arg Leu Asn Glu Arg His Tyr Gly Gly Leu Thr 85
90 95 Gly Leu Asn Lys Ala Glu Thr Ala
Ala Lys His Gly Glu Ala Gln Val 100 105
110 Lys Ile Trp Arg Arg Ser Tyr Asp Val Pro Pro Pro Pro
Met Glu Pro 115 120 125
Asp His Pro Phe Tyr Ser Asn Ile Ser Lys Asp Arg Arg Tyr Ala Asp 130
135 140 Leu Thr Glu Asp
Gln Leu Pro Ser Cys Glu Ser Leu Lys Asp Thr Ile 145 150
155 160 Ala Arg Ala Leu Pro Phe Trp Asn Glu
Glu Ile Val Pro Gln Ile Lys 165 170
175 Glu Gly Lys Arg Val Leu Ile Ala Ala His Gly Asn Ser Leu
Arg Gly 180 185 190
Ile Val Lys His Leu Glu Gly Leu Ser Glu Glu Ala Ile Met Glu Leu
195 200 205 Asn Leu Pro Thr
Gly Ile Pro Ile Val Tyr Glu Leu Asp Lys Asn Leu 210
215 220 Lys Pro Ile Lys Pro Met Gln Phe
Leu Gly Asp Glu Glu Thr Val Arg 225 230
235 240 Lys Ala Met Glu Ala Val Ala Ala Gln Gly Lys Ala
Lys Lys 245 250
11261PRTHomo sapiens 11Met Ala Ala Ala Val Pro Arg Ala Ala Phe Leu Ser
Pro Leu Leu Pro 1 5 10
15 Leu Leu Leu Gly Phe Leu Leu Leu Ser Ala Pro His Gly Gly Ser Gly
20 25 30 Leu His Thr
Lys Gly Ala Leu Pro Leu Asp Thr Val Thr Phe Tyr Lys 35
40 45 Val Ile Pro Lys Ser Lys Phe Val
Leu Val Lys Phe Asp Thr Gln Tyr 50 55
60 Pro Tyr Gly Glu Lys Gln Asp Glu Phe Lys Arg Leu Ala
Glu Asn Ser 65 70 75
80 Ala Ser Ser Asp Asp Leu Leu Val Ala Glu Val Gly Ile Ser Asp Tyr
85 90 95 Gly Asp Lys Leu
Asn Met Glu Leu Ser Glu Lys Tyr Lys Leu Asp Lys 100
105 110 Glu Ser Tyr Pro Val Phe Tyr Leu Phe
Arg Asp Gly Asp Phe Glu Asn 115 120
125 Pro Val Pro Tyr Thr Gly Ala Val Lys Val Gly Ala Ile Gln
Arg Trp 130 135 140
Leu Lys Gly Gln Gly Val Tyr Leu Gly Met Pro Gly Cys Leu Pro Val 145
150 155 160 Tyr Asp Ala Leu Ala
Gly Glu Phe Ile Arg Ala Ser Gly Val Glu Ala 165
170 175 Arg Gln Ala Leu Leu Lys Gln Gly Gln Asp
Asn Leu Ser Ser Val Lys 180 185
190 Glu Thr Gln Lys Lys Trp Ala Glu Gln Tyr Leu Lys Ile Met Gly
Lys 195 200 205 Ile
Leu Asp Gln Gly Glu Asp Phe Pro Ala Ser Glu Met Thr Arg Ile 210
215 220 Ala Arg Leu Ile Glu Lys
Asn Lys Met Ser Asp Gly Lys Lys Glu Glu 225 230
235 240 Leu Gln Lys Ser Leu Asn Ile Leu Thr Ala Phe
Gln Lys Lys Gly Ala 245 250
255 Glu Lys Glu Glu Leu 260 12234PRTMus musculus
12Met Ala Glu Arg Gly Tyr Ser Phe Ser Leu Thr Thr Phe Ser Pro Ser 1
5 10 15 Gly Lys Leu Val
Gln Ile Glu Tyr Ala Leu Ala Ala Val Ala Gly Gly 20
25 30 Ala Pro Ser Val Gly Ile Lys Ala Ala
Asn Gly Val Val Leu Ala Thr 35 40
45 Glu Lys Lys Gln Lys Ser Ile Leu Tyr Asp Glu Arg Ser Val
His Lys 50 55 60
Val Glu Pro Ile Thr Lys His Ile Gly Leu Val Tyr Ser Gly Met Gly 65
70 75 80 Pro Asp Tyr Arg Val
Leu Val His Arg Ala Arg Lys Leu Ala Gln Gln 85
90 95 Tyr Tyr Leu Val Tyr Gln Glu Pro Ile Pro
Thr Ala Gln Leu Val Gln 100 105
110 Arg Val Ala Ser Val Met Gln Glu Tyr Thr Gln Ser Gly Gly Val
Arg 115 120 125 Pro
Phe Gly Val Ser Leu Leu Ile Cys Gly Trp Asn Glu Gly Arg Pro 130
135 140 Tyr Leu Phe Gln Ser Asp
Pro Ser Gly Ala Tyr Phe Ala Trp Lys Ala 145 150
155 160 Thr Ala Met Gly Lys Asn Tyr Val Asn Gly Lys
Thr Phe Leu Glu Lys 165 170
175 Arg Tyr Asn Glu Asp Leu Glu Leu Glu Asp Ala Ile His Thr Ala Ile
180 185 190 Leu Thr
Leu Lys Glu Ser Phe Glu Gly Gln Met Thr Glu Asp Asn Ile 195
200 205 Glu Val Gly Ile Cys Asn Glu
