Major Histocompatibility Complex: Interaction with Peptides

Jun Liu, CAS Key Laboratory of Pathogenic Microbiology and Immunology, Beijing, China
George F Gao, CAS Key Laboratory of Pathogenic Microbiology and Immunology, Beijing, China

Published online: August 2011

DOI: 10.1002/9780470015902.a0000922.pub2

T-cell-specific immunity functions in a major histocompatibility complex (MHC)-dependent manner. MHC molecules present antigenic peptides on the surface of cells to be recognised by specific T-cells. MHC class I and class II molecules possess highly similar structural features used to load peptides. Specifically, both contain peptide-binding grooves formed by two -helices and eight -strands. In the peptide-binding groove, specific amino acids compose pockets that accommodate the corresponding side chains of the anchor residues of the presented peptides. Peptide-binding preferences exist among different alleles of both of MHC I and MHC II molecules, which are mainly dependent on amino acid polymorphisms in the peptide-binding grooves of MHC chains. Aside from the common binding of peptides to MHC molecules, the currently determined structures of post-translationally modified peptides to MHC molecules demonstrate that the modified groups have important roles in the peptide–MHC interaction. The illumination of the binding features of peptides to MHC molecules has aided our understanding of T-cell-specific immunity and the development of T-cell epitope-related vaccines.

Key Concepts:

  • MHC I and class II molecules fold into a highly similar conformations featuring a peptide-binding groove to present T-cell epitopes.
  • Peptide-binding grooves of MHC I molecules are composed of two -helices and eight -strands formed by one heavy chain, while MHC II uses two domains from different chains to construct the peptide-binding groove.
  • Peptides bind to MHC molecules through primary and secondary anchor residues protruding into the pockets in the peptide-binding grooves.
  • Peptide preferences are dependent on the amino acids polymorphisms comprising the anchor pockets, which are related to the various alleles of MHC.
  • The conformations of peptides presented by MHC I molecules are length-dependant.
  • The modified groups of post-translationally modified peptides have important roles in the peptide–MHC interaction.
  • MHC is called HLA, human leucocyte antigen, in human; H-2 in mice.

Keywords: MHC; peptide; class I; Class II; binding; interaction; anchor residue; groove; pocket; post-translational modification

