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1.A.3.1.2
The Ryanodine receptor Ca2+/K+ release tetrameric channel, RyR1, present in skeletal muscle, is 5038 aas long. Mutants are linked to core myopathies such as Central Core Disease, Malignant Hyperthermia and Multiple Minicore Disease) (Xu et al., 2008). RyR1 interacts with CLIC2 to modulate its channel activity (Meng et al., 2009).  A model pf RyR1 has been constructed encompassing the six transmembrane helices to calculate the RyR1 pore region conductance, to analyze its structural stability, and to hypothesize the mechanism of the Ile4897 CCD-associated mutation. The calculated conductance of the wild-type RyR1 suggests that the pore structure can sustain ion currents measured in single-channel experiments. Shirvanyants et al. 2014 observed a stable pore structure with multiple cations occupying the selectivity filter and cytosolic vestibule, but not the inner chamber. Stability of the selectivity filter depends on interactions between the I4897 residue and several hydrophobic residues of the neighboring subunit. Loss of these interactions in the case of the polar substitution, I4897T, results in destabilization of the selectivity filter, a possible cause of the CCD-specific reduced Ca2+ conductance.  A 4.8 Å structure of the rabbit orthologue in the closed state of this 2.3 MDa tetramer (3757 aas/protomer) reveals the pore, the VIC superfamily fold and a potential mechanism of Ca2+ gating (Zalk et al. 2015).  A cryo-electron microscopy analysis revealed the structure at 6.1 Å resolution (Efremov et al. 2015). The transmembrane domain represents a chimaera of voltage-gated sodium and pH-activated ion channels. They identified the calcium-binding EF-hand domain and showed that it functions as a conformational switch, allosterically gating the channel.  Malignant hyperthermia-associated RyR1 mutations in the S2-S3 loop confer RyR2-type Ca2+- and Mg2+-dependent channel regulation (Gomez et al. 2016).  Structural analyses have elucidated a novel channel-gating mechanism and a novel ion selectivity mechanism for RyR1 (Wei et al. 2016).  Samsó 2016 reviewed structural determinations of RyR by cryoEM and  analyzed the first near-atomic structures, revealing a complex orchestration of domains controlling channel function.  The structural basis for gating and activation have been determined (des Georges et al. 2016). Junctin and triadin bind to different sites on RyR1; triadin plays an important role in ensuring rapid Ca2+ release during excitation-contraction coupling in skeletal muscle.  RyR1 structure/functioin has been reviewed (Zalk and Marks 2017).

Accession Number:P21817
Protein Name:RYR-1
Length:5038
Molecular Weight:565176.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:6
Location1 / Topology2 / Orientation3: Membrane1 / Multi-pass membrane protein2
Substrate Ca2+, K+

Cross database links:

Genevestigator: P21817
HEGENOM: HBG315203
DIP: DIP-29708N
RefSeq: NP_000531.2    NP_001036188.1   
Entrez Gene ID: 6261   
Pfam: PF08709    PF00520    PF02815    PF08454    PF06459    PF01365    PF02026    PF00622   
Drugbank: Drugbank Link   
OMIM: 117000  phenotype
145600  phenotype
180901  gene
255320  phenotype
KEGG: hsa:6261   

Gene Ontology

GO:0005938 C:cell cortex
GO:0031674 C:I band
GO:0005887 C:integral to plasma membrane
GO:0014701 C:junctional sarcoplasmic reticulum membrane
GO:0005790 C:smooth endoplasmic reticulum
GO:0014802 C:terminal cisterna
GO:0005509 F:calcium ion binding
GO:0005516 F:calmodulin binding
GO:0004872 F:receptor activity
GO:0005219 F:ryanodine-sensitive calcium-release channel...
GO:0006936 P:muscle contraction
GO:0051209 P:release of sequestered calcium ion into cyt...
