HLA-DO acts as a substrate mimic to inhibit HLA-DM by a competitive mechanism

Nat Struct Mol Biol. 2013 Jan;20(1):90-8. doi: 10.1038/nsmb.2460. Epub 2012 Dec 9.


Mammalian class II major histocompatibility (MHCII) proteins bind peptide antigens in endosomal compartments of antigen-presenting cells. The nonclassical MHCII protein HLA-DM chaperones peptide-free MHCII, protecting it against inactivation, and catalyzes peptide exchange on loaded MHCII. Another nonclassical MHCII protein, HLA-DO, binds HLA-DM and influences the repertoire of peptides presented by MHCII proteins. However, the mechanism by which HLA-DO functions is unclear. Here we have used X-ray crystallography, enzyme kinetics and mutagenesis approaches to investigate human HLA-DO structure and function. In complex with HLA-DM, HLA-DO adopts a classical MHCII structure, with alterations near the α subunit's 3₁₀ helix. HLA-DO binds to HLA-DM at the same sites implicated in MHCII interaction, and kinetic analysis showed that HLA-DO acts as a competitive inhibitor. These results show that HLA-DO inhibits HLA-DM function by acting as a substrate mimic, and the findings also limit the possible functional roles for HLA-DO in antigen presentation.

Publication types

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

MeSH terms

  • Animals
  • Antigen Presentation
  • Antigen-Presenting Cells
  • Binding Sites
  • Cell Line
  • Crystallography, X-Ray
  • Drosophila melanogaster
  • HLA-D Antigens / chemistry*
  • HLA-D Antigens / immunology
  • HLA-D Antigens / metabolism*
  • Humans
  • Molecular Chaperones / immunology
  • Molecular Chaperones / metabolism
  • Mutation
  • Protein Conformation


  • HLA-D Antigens
  • HLA-DM antigens
  • HLA-DO antigens
  • Molecular Chaperones

Associated data

  • PDB/4I0P