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Introduction to MHC

Sequence/Structure Variability in the Major Histocompatibility Complex Protein Class I alpha chain. Errol Archibold, Mark Maloney and Rafael Tosado. BioQuest / SCALE-IT Curriculum Workshop, 2009. Introduction to MHC. MHC I Alpha Chain Human Variants.

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Introduction to MHC

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  1. Sequence/Structure Variability in the Major Histocompatibility Complex Protein Class I alpha chain. Errol Archibold, Mark Maloney and Rafael Tosado.BioQuest / SCALE-IT Curriculum Workshop, 2009 Introduction to MHC MHC I Alpha Chain Human Variants • Presentation of antigenic peptides to T cells. • Rejection of transplanted tissues. • Highly polymorphic genes. • Unlike enzymes, variation tends to be in the “active” site • Class I and II molecules • Class I in all nucleated cells. • Class II in Antigen (Ag) Presenting Cells (APC). • T-cell receptor (TCR) –Ag complex • CD8 interact with Ag on MHCI • CD4 interact with Ag on MHCII • Crystal Structure revealed differences and similarities • Antigen-binding groove • Opposing alpha helixes at the opening • Beta chains for the floor of the groove • MHC I • Alpha (heavy) chain + Beta micro-globulin • Ag groove within the alpha chain • MHC II • Equivalent alpha and beta chains • Both chains combine to form the Ag groove MHC Structure MHC I Alpha Chain Structure MHC I Alpha Chain Species Tree MHC I Alpha Chain from Different Species SIXFRAME Analysis of Human MHC alpha I DNA Sequence >BWB5471 Translated - Frame 1 KAVYGLGSPSLGDSPTPQFLFSLSQPM*GPSSWILTTRTQFSLPSGVGFPEKPISVVAVAVLKSARTHRD SDSPQTPRMAVMAPRTLVLLLSGALALTQTWAGSHSMRYFFTSVSRPGRGEPRFIAVGYVDDTQFVRFDS DAASQRMEPRAPWIEQEGPEYWDGETRKVKAHSQTHRVDLGTLRGYYNQSEAGSHTVQRMYGCDVGSDWR FLRGYHQYAYDGKDYIALKEDLRSWTAADMAAQTTKHKWEAAHVAEQLRAYLEGTCVEWLRRYLENGKET LQRTDAPKTHMTHHAVSDHEATLRCWALSFYPAEITLTWQRDGEDQTQDTELVETRPAGDGTFQKWAAVV VPSGQEQRYTCHVQHEGLPKPLTLRWEPSSQPTIPIVGIIAGLVLFGAVITGAVVAAVMWRRKSSDRKGG SYSQAASSDSAQGSDVSLTACKV* >BWB5471 Translated - Frame 2 RRCMDWGVPALGIPQLRSFFSPSPNLCRVLLPGYSRRGPSSHSHRVSGFQRSQSVSSRSRF*SPHAPTGT QILPRRRGWPSWRPEPSSCYSRGLWP*PRPGRALTP*GISSHPCPGPAAGSPASSQWATWTTRSSCGSTA TPRARGWSRGRRG*SRRVRSIGTGRHGK*RPTHRLTEWTWGPCAATTTRARPVLTPSRGCMAATWGRTGA SSAGTTSTPTTARITSP*KRTCALGPRRTWQLRPPSTSGRRPMWRSS*EPTWRARAWSGSADTWRTGRRR CSARTPPKRI*LTTLSLTMKPP*GAGP*ASTLRRSH*PGSGMGRTRPRTRSSWRPGLQGMEPSRSGRLWW CLLDRSRDTPAMCSMRVCPSPSP*DGSRLPSPPSPSWASLLAWFSLEL*SLELWSLL*CGGGRAQIEKEG ATLRLQAVTVPRALMCLSQLVKC >BWB5471 Translated - Frame 3 GGVWIGESQPWGFPNSAVSFLPLPTYVGSFFLDTHDADPVLTPIGCRVSREANQCRRGRGSKVRTHPPGL RFSPDAEDGRHGAPNPRPATLGGSGPDPDLGGLSLHEVFLHIRVPARPRGAPLHRSGLRGRHAVRAVRQR