GO:0031000 P:response to caffeine
GO:0001666 P:response to hypoxia
GO:0055085 P:transmembrane transport

References (59)

[1] “Molecular cloning of cDNA encoding human and rabbit forms of the Ca2+ release channel (ryanodine receptor) of skeletal muscle sarcoplasmic reticulum.”  Zorzato F.et.al.   2298749
[2] “Polymorphisms and deduced amino acid substitutions in the coding sequence of the ryanodine receptor (RYR1) gene in individuals with malignant hyperthermia.”  Gillard E.F.et.al.   1354642
[3] “A mutation in the human ryanodine receptor gene associated with central core disease.”  Zhang Y.et.al.   8220422
[4] “The structural organization of the human skeletal muscle ryanodine receptor (RYR1) gene.”  Phillips M.S.et.al.   8661021
[5] “The DNA sequence and biology of human chromosome 19.”  Grimwood J.et.al.   15057824
[6] “Refinement of diagnostic assays for a probable causal mutation for porcine and human malignant hyperthermia.”  Otsu K.et.al.   1639409
[7] “A substitution of cysteine for arginine 614 in the ryanodine receptor is potentially causative of human malignant hyperthermia.”  Gillard E.F.et.al.   1774074
[8] “Ryanodine receptor gene point mutation and malignant hyperthermia susceptibility.”  Moroni I.et.al.   7751854
[9] “Isolation and partial cloning of ryanodine-sensitive Ca2+ release channel protein isoforms from human myometrial smooth muscle.”  Lynn S.et.al.   7556644
[10] “Partial cloning and differential expression of ryanodine receptor/calcium-release channel genes in human tissues including the hippocampus and cerebellum.”  Martin C.et.al.   9607712
[11] “Cysteine-3635 is responsible for skeletal muscle ryanodine receptor modulation by NO.”  Sun J.et.al.   11562475
[12] “Large-scale phosphoproteome analysis of human liver tissue by enrichment and fractionation of phosphopeptides with strong anion exchange chromatography.”  Han G.et.al.   18318008
[13] “Mutations in the ryanodine receptor gene in central core disease and malignant hyperthermia.”  Quane K.A.et.al.   8220423
[14] “Mutation screening of the RYR1 gene in malignant hyperthermia: detection of a novel Tyr to Ser mutation in a pedigree with associated central cores.”  Quane K.A.et.al.   7829078
[15] “Detection of a novel common mutation in the ryanodine receptor gene in malignant hyperthermia: implications for diagnosis and heterogeneity studies.”  Quane K.A.et.al.   8012359
[16] “Detection of a novel RYR1 mutation in four malignant hyperthermia pedigrees.”  Keating K.E.et.al.   7849712
[17] “The substitution of Arg for Gly2433 in the human skeletal muscle ryanodine receptor is associated with malignant hyperthermia.”  Phillips M.S.et.al.   7881417