Figure 1. Overall view of MHC I and class II molecules and their peptide-binding grooves. (a) Representation of an MHC I structure, human HLA-A*0201, in complex with a nonameric peptide from SARS-CoV (PDB code 3I6G). The heavy chain in blue is composed of the 1, 2 and 3 domains. The light chain, 2-microglobulin (2m), is depicted in pink, and the peptide that binds in the antigen-presenting cleft is coloured yellow. (b) Peptide-binding groove of MHC I molecule. (c) Representation of an MHC II structure, human HLA-DR1 complexed with an influenza virus peptide (PDB code 1DLH). The -chain (purple) and -chain (deep blue) fold with the peptide (green) to form the complex. The amino-terminal 1 and 1 domains from each chain form the peptide-binding cleft. (d) Peptide-binding groove of MHC II.
Figure 2. MHC-binding pockets. In MHC I molecules (A, PDB code 3I6G), the peptide is bound in an elongated conformation with both ends tightly associated at either end of the groove. The peptide is also bound in an elongated form in the case of MHC II molecules (B, PBD code 1DLH), but the termini extend out at both ends of the groove. The electrostatic potential of the MHC molecule surfaces is shown, with blue areas indicating a positive potential and red a negative potential. Six pockets are defined in the peptide-binding groove of MHC I molecules (C). The pockets are coloured differently.
Figure 3. Specificity of the peptide binding revealed by the interaction of anchor residues of peptides and pockets in MHC grooves. Longitudinal planes of peptide-binding grooves of MHC I (A, PDB code 3I6G) and MHC II (B, PBD code 1DLH) molecules (observed from the 2 helix to the 1 helix) represent the major peptide-binding pockets of these molecules. The anchor residues point their side chains into the pockets.
Figure 4. Diverse peptide presentation manners of MHC I molecules from different species. (a) Human HLA-A*0201 molecule presenting a SARS-CoV-derived nonamer peptide (deep blue, PDB code 3I6G). (b) Mouse H-2Kb molecule bound to a peptide derived from Sendai virus (cyan, PDB code 2VAB). (c) SIV-derived peptide in the binding groove of rhesus macaque MHC I, Mamu-A*01 (Purple, PDB code 1ZVS). (d) Binding groove of the chicken BF2*2101 molecule containing a self-derived peptide (yellow, PDB code 3BEV). (e) Alignment of peptides from different species reveals the primary anchor residues and peptide conformations.
Figure 5. Peptide conformations in the binding groove. Octamer (green, PDB code 1FO0), nonamer (cyan, PDB code 3I6G) and decamer (purple, PDB code 3I6K) peptides display different conformations when bound to HLA-A*0201. Longer peptides prefer the bulged conformation compared to short peptides.
Figure 6. Presentation of post-translationally modified peptides. (a) Phosphorylated MHC I-restricted peptide presented by HLA-A*0201 (PDB code 3FQX). (b) Phosphorylated MHC II-restricted peptide presented by HLA-DR1 (PDB code 3L6F).
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 References
    Bjorkman PJ, Saper MA, Samraoui B et al. (1987) Structure of the human class I histocompatibility antigen, HLA-A2. Nature 329: 506–512.
    Borbulevych OY, Baxter TK, Yu Z, Restifo NP and Baker BM (2005) Increased immunogenicity of an anchor-modified tumor-associated antigen is due to the enhanced stability of the peptide/MHC complex: implications for vaccine design. Journal of Immunology 174: 4812–4820.
    Brown JH, Jardetzky TS, Gorga JC et al. (1993) Three-dimensional structure of the human class II histocompatibility antigen HLA-DR1. Nature 364: 33–39.
    Chen Y, Shi Y, Cheng H, An YQ and Gao GF (2009) Structural immunology and crystallography help immunologists see the immune system in action: how T and NK cells touch their ligands. IUBMB Life 61: 579–590.
    Chu F, Lou Z, Chen YW et al. (2007) First glimpse of the peptide presentation by rhesus macaque MHC class I: crystal structures of Mamu-A*01 complexed with two immunogenic SIV epitopes and insights into CTL escape. Journal of Immunology 178: 944–952.
    Cole DK, Rizkallah PJ, Gao F et al. (2006) Crystal structure of HLA-A*2402 complexed with a telomerase peptide. European Journal of Immunology 36: 170–179.
    Collins EJ, Garboczi DN and Wiley DC (1994) Three-dimensional structure of a peptide extending from one end of a class I MHC binding site. Nature 371: 626–629.
    Doyle HA and Mamula MJ (2001) Post-translational protein modifications in antigen recognition and autoimmunity. Trends in Immunology 22: 443–449.
    Engelhard VH (1994) Structure of peptides associated with class I and class II MHC molecules. Annual Review of Immunology 12: 181–207.
