Cutting edge: HLA-DM-mediated peptide exchange functions normally on MHC class II-peptide complexes that have been weakened by elimination of a conserved hydrogen bond

J Immunol. 2010 Feb 1;184(3):1153-8. doi: 10.4049/jimmunol.0902878. Epub 2009 Dec 28.

Abstract

The mechanism by which HLA-DM (DM) promotes exchange of peptides bound to HLA-DR (DR) is still unclear. We have shown that peptide interaction with DR1 can be considered a folding process as evidenced by cooperativity. However, in DM-mediated ligand exchange, prebound peptide release is noncooperative, which could be a function of the breaking of a critical interaction. The hydrogen bond (H-bond) between beta-chain His(81) and the peptide backbone at the -1 position is a candidate for such a target. In this study, we analyze the exchange of peptides bound to a DR1 mutant in which formation of this H-bond is impaired. We observe that DM still functions normally. However, as expected of a cooperative model, this H-bond contributes to the overall energetics of the complex and its disruption impacts the ability of the exchange ligand to fold with the binding groove into a stable complex.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Substitution / genetics
  • Amino Acid Substitution / immunology
  • Binding, Competitive / genetics
  • Binding, Competitive / immunology
  • Cell Line
  • Conserved Sequence* / genetics
  • HLA-D Antigens / metabolism
  • HLA-D Antigens / physiology*
  • HLA-DR1 Antigen / genetics
  • HLA-DR1 Antigen / metabolism
  • Hemagglutinin Glycoproteins, Influenza Virus / genetics
  • Hemagglutinin Glycoproteins, Influenza Virus / metabolism
  • Hemagglutinin Glycoproteins, Influenza Virus / physiology
  • Humans
  • Hydrogen Bonding
  • Influenza A virus / immunology
  • Ligands
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism
  • Multiprotein Complexes / physiology*
  • Mutagenesis, Site-Directed
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism*
  • Peptide Fragments / physiology
  • Protein Binding / genetics
  • Protein Binding / immunology
  • Protein Conformation
  • Protein Folding
  • Protein Stability

Substances

  • HLA-D Antigens
  • HLA-DM antigens
  • HLA-DR1 Antigen
  • Hemagglutinin Glycoproteins, Influenza Virus
  • Ligands
  • Multiprotein Complexes
  • Peptide Fragments