[18] “Identification of heterozygous and homozygous individuals with the novel RYR1 mutation Cys35Arg in a large kindred.”  Lynch P.J.et.al.   9066328
[19] “Detection of a novel mutation at amino acid position 614 in the ryanodine receptor in malignant hyperthermia.”  Quane K.A.et.al.   9389851
[20] “Detection of a novel mutation in the ryanodine receptor gene in an Irish malignant hyperthermia pedigree: correlation of the IVCT response with the affected and unaffected haplotypes.”  Keating K.E.et.al.   9138151
[21] “Identification of novel mutations in the ryanodine-receptor gene (RYR1) in malignant hyperthermia: genotype-phenotype correlation.”  Manning B.M.et.al.   9497245
[22] “Novel mutations at a CpG dinucleotide in the ryanodine receptor in malignant hyperthermia.”  Manning B.M.et.al.   9450902
[23] “Screening of the ryanodine receptor gene in 105 malignant hyperthermia families: novel mutations and concordance with the in vitro contracture test.”  Brandt A.et.al.   10484775
[24] “Mutation screening of the RYR1 gene and identification of two novel mutations in Italian malignant hyperthermia families.”  Barone V.et.al.   10051009
[25] “A mutation in the transmembrane/luminal domain of the ryanodine receptor is associated with abnormal Ca(2+) release channel function and severe central core disease.”  Lynch P.J.et.al.   10097181
[26] “Malignant hyperthermia in infancy and identification of novel RYR1 mutation.”  Chamley D.et.al.   10823104
[27] “A novel ryanodine receptor mutation and genotype-phenotype correlation in a large malignant hyperthermia New Zealand Maori pedigree.”  Brown R.L.et.al.   10888602
[28] “Novel mutation in the RYR1 gene (R2454C) in a patient with malignant hyperthermia.”  Gencik M.et.al.   10612851
[29] “A novel ryanodine receptor gene mutation causing both cores and rods in congenital myopathy.”  Scacheri P.C.et.al.   11113224
[30] “Single-amino-acid deletion in the RYR1 gene, associated with malignant hyperthermia susceptibility and unusual contraction phenotype.”  Sambuughin N.et.al.   11389482
[31] “North American malignant hyperthermia population: screening of the ryanodine receptor gene and identification of novel mutations.”  Sambuughin N.et.al.   11575529
[32] “Familial and sporadic forms of central core disease are associated with mutations in the C-terminal domain of the skeletal muscle ryanodine receptor.”  Monnier N.et.al.   11709545
[33] “Identification of four novel mutations in the C-terminal membrane spanning domain of the ryanodine receptor 1: association with central core disease and alteration of calcium homeostasis.”  Tilgen N.et.al.   11741831
