SequenceStructure Variability in the Major Histocompatibility Complex Protein

Sequence/Structure Variability in the Major Histocompatibility Complex Protein Class I alpha chain. Errol Archibold, Mark Maloney and Rafael Tosado. Bio. Quest / SCALE-IT Curriculum Workshop, 2009 Introduction to MHC • Presentation of antigenic peptides to T cells. • Rejection of transplanted tissues. • Highly polymorphic genes. • Unlike enzymes, variation tends to be in the “active” site MHC I Alpha Chain Human Variants MHC Structure MHC I Alpha Chain Structure • 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 • CD 8 interact with Ag on MHCI • CD 4 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 I Alpha Chain Species Tree MHC I Alpha Chain from Different Species SIXFRAME Analysis of Human MHC alpha I DNA Sequence >BWB 5471 Translated - Frame 1 KAVYGLGSPSLGDSPTPQFLFSLSQPM*GPSSWILTTRTQFSLPSGVGFPEKPISVVAVAVLKS ARTHRD SDSPQTPRMAVMAPRTLVLLLSGALALTQTWAGSHSMRYFFTSVSRPGRGEPRFIAVGYVDD TQFVRFDS DAASQRMEPRAPWIEQEGPEYWDGETRKVKAHSQTHRVDLGTLRGYYNQSEAGSHTVQRM YGCDVGSDWR FLRGYHQYAYDGKDYIALKEDLRSWTAADMAAQTTKHKWEAAHVAEQLRAYLEGTCVEWLRR YLENGKET LQRTDAPKTHMTHHAVSDHEATLRCWALSFYPAEITLTWQRDGEDQTQDTELVETRPAGDGT FQKWAAVV VPSGQEQRYTCHVQHEGLPKPLTLRWEPSSQPTIPIVGIIAGLVLFGAVITGAVVAAVMWRRKS SDRKGG SYSQAASSDSAQGSDVSLTACKV* >BWB 5471 Translated - Frame 2 RRCMDWGVPALGIPQLRSFFSPSPNLCRVLLPGYSRRGPSSHSHRVSGFQRSQSVSSRSRF* SPHAPTGT QILPRRRGWPSWRPEPSSCYSRGLWP*PRPGRALTP*GISSHPCPGPAAGSPASSQWATWTT RSSCGSTA TPRARGWSRGRRG*SRRVRSIGTGRHGK*RPTHRLTEWTWGPCAATTTRARPVLTPSRGCM AATWGRTGA SSAGTTSTPTTARITSP*KRTCALGPRRTWQLRPPSTSGRRPMWRSS*EPTWRARAWSGSAD TWRTGRRR CSARTPPKRI*LTTLSLTMKPP*GAGP*ASTLRRSH*PGSGMGRTRPRTRSSWRPGLQGMEPS RSGRLWW CLLDRSRDTPAMCSMRVCPSPSP*DGSRLPSPPSPSWASLLAWFSLEL*SLELWSLL*CGGGR AQIEKEG ATLRLQAVTVPRALMCLSQLVKC >BWB 5471 Translated - Frame 3 GGVWIGESQPWGFPNSAVSFLPLPTYVGSFFLDTHDADPVLTPIGCRVSREANQCRRGRGSK VRTHPPGL RFSPDAEDGRHGAPNPRPATLGGSGPDPDLGGLSLHEVFLHIRVPARPRGAPLHRSGLRGRH AVRAVRQR RREPEDGAAGAVDRAGGSGVLGRGDTESEGPLTDSPSGPGDPARLLQPERGRFSHRPEDVW LRRGVGLAL PPRVPPVRLRRQGLHRPERGPALLDRGGHGSSDHQAQVGGGPCGGAVESLPGGHVRGVAP QIPGEREGDA AAHGRPQNAYDSPRCL*P*SHPEVLGPELLPCGDHTDLAAGWGGPDPGHGARGDQACRGWN LPEVGGCGG AFWTGAEIHLPCAA*GFAQAPHPEMGAVFPAHHPHRGHHCWPGSLWSCDHWSCGRCCDVE EEELR*KRRE LLSGCKQ*QCPGL*CVSHSL*SV >BWB 5471 Translated - Frame 4 SHFTSCERHIRALGTVTACSLRVAPSFSI*ALPPPHHSSDHSSKENQASNDAHDGDGGL GRRLPS QGEGLGQTLMLHMAGVSLLLSRRHHHSRPLLEGSIPCRPGLHELRVLGLVLPIPLPGQCDLRR VEAQGPA PQGGFMVRDSVVSHMRFGGVRALQRLLPVLQVSAEPLHARALQVGSQLLRHMGRLPLVLGGL SCHVRRGP RAQVLFQGDVILAVVGVLVVPAEEAPVRPHVAAIHPLDGVRTGLALVVVAAQGPQVHSVSL*VG LHFPCL PVPILRTLLLYPRRPRLHPLARGVAVEPHELRVVHVAHCDEAGLPAAGPGHGCEEIPHGVRAR PGLGQGQ SPRE*QDEGSGRHDGHPRRLGRI*VPVGACGL*NRDRDDTDWLLWKPDTRWE*ELGPRREYP GRRTLHRL GEGEKKLRSWGIPKAGTPQSIHRL >BWB 5471 Translated - Frame 5 HTLQAVRDTSEPWALSLLAA*E*LPPFLSELFLLHITAATTAPVITAPKRTRPAMMPTMGMVGWE DGSHL RVRGLGKPSCCTWQVYLCSCPEGTTTAAHFWKVPSPAGLVSTSSVSWVWSSPSRCQVSVIS AG*KLRAQH http: //consurf. tau. ac. il/fgij/fg. htm? mol=/results/1245796831/2 guo_consurf 1245 796831_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-A 2 alpha chain using SIXFRAME and BLASTp analyses revealed alleles corresponding to both frame 1 and frame 3 • Con. Surf 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).