Ala Gly Phe Arg Arg Leu Thr Pro Thr 210 215
220 Glu Val Lys Asp Tyr Leu Ala Ala Ile Ala 225
230 13210PRTHomo sapiens 13Met Pro Pro Tyr
Thr Val Val Tyr Phe Pro Val Arg Gly Arg Cys Ala 1 5
10 15 Ala Leu Arg Met Leu Leu Ala Asp Gln
Gly Gln Ser Trp Lys Glu Glu 20 25
30 Val Val Thr Val Glu Thr Trp Gln Glu Gly Ser Leu Lys Ala
Ser Cys 35 40 45
Leu Tyr Gly Gln Leu Pro Lys Phe Gln Asp Gly Asp Leu Thr Leu Tyr 50
55 60 Gln Ser Asn Thr Ile
Leu Arg His Leu Gly Arg Thr Leu Gly Leu Tyr 65 70
75 80 Gly Lys Asp Gln Gln Glu Ala Ala Leu Val
Asp Met Val Asn Asp Gly 85 90
95 Val Glu Asp Leu Arg Cys Lys Tyr Ile Ser Leu Ile Tyr Thr Asn
Tyr 100 105 110 Glu
Ala Gly Lys Asp Asp Tyr Val Lys Ala Leu Pro Gly Gln Leu Lys 115
120 125 Pro Phe Glu Thr Leu Leu
Ser Gln Asn Gln Gly Gly Lys Thr Phe Ile 130 135
140 Val Gly Asp Gln Ile Ser Phe Ala Asp Tyr Asn
Leu Leu Asp Leu Leu 145 150 155
160 Leu Ile His Glu Val Leu Ala Pro Gly Cys Leu Asp Ala Phe Pro Leu
165 170 175 Leu Ser
Ala Tyr Val Gly Arg Leu Ser Pro Arg Pro Lys Leu Lys Ala 180
185 190 Phe Leu Ala Ser Pro Glu Tyr
Val Asn Leu Pro Ile Asn Gly Asn Gly 195 200
205 Lys Gln 210 14111PRTMus musculus 14Val Asp
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 1 5
10 15 Ser His Tyr Ala Val His Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu 20 25
30 Glu Trp Leu Ala Phe Ile Ser Ala Asp Gly Ser Asp
Thr Asp His Ala 35 40 45
Pro Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Arg Asn
50 55 60 Met Leu Phe
Leu Gln Met Asn Asn Val Arg Val Asp Asp Thr Ala Val 65
70 75 80 Tyr Tyr Cys Ala Arg Glu Tyr
Gly Arg Asp Tyr Asp Asp Tyr Gly Thr 85
90 95 Tyr Tyr Tyr Asp Ser Trp Gly Arg Gly Thr Leu
Val Thr Val Asp 100 105 110
15151PRTHomo sapiens 15Met Cys Asp Phe Thr Glu Asp Gln Thr Ala Glu Phe
Lys Glu Ala Phe 1 5 10
15 Gln Leu Phe Asp Arg Thr Gly Asp Gly Lys Ile Leu Tyr Ser Gln Cys
20 25 30 Gly Asp Val
Met Arg Ala Leu Gly Gln Asn Pro Thr Asn Ala Glu Val 35
40 45 Leu Lys Val Leu Gly Asn Pro Lys
Ser Asp Glu Met Asn Val Lys Val 50 55
60 Leu Asp Phe Glu His Phe Leu Pro Met Leu Gln Thr Val
Ala Lys Asn 65 70 75
80 Lys Asp Gln Gly Thr Tyr Glu Asp Tyr Val Glu Gly Leu Arg Val Phe
85 90 95 Asp Lys Glu Gly
Asn Gly Thr Val Met Gly Ala Glu Ile Arg His Val 100
105 110 Leu Val Thr Leu Gly Glu Lys Met Thr
Glu Glu Glu Val Glu Met Leu 115 120
125 Val Ala Gly His Glu Asp Ser Asn Gly Cys Ile Asn Tyr Glu
Ala Phe 130 135 140
Val Arg His Ile Leu Ser Gly 145 150 16135PRTHomo
sapiens 16Met Ala Thr Val Gln Gln Leu Glu Gly Arg Trp Arg Leu Val Asp Ser
1 5 10 15 Lys Gly
Phe Asp Glu Tyr Met Lys Glu Leu Gly Val Gly Ile Ala Leu 20
25 30 Arg Lys Met Gly Ala Met Ala
Lys Pro Asp Cys Ile Ile Thr Cys Asp 35 40
45 Gly Lys Asn Leu Thr Ile Lys Thr Glu Ser Thr Leu
Lys Thr Thr Gln 50 55 60
Phe Ser Cys Thr Leu Gly Glu Lys Phe Glu Glu Thr Thr Ala Asp Gly 65
70 75 80 Arg Lys Thr
Gln Thr Val Cys Asn Phe Thr Asp Gly Ala Leu Val Gln 85
90 95 His Gln Glu Trp Asp Gly Lys Glu
Ser Thr Ile Thr Arg Lys Leu Lys 100 105
110 Asp Gly Lys Leu Val Val Glu Cys Val Met Asn Asn Val
Thr Cys Thr 115 120 125
Arg Ile Tyr Glu Lys Val Glu 130 135
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