[34] “Identification of a novel mutation in the ryanodine receptor gene (RYR1) in patients with malignant hyperthermia.”  Rueffert H.et.al.   11241852
[35] “Identification and functional characterization of a novel ryanodine receptor mutation causing malignant hyperthermia in North American and South American families.”  Sambuughin N.et.al.   11525881
[36] “Mutation screening in the ryanodine receptor 1 gene (RYR1) in patients susceptible to malignant hyperthermia who show definite IVCT results: identification of three novel mutations.”  Rueffert H.et.al.   12059893
[37] “Presence of two different genetic traits in malignant hyperthermia families: implication for genetic analysis, diagnosis, and incidence of malignant hyperthermia susceptibility.”  Monnier N.et.al.   12411788
[38] “A recessive form of central core disease, transiently presenting as multi-minicore disease, is associated with a homozygous mutation in the ryanodine receptor type 1 gene.”  Ferreiro A.et.al.   12112081
[39] “Malignant hyperthermia associated with exercise-induced rhabdomyolysis or congenital abnormalities and a novel RYR1 mutation in New Zealand and Australian pedigrees.”  Davis M.et.al.   12066726
[40] “Mutations in the RYR1 gene in Italian patients at risk for malignant hyperthermia: evidence for a cluster of novel mutations in the C-terminal region.”  Galli L.et.al.   12208234
[41] “Novel skeletal muscle ryanodine receptor mutation in a large Brazilian family with malignant hyperthermia.”  McWilliams S.et.al.   12123492
[42] “Novel mutations in C-terminal channel region of the ryanodine receptor in malignant hyperthermia patients.”  Oyamada H.et.al.   11928716
[43] “Autosomal recessive inheritance of RYR1 mutations in a congenital myopathy with cores.”  Jungbluth H.et.al.   12136074
[44] “Detection of a novel ryanodine receptor subtype 1 mutation (R328W) in a malignant hyperthermia family by sequencing of a leukocyte transcript.”  Loke J.C.P.et.al.   12883402
[45] “Central core disease: clinical, pathological, and genetic features.”  Quinlivan R.M.et.al.   14670767
[46] “Dominant and recessive central core disease associated with RYR1 mutations and fetal akinesia.”  Romero N.B.et.al.   12937085
[47] “Scanning for mutations of the ryanodine receptor (RYR1) gene by denaturing HPLC: detection of three novel malignant hyperthermia alleles.”  Tammaro A.et.al.   12709367
[48] “Clinical and functional effects of a deletion in a COOH-terminal lumenal loop of the skeletal muscle ryanodine receptor.”  Zorzato F.et.al.   12566385
[49] “A homozygous splicing mutation causing a depletion of skeletal muscle RYR1 is associated with multi-minicore disease congenital myopathy with ophthalmoplegia.”  Monnier N.et.al.   12719381