RREPEDGAAGAVDRAGGSGVLGRGDTESEGPLTDSPSGPGDPARLLQPERGRFSHRPEDVWLRRGVGLAL PPRVPPVRLRRQGLHRPERGPALLDRGGHGSSDHQAQVGGGPCGGAVESLPGGHVRGVAPQIPGEREGDA AAHGRPQNAYDSPRCL*P*SHPEVLGPELLPCGDHTDLAAGWGGPDPGHGARGDQACRGWNLPEVGGCGG AFWTGAEIHLPCAA*GFAQAPHPEMGAVFPAHHPHRGHHCWPGSLWSCDHWSCGRCCDVEEEELR*KRRE LLSGCKQ*QCPGL*CVSHSL*SV >BWB5471 Translated - Frame 4 SHFTSCERHIRALGTVTACSLRVAPSFSI*ALPPPHHSSDHSSSDHSSKENQASNDAHDGDGGLGRRLPS QGEGLGQTLMLHMAGVSLLLSRRHHHSRPLLEGSIPCRPGLHELRVLGLVLPIPLPGQCDLRRVEAQGPA PQGGFMVRDSVVSHMRFGGVRALQRLLPVLQVSAEPLHARALQVGSQLLRHMGRLPLVLGGLSCHVRRGP RAQVLFQGDVILAVVGVLVVPAEEAPVRPHVAAIHPLDGVRTGLALVVVAAQGPQVHSVSL*VGLHFPCL PVPILRTLLLYPRRPRLHPLARGVAVEPHELRVVHVAHCDEAGLPAAGPGHGCEEIPHGVRARPGLGQGQ SPRE*QDEGSGRHDGHPRRLGRI*VPVGACGL*NRDRDDTDWLLWKPDTRWE*ELGPRREYPGRRTLHRL GEGEKKLRSWGIPKAGTPQSIHRL >BWB5471 Translated - Frame 5 HTLQAVRDTSEPWALSLLAA*E*LPPFLSELFLLHITAATTAPVITAPKRTRPAMMPTMGMVGWEDGSHL RVRGLGKPSCCTWQVYLCSCPEGTTTAAHFWKVPSPAGLVSTSSVSWVWSSPSRCQVSVISAG*KLRAQH LRVASWSETAW*VICVLGASVRCSVSFPFSRYLRSHSTHVPSR*ALNCSATWAASHLCLVV*AAMSAAVQ ERRSSFRAM*SLPS*AYWWYPRRKRQSDPTSQPYILWTV*EPASLWL**PRRVPRSTR*VCEWAFTFRVS PSQYSGPSCSIHGARGSILWLAASLSNRTNCVSST*PTAMKRGSPRPGRDTDVKKYLME*EPAQVWVRAR APESSRTRVRGAMTAILGVWGESESRWVRADFRTATATTLIGFSGNPTPDGSENWVRVVSIQEEGPYIGW EREKRNCGVGESPRLGLPNPYTA >BWB5471 Translated - Frame 6 TLYKL*ETHQSPGHCHCLQPESSSLLFYLSSSSSTSQQRPQLQ*SQLQREPGQQ*CPRWGWWAGKTAPIS G*GAWANPHAAHGRCISAPVQKAPPQPPTSGRFHPLQAWSPRAPCPGSGPPHPAARSV*SPQGRSSGPST SGWLHGQRQRGESYAFWGRPCAAASPSRSPGICGATPRTCPPGRLSTAPPHGPPPTCAWWSELPCPPRSK SAGPLSGRCNPCRRRRTGGTRGGSASPTPRRSHTSSGRCENRPRSGCSSRAGSPGPLGESVSGPSLSVSP RPNTPDPPALSTAPAAPSSGSRRRCRTARTACRPRSPLR*SGAPRGRAGTRM*RNTSWSESPPRSGSGPE PPRVAGRGFGAP*RPSSASGENLSPGGCVRTLEPRPRRH*LASLETRHPMGVRTGSAS*VSRKKDPT*VG RGRKETAELGNPQGWDSPIHTPP http://consurf.tau.ac.il/fgij/fg.htm?mol=/results/1245796831/2guo_consurf1245796831_pipe.pdb Conclusions • Class I alleles are more variable than WE had imagined! • Despite the variation inherent in MHC genes, interspecies variation of MHC class I alleles was overall in line with other dendrograms based on hemoglobin or cytochrome c • Investigation of the human HLA-A2 alpha chain using SIXFRAME and BLASTp analyses revealed alleles corresponding to both frame 1 and frame 3 • ConSurf analysis indicated that the majority of variation at the peptide binding groove was in only one of the two alpha helices Future Directions • In the future, we would determine where the interspecies variation is highest one the MHC class I molecules. • We would also like to further define the relationship between HLA-A alleles and alleles of the other MHC class I loci (HLA-B and HLA-C).

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