Major Histocompatibility Complex: Interaction with Peptides


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 α‐helices and eight β‐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 α‐helices and eight β‐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 α1, α2 and α3 domains. The light chain, β2‐microglobulin (β2m), 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 α‐chain (purple) and β‐chain (deep blue) fold with the peptide (green) to form the complex. The amino‐terminal α1 and β1 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 α2 helix to the α1 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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Further Reading

Neefjes JJ (1996) Antigen presentation by MHC I and II molecules. Immunobiology 195(4–5): 456–460.

Web Links

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‐

Amino acid Sequence Alignments of MHC I and II Proteins.

Amino Acid Sequence Alignments of MHC I and II Proteins.

Database of MHC I and Class II Peptide Motifs.

Database of MHC I and Class II Peptide Motifs.

Database of T‐Cell Epitopes and of MHC Alleles of Human and Other Species.

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Liu, Jun, and Gao, George F(Aug 2011) Major Histocompatibility Complex: Interaction with Peptides. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0000922.pub2]