[50] “Principal mutation hotspot for central core disease and related myopathies in the C-terminal transmembrane region of the RYR1 gene.”  Davis M.R.et.al.   12565913
[51] “Malignant hyperthermia in North America: genetic screening of the three hot spots in the type I ryanodine receptor gene.”  Sei Y.et.al.   15448513
[52] “Multiminicore disease in a family susceptible to malignant hyperthermia: histology, in vitro contracture tests, and genetic characterization.”  Guis S.et.al.   14732627
[53] “RYR1 mutations in UK central core disease patients: more than just the C-terminal transmembrane region of the RYR1 gene.”  Shepherd S.et.al.   14985404
[54] “Mutation analysis of two patients with hypokalemic periodic paralysis and suspected malignant hyperthermia.”  Marchant C.L.et.al.   15221887
[55] “Correlations between genotype and pharmacological, histological, functional, and clinical phenotypes in malignant hyperthermia susceptibility.”  Monnier N.et.al.   16163667
[56] “Minicore myopathy with ophthalmoplegia caused by mutations in the ryanodine receptor type 1 gene.”  Jungbluth H.et.al.   16380615
[57] “Central core disease due to recessive mutations in RYR1 gene: is it more common than described?”  Kossugue P.M.et.al.   17226826
[58] “Null mutations causing depletion of the type 1 ryanodine receptor (RYR1) are commonly associated with recessive structural congenital myopathies with cores.”  Monnier N.et.al.   18253926
[59] “Increasing the number of diagnostic mutations in malignant hyperthermia.”  Levano S.et.al.   19191329
Structure:
4uwa     

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Predict TMSs (Predict number of transmembrane segments)
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FASTA formatted sequence
1:	MGDAEGEDEV QFLRTDDEVV LQCSATVLKE QLKLCLAAEG FGNRLCFLEP TSNAQNVPPD 
61:	LAICCFVLEQ SLSVRALQEM LANTVEAGVE SSQGGGHRTL LYGHAILLRH AHSRMYLSCL 
121:	TTSRSMTDKL AFDVGLQEDA TGEACWWTMH PASKQRSEGE KVRVGDDIIL VSVSSERYLH 
181:	LSTASGELQV DASFMQTLWN MNPICSRCEE GFVTGGHVLR LFHGHMDECL TISPADSDDQ 
241:	RRLVYYEGGA VCTHARSLWR LEPLRISWSG SHLRWGQPLR VRHVTTGQYL ALTEDQGLVV 
301:	VDASKAHTKA TSFCFRISKE KLDVAPKRDV EGMGPPEIKY GESLCFVQHV ASGLWLTYAA 
361:	PDPKALRLGV LKKKAMLHQE GHMDDALSLT RCQQEESQAA RMIHSTNGLY NQFIKSLDSF 
421:	SGKPRGSGPP AGTALPIEGV ILSLQDLIIY FEPPSEDLQH EEKQSKLRSL RNRQSLFQEE 
481:	GMLSMVLNCI DRLNVYTTAA HFAEFAGEEA AESWKEIVNL LYELLASLIR GNRSNCALFS 
541:	TNLDWLVSKL DRLEASSGIL EVLYCVLIES PEVLNIIQEN HIKSIISLLD KHGRNHKVLD 
601:	VLCSLCVCNG VAVRSNQDLI TENLLPGREL LLQTNLINYV TSIRPNIFVG RAEGTTQYSK 