    Engelhard VH, Altrich-Vanlith M, Ostankovitch M and Zarling AL (2006) Post-translational modifications of naturally processed MHC-binding epitopes. Current Opinion in Immunology 18: 92–97.
    Gao GF, Rao ZH and Bell JI (2002) Molecular coordination of alpha beta T-cell receptors and coreceptors CD8 and CD4 in their recognition of peptide–MHC ligands. Trends in Immunology 23: 408–413.
    Gao GF, Tormo J, Gerth UC et al. (1997) Crystal structure of the complex between human CD8alpha(alpha) and HLA-A2. Nature 387: 630–634.
    Garcia KC, Degano M, Stanfield RL et al. (1996) An alpha beta T cell receptor structure at 2.5 angstrom and its orientation in the TCR–MHC complex. Science 274: 209–219.
    Jardetzky TS, Brown JH, Gorga JC et al. (1996) Crystallographic analysis of endogenous peptides associated with HLA-DR1 suggests a common, polyproline II-like conformation for bound peptides. Proceedings of the National Academy of Sciences of the USA 93: 734–738.
    Kersh GJ and Allen PM (1996) Structural basis for T cell recognition of altered peptide ligands: a single T cell receptor can productively recognize a large continuum of related ligands. Journal of Experimental Medicine 184: 1259–1268.
    Kobayashi H (1983) Modification of tumor cell antigen. Progress in Clinical and Biological Research 132E: 305–314.
    Koch M, Camp S, Collen T et al. (2007) Structures of an MHC class I molecule from B21 chickens illustrate promiscuous peptide binding. Immunity 27: 885–899.
    Li X, Liu J, Qi J et al. (2011) Two distinct conformations of a rinderpest virus epitope presented by bovine major histocompatibility complex class I N*01801: a host strategy to present featured peptides. Journal of Virology 85: 6038–6048.
    Li Y, Depontieu FR, Sidney J et al. (2010) Structural basis for the presentation of tumor-associated MHC class II-restricted phosphopeptides to CD4+ T cells. Journal of Molecular Biology 399: 596–603.
    Liu J, Dai L, Qi J et al. (2011) Diverse peptide presentation of rhesus macaque major histocompatibility complex class I Mamu-A*02 revealed by two peptide complex structures and insights into immune escape of simian immunodeficiency virus. Journal of Virology 85: 7372–7383.
    Liu J, Sun Y, Qi J et al. (2010a) The membrane protein of severe acute respiratory syndrome coronavirus acts as a dominant immunogen revealed by a clustering region of novel functionally and structurally defined cytotoxic T-lymphocyte epitopes. Journal of Infectious Diseases 202: 1171–1180.
    Liu J, Wu P, Gao F et al. (2010b) Novel immunodominant peptide presentation strategy: a featured HLA-A*2402-restricted cytotoxic T-lymphocyte epitope stabilized by intrachain hydrogen bonds from severe acute respiratory syndrome coronavirus nucleocapsid protein. Journal of Virology 84: 11849–11857.
    Liu J, Zhang S, Tan S et al. (2011) Revival of the identification of cytotoxic T-lymphocyte epitopes for immunological diagnosis, therapy and vaccine development. Experimental Biology and Medicine 236: 253–567.
    Lund O, Nielsen M, Kesmir C et al. (2004) Definition of supertypes for HLA molecules using clustering of specificity matrices. Immunogenetics 55: 797–810.
    Madden DR (1995) The three-dimensional structure of peptide–MHC complexes. Annual Review of Immunology 13: 587–622.
    Madden DR, Gorga JC, Strominger JL and Wiley DC (1992) The three-dimensional structure of HLA-B27 at 2.1 A resolution suggests a general mechanism for tight peptide binding to MHC. Cell 70: 1035–1048.
    Matsui M, Hioe CE and Frelinger JA (1993) Roles of the six peptide-binding pockets of the HLA-A2 molecule in allorecognition by human cytotoxic T-cell clones. Proceedings of the National Academy of Sciences of the USA 90: 674–678.
    Mohammed F, Cobbold M, Zarling AL et al. (2008) Phosphorylation-dependent interaction between antigenic peptides and MHC class I: a molecular basis for the presentation of transformed self. Nature Immunology 9: 1236–1243.
    Petersen J, Wurzbacher SJ, Williamson NA et al. (2009) Phosphorylated self-peptides alter human leukocyte antigen class I-restricted antigen presentation and generate tumor-specific epitopes. Proceedings of the National Academy of Sciences of the USA 106: 2776–2781.
    Reche PA and Reinherz EL (2004) Definition of MHC supertypes through clustering of MHC peptide binding repertoires. Artificial Immune Systems, Proceedings 3239: 189–196.
    book Roitt IM and Delves PJ (2001) Roitt's Essential Immunology, 10th edn. Oxford: Blackwell Publishing Ltd.
    Rosenberg SA, Yang JC, Schwartzentruber DJ et al. (1998) Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma. Natural Medicines 4: 321–327.
