Although divergent in residues of the peptide binding site, conserved chimpanzee Patr-AL and polymorphic human HLA-A*02 have overlapping peptide-binding repertoires

J Immunol. 2011 Feb 1;186(3):1575-88. doi: 10.4049/jimmunol.1002990. Epub 2011 Jan 5.

Abstract

Patr-AL is an expressed, non-polymorphic MHC class I gene carried by ∼50% of chimpanzee MHC haplotypes. Comparing Patr-AL(+) and Patr-AL(-) haplotypes showed Patr-AL defines a unique 125-kb genomic block flanked by blocks containing classical Patr-A and pseudogene Patr-H. Orthologous to Patr-AL are polymorphic orangutan Popy-A and the 5' part of human pseudogene HLA-Y, carried by ∼10% of HLA haplotypes. Thus, the AL gene alternatively evolved in these closely related species to become classical, nonclassical, and nonfunctional. Although differing by 30 aa substitutions in the peptide-binding α(1) and α(2) domains, Patr-AL and HLA-A*0201 bind overlapping repertoires of peptides; the overlap being comparable with that between the A*0201 and A*0207 subtypes differing by one substitution. Patr-AL thus has the A02 supertypic peptide-binding specificity. Patr-AL and HLA-A*0201 have similar three-dimensional structures, binding peptides in similar conformation. Although comparable in size and shape, the B and F specificity pockets of Patr-AL and HLA-A*0201 differ in both their constituent residues and contacts with peptide anchors. Uniquely shared by Patr-AL, HLA-A*0201, and other members of the A02 supertype are the absence of serine at position 9 in the B pocket and the presence of tyrosine at position 116 in the F pocket. Distinguishing Patr-AL from HLA-A*02 is an unusually electropositive upper face on the α(2) helix. Stimulating PBMCs from Patr-AL(-) chimpanzees with B cells expressing Patr-AL produced potent alloreactive CD8 T cells with specificity for Patr-AL and no cross-reactivity toward other MHC class I molecules, including HLA-A*02. In contrast, PBMCs from Patr-AL(+) chimpanzees are tolerant of Patr-AL.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites / genetics
  • Binding Sites / immunology
  • Cloning, Molecular
  • Conserved Sequence / genetics
  • Conserved Sequence / immunology*
  • Genes, Overlapping / immunology*
  • HLA-A Antigens / chemistry
  • HLA-A Antigens / genetics
  • HLA-A Antigens / metabolism*
  • HLA-A2 Antigen
  • Histocompatibility Antigens Class I / chemistry
  • Histocompatibility Antigens Class I / genetics
  • Histocompatibility Antigens Class I / metabolism*
  • Humans
  • Molecular Sequence Data
  • Pan troglodytes
  • Peptides / chemistry
  • Peptides / genetics
  • Peptides / metabolism*
  • Polymorphism, Genetic*
  • Protein Binding / genetics
  • Protein Binding / immunology
  • Receptors, Antigen, T-Cell / metabolism

Substances

  • HLA-A Antigens
  • HLA-A*02 antigen
  • HLA-A2 Antigen
  • Histocompatibility Antigens Class I
  • Peptides
  • Receptors, Antigen, T-Cell

Associated data

  • GENBANK/HM629928
  • GENBANK/HM629929
  • GENBANK/HM629930
  • GENBANK/HM629931
  • GENBANK/HM629932