661:	WYFEVMVDEV TPFLTAQATH LRVGWALTEG YTPYPGAGEG WGGNGVGDDL YSYGFDGLHL 
721:	WTGHVARPVT SPGQHLLAPE DVISCCLDLS VPSISFRING CPVQGVFESF NLDGLFFPVV 
781:	SFSAGVKVRF LLGGRHGEFK FLPPPGYAPC HEAVLPRERL HLEPIKEYRR EGPRGPHLVG 
841:	PSRCLSHTDF VPCPVDTVQI VLPPHLERIR EKLAENIHEL WALTRIEQGW TYGPVRDDNK 
901:	RLHPCLVDFH SLPEPERNYN LQMSGETLKT LLALGCHVGM ADEKAEDNLK KTKLPKTYMM 
961:	SNGYKPAPLD LSHVRLTPAQ TTLVDRLAEN GHNVWARDRV GQGWSYSAVQ DIPARRNPRL 
1021:	VPYRLLDEAT KRSNRDSLCQ AVRTLLGYGY NIEPPDQEPS QVENQSRCDR VRIFRAEKSY 
1081:	TVQSGRWYFE FEAVTTGEMR VGWARPELRP DVELGADELA YVFNGHRGQR WHLGSEPFGR 
1141:	PWQPGDVVGC MIDLTENTII FTLNGEVLMS DSGSETAFRE IEIGDGFLPV CSLGPGQVGH 
1201:	LNLGQDVSSL RFFAICGLQE GFEPFAINMQ RPVTTWFSKG LPQFEPVPLE HPHYEVSRVD 
1261:	GTVDTPPCLR LTHRTWGSQN SLVEMLFLRL SLPVQFHQHF RCTAGATPLA PPGLQPPAED 
1321:	EARAAEPDPD YENLRRSAGG WSEAENGKEG TAKEGAPGGT PQAGGEAQPA RAENEKDATT 
1381:	EKNKKRGFLF KAKKVAMMTQ PPATPTLPRL PHDVVPADNR DDPEIILNTT TYYYSVRVFA 
1441:	GQEPSCVWAG WVTPDYHQHD MSFDLSKVRV VTVTMGDEQG NVHSSLKCSN CYMVWGGDFV 
1501:	SPGQQGRISH TDLVIGCLVD LATGLMTFTA NGKESNTFFQ VEPNTKLFPA VFVLPTHQNV 
1561:	IQFELGKQKN IMPLSAAMFQ SERKNPAPQC PPRLEMQMLM PVSWSRMPNH FLQVETRRAG 
1621:	ERLGWAVQCQ EPLTMMALHI PEENRCMDIL ELSERLDLQR FHSHTLRLYR AVCALGNNRV 
1681:	AHALCSHVDQ AQLLHALEDA HLPGPLRAGY YDLLISIHLE SACRSRRSML SEYIVPLTPE 
1741:	TRAITLFPPG RSTENGHPRH GLPGVGVTTS LRPPHHFSPP CFVAALPAAG AAEAPARLSP 
1801:	AIPLEALRDK ALRMLGEAVR DGGQHARDPV GGSVEFQFVP VLKLVSTLLV MGIFGDEDVK 
1861:	QILKMIEPEV FTEEEEEEDE EEEGEEEDEE EKEEDEEETA QEKEDEEKEE EEAAEGEKEE 
1921:	GLEEGLLQMK LPESVKLQMC HLLEYFCDQE LQHRVESLAA FAERYVDKLQ ANQRSRYGLL 
1981:	IKAFSMTAAE TARRTREFRS PPQEQINMLL QFKDGTDEED CPLPEEIRQD LLDFHQDLLA 
2041:	HCGIQLDGEE EEPEEETTLG SRLMSLLEKV RLVKKKEEKP EEERSAEESK PRSLQELVSH 
2101:	MVVRWAQEDF VQSPELVRAM FSLLHRQYDG LGELLRALPR AYTISPSSVE DTMSLLECLG 
2161:	QIRSLLIVQM GPQEENLMIQ SIGNIMNNKV FYQHPNLMRA LGMHETVMEV MVNVLGGGES 
2221:	KEIRFPKMVT SCCRFLCYFC RISRQNQRSM FDHLSYLLEN SGIGLGMQGS TPLDVAAASV 
2281:	IDNNELALAL QEQDLEKVVS YLAGCGLQSC PMLVAKGYPD IGWNPCGGER YLDFLRFAVF 
2341:	VNGESVEENA NVVVRLLIRK PECFGPALRG EGGSGLLAAI EEAIRISEDP ARDGPGIRRD 
2401:	RRREHFGEEP PEENRVHLGH AIMSFYAALI DLLGRCAPEM HLIQAGKGEA LRIRAILRSL 
2461:	VPLEDLVGII SLPLQIPTLG KDGALVQPKM SASFVPDHKA SMVLFLDRVY GIENQDFLLH 
2521:	VLDVGFLPDM RAAASLDTAT FSTTEMALAL NRYLCLAVLP LITKCAPLFA GTEHRAIMVD 
2581:	SMLHTVYRLS RGRSLTKAQR DVIEDCLMSL CRYIRPSMLQ HLLRRLVFDV PILNEFAKMP 
2641:	LKLLTNHYER CWKYYCLPTG WANFGVTSEE ELHLTRKLFW GIFDSLAHKK YDPELYRMAM 
2701:	PCLCAIAGAL PPDYVDASYS SKAEKKATVD AEGNFDPRPV ETLNVIIPEK LDSFINKFAE 
2761:	YTHEKWAFDK IQNNWSYGEN IDEELKTHPM LRPYKTFSEK DKEIYRWPIK ESLKAMIAWE 
2821:	WTIEKAREGE EEKTEKKKTR KISQSAQTYD PREGYNPQPP DLSAVTLSRE LQAMAEQLAE 
