Sequence variability analysis of human class I and class II MHC molecules: functional and structural correlates of amino acid polymorphisms

J Mol Biol. 2003 Aug 15;331(3):623-41. doi: 10.1016/s0022-2836(03)00750-2.

Abstract

Major histocompatibility complex class I (MHCI) and class II (MHCII) molecules display peptides on antigen-presenting cell surfaces for subsequent T-cell recognition. Within the human population, allelic variation among the classical MHCI and II gene products is the basis for differential peptide binding, thymic repertoire bias and allograft rejection. While available 3D structural analysis suggests that polymorphisms are found primarily within the peptide-binding site, a broader informatic approach pinpointing functional polymorphisms relevant for immune recognition is currently lacking. To this end, we have now analyzed known human class I (774) and class II (485) alleles at each amino acid position using a variability metric (V). Polymorphisms (V>1) have been identified in residues that contact the peptide and/or T-cell receptor (TCR). Using sequence logos to investigate TCR contact sites on HLA molecules, we have identified conserved MHCI residues distinct from those of conserved MHCII residues. In addition, specific class II (HLA-DP, -DQ, -DR) and class I (HLA-A, -B, -C) contacts for TCR binding are revealed. We discuss these findings in the context of TCR restriction and alloreactivity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alleles
  • Amino Acid Sequence
  • Antigen Presentation
  • Binding Sites
  • Consensus Sequence
  • Histocompatibility Antigens Class I / chemistry*
  • Histocompatibility Antigens Class I / genetics
  • Histocompatibility Antigens Class I / immunology
  • Histocompatibility Antigens Class I / metabolism*
  • Histocompatibility Antigens Class II / chemistry*
  • Histocompatibility Antigens Class II / genetics
  • Histocompatibility Antigens Class II / immunology
  • Histocompatibility Antigens Class II / metabolism*
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Peptides / immunology
  • Peptides / metabolism
  • Polymorphism, Genetic / genetics*
  • Protein Binding
  • Protein Structure, Tertiary
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Antigen, T-Cell / metabolism

Substances

  • Histocompatibility Antigens Class I
  • Histocompatibility Antigens Class II
  • Peptides
  • Receptors, Antigen, T-Cell