    Rosenberg SA, Yang JC, Schwartzentruber DJ et al. (2003) Recombinant fowlpox viruses encoding the anchor-modified gp100 melanoma antigen can generate antitumor immune responses in patients with metastatic melanoma. Clinical Cancer Research 9: 2973–2980.
    Rotzschke O, Falk K, Deres K et al. (1990) Isolation and analysis of naturally processed viral peptides as recognized by cytotoxic T cells. Nature 348: 252–254.
    Saper MA, Bjorkman PJ and Wiley DC (1991) Refined structure of the human histocompatibility antigen HLA-A2 at 2.6 A resolution. Journal of Molecular Biology 219: 277–319.
    Sette A and Sidney J (1999) Nine major HLA class I supertypes account for the vast preponderance of HLA-A and -B polymorphism. Immunogenetics 50: 201–212.
    Sidney J, Peters B, Frahm N, Brander C and Sette A (2008) HLA class I supertypes: a revised and updated classification. BMC Immunology 9: 1.
    Silver ML, Guo HC, Strominger JL and Wiley DC (1992) Atomic structure of a human MHC molecule presenting an influenza virus peptide. Nature 360: 367–369.
    Slansky JE, Rattis FM, Boyd LF et al. (2000) Enhanced antigen-specific antitumor immunity with altered peptide ligands that stabilize the MHC-peptide–TCR complex. Immunity 13: 529–538.
    Sloan-Lancaster J and Allen PM (1996) Altered peptide ligand-induced partial T cell activation: molecular mechanisms and role in T cell biology. Annual Review of Immunology 14: 1–27.
    Stern LJ, Brown JH, Jardetzky TS et al. (1994) Crystal structure of the human class II MHC protein HLA-DR1 complexed with an influenza virus peptide. Nature 368: 215–221.
    Sun Y, Liu J, Yang M et al. (2010) Identification and structural definition of H5-specific CTL epitopes restricted by HLA-A*0201 derived from the H5N1 subtype of influenza A viruses. Journal of General Virology 91: 919–930.
    Townsend AR, Rothbard J, Gotch FM et al. (1986) The epitopes of influenza nucleoprotein recognized by cytotoxic T lymphocytes can be defined with short synthetic peptides. Cell 44: 959–968.
    Turner SJ, Kedzierska K, Komodromou H et al. (2005) Lack of prominent peptide–major histocompatibility complex features limits repertoire diversity in virus-specific CD8+ T cell populations. Nature Immunology 6: 382–389.
    Wang CR, Castano AR, Peterson PA et al. (1995) Nonclassical binding of formylated peptide in crystal structure of the MHC class Ib molecule H2-M3. Cell 82: 655–664.
    Willcox BE, Gao GF, Wyer JR et al. (1999) TCR binding to peptide–MHC stabilizes a flexible recognition interface. Immunity 10: 357–365.
    Windhagen A, Scholz C, Hollsberg P et al. (1995) Modulation of cytokine patterns of human autoreactive T cell clones by a single amino acid substitution of their peptide ligand. Immunity 2: 373–380.
    Zhang W, Young AC, Imarai M, Nathenson SG and Sacchettini JC (1992) Crystal structure of the major histocompatibility complex class I H-2Kb molecule containing a single viral peptide: implications for peptide binding and T-cell receptor recognition. Proceedings of the National Academy of Sciences of the USA 89: 8403–8407.
    Zhou M, Xu Y, Lou Z et al. (2004) Complex assembly, crystallization and preliminary X-ray crystallographic studies of MHC H-2Kd complexed with an HBV-core nonapeptide. Acta Crystallographica Section D Biological Crystallography 60: 1473–1475.
    Zinkernagel RM and Doherty PC (1974) Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system. Nature 248: 701–702.
    Zong LL, Chen Y, Peng H et al. (2009) Rhesus macaque: a tight homodimeric CD8 alpha alpha. Proteins 75: 241–244.
 Further Reading
    Neefjes JJ (1996) Antigen presentation by MHC I and II molecules. Immunobiology 195(4–5): 456–460.
 Web Links
    ePath Algorithm that Allows a Prediction of Candidates for MHC I- and II-Restricted Peptides Based on the Amino Acid Sequence of the Protein of Interest. http://www-bimas.cit.nih.gov/molbio/hla_bind/
    ePath Amino acid Sequence Alignments of MHC I and II Proteins. http://histo.cryst.bbk.ac.uk/
    ePath Amino Acid Sequence Alignments of MHC I and II Proteins. http://immuno.bme.nwu.edu/
    ePath Database of MHC I and Class II Peptide Motifs. http://wehih.wehi.edu.au/mhcpep/
    ePath Database of MHC I and Class II Peptide Motifs. http://www.ebi.ac.uk/imgt/hla/
    ePath Database of T-Cell Epitopes and of MHC Alleles of Human and Other Species. http://www.immuneepitope.com/

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Major Histocompatibility Complex | Protein Structure
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Article Title: Major Histocompatibility Complex: Interaction with Peptides
 
How to Cite close
Liu, Jun, and Gao, George F(Aug 2011) Major Histocompatibility Complex: Interaction with Peptides. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000922.pub2]