2881:	NYHNTWGRKK KQELEAKGGG THPLLVPYDT LTAKEKARDR EKAQELLKFL QMNGYAVTRG 
2941:	LKDMELDSSS IEKRFAFGFL QQLLRWMDIS QEFIAHLEAV VSSGRVEKSP HEQEIKFFAK 
3001:	ILLPLINQYF TNHCLYFLST PAKVLGSGGH ASNKEKEMIT SLFCKLAALV RHRVSLFGTD 
3061:	APAVVNCLHI LARSLDARTV MKSGPEIVKA GLRSFFESAS EDIEKMVENL RLGKVSQART 
3121:	QVKGVGQNLT YTTVALLPVL TTLFQHIAQH QFGDDVILDD VQVSCYRTLC SIYSLGTTKN 
3181:	TYVEKLRPAL GECLARLAAA MPVAFLEPQL NEYNACSVYT TKSPRERAIL GLPNSVEEMC 
3241:	PDIPVLERLM ADIGGLAESG ARYTEMPHVI EITLPMLCSY LPRWWERGPE APPSALPAGA 
3301:	PPPCTAVTSD HLNSLLGNIL RIIVNNLGID EASWMKRLAV FAQPIVSRAR PELLQSHFIP 
3361:	TIGRLRKRAG KVVSEEEQLR LEAKAEAQEG ELLVRDEFSV LCRDLYALYP LLIRYVDNNR 
3421:	AQWLTEPNPS AEELFRMVGE IFIYWSKSHN FKREEQNFVV QNEINNMSFL TADNKSKMAK 
3481:	AGDIQSGGSD QERTKKKRRG DRYSVQTSLI VATLKKMLPI GLNMCAPTDQ DLITLAKTRY 
3541:	ALKDTDEEVR EFLHNNLHLQ GKVEGSPSLR WQMALYRGVP GREEDADDPE KIVRRVQEVS 
3601:	AVLYYLDQTE HPYKSKKAVW HKLLSKQRRR AVVACFRMTP LYNLPTHRAC NMFLESYKAA 
3661:	WILTEDHSFE DRMIDDLSKA GEQEEEEEEV EEKKPDPLHQ LVLHFSRTAL TEKSKLDEDY 
3721:	LYMAYADIMA KSCHLEEGGE NGEAEEEVEV SFEEKQMEKQ RLLYQQARLH TRGAAEMVLQ 
3781:	MISACKGETG AMVSSTLKLG ISILNGGNAE VQQKMLDYLK DKKEVGFFQS IQALMQTCSV 
3841:	LDLNAFERQN KAEGLGMVNE DGTVINRQNG EKVMADDEFT QDLFRFLQLL CEGHNNDFQN 
3901:	YLRTQTGNTT TINIIICTVD YLLRLQESIS DFYWYYSGKD VIEEQGKRNF SKAMSVAKQV 
3961:	FNSLTEYIQG PCTGNQQSLA HSRLWDAVVG FLHVFAHMMM KLAQDSSQIE LLKELLDLQK 
4021:	DMVVMLLSLL EGNVVNGMIA RQMVDMLVES SSNVEMILKF FDMFLKLKDI VGSEAFQDYV 
4081:	TDPRGLISKK DFQKAMDSQK QFSGPEIQFL LSCSEADENE MINCEEFANR FQEPARDIGF 
4141:	NVAVLLTNLS EHVPHDPRLH NFLELAESIL EYFRPYLGRI EIMGASRRIE RIYFEISETN 
4201:	RAQWEMPQVK ESKRQFIFDV VNEGGEAEKM ELFVSFCEDT IFEMQIAAQI SEPEGEPETD 
4261:	EDEGAGAAEA GAEGAEEGAA GLEGTAATAA AGATARVVAA AGRALRGLSY RSLRRRVRRL 
4321:	RRLTAREAAT AVAALLWAAV TRAGAAGAGA AAGALGLLWG SLFGGGLVEG AKKVTVTELL 
4381:	AGMPDPTSDE VHGEQPAGPG GDADGEGASE GAGDAAEGAG DEEEAVHEAG PGGADGAVAV 
4441:	TDGGPFRPEG AGGLGDMGDT TPAEPPTPEG SPILKRKLGV DGVEEELPPE PEPEPEPELE 
4501:	PEKADAENGE KEEVPEPTPE PPKKQAPPSP PPKKEEAGGE FWGELEVQRV KFLNYLSRNF 
4561:	YTLRFLALFL AFAINFILLF YKVSDSPPGE DDMEGSAAGD VSGAGSGGSS GWGLGAGEEA 
4621:	EGDEDENMVY YFLEESTGYM EPALRCLSLL HTLVAFLCII GYNCLKVPLV IFKREKELAR 
4681:	KLEFDGLYIT EQPEDDDVKG QWDRLVLNTP SFPSNYWDKF VKRKVLDKHG DIYGRERIAE 
4741:	LLGMDLATLE ITAHNERKPN PPPGLLTWLM SIDVKYQIWK FGVIFTDNSF LYLGWYMVMS 
4801:	LLGHYNNFFF AAHLLDIAMG VKTLRTILSS VTHNGKQLVM TVGLLAVVVY LYTVVAFNFF 
4861:	RKFYNKSEDE DEPDMKCDDM MTCYLFHMYV GVRAGGGIGD EIEDPAGDEY ELYRVVFDIT 
4921:	FFFFVIVILL AIIQGLIIDA FGELRDQQEQ VKEDMETKCF ICGIGSDYFD TTPHGFETHT 
4981:	LEEHNLANYM FFLMYLINKD ETEHTGQESY VWKMYQERCW DFFPAGDCFR KQYEDQLS