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Interaction of HLA-DR with an acidic face of HLA-DM disrupts sequence-dependent interactions with peptides.

HLA-DM (DM) edits major histocompatibility complex class II (MHCII)-bound peptides in endocytic compartments and stabilizes empty MHCII molecules. Crystal structures of DM have revealed similarity to MHCII but not how DM and MHCII interact. We used mutagenesis to map a MHCII-interacting surface on DM. Mutations on this surface impair DM action on HLA-DR and -DP in cells and DM-dependent peptide loading in vitro. The orientation of DM and MHCII predicted by these studies guided design of soluble DM and DR molecules fused to leucine zippers via their beta chains, resulting in stable DM/DR complexes. Peptide release from the complexes was fast and only weakly sequence dependent, arguing that DM diminishes the selectivity of the MHCII groove. Analysis of soluble DM action on soluble DR/peptide complexes corroborates this conclusion.

Pubmed ID: 12932352


  • Pashine A
  • Busch R
  • Belmares MP
  • Munning JN
  • Doebele RC
  • Buckingham M
  • Nolan GP
  • Mellins ED



Publication Data

August 22, 2003

Associated Grants

  • Agency: NIAID NIH HHS, Id: R01-AI28809

Mesh Terms

  • Antigens, Differentiation, B-Lymphocyte
  • Base Sequence
  • Cell Line
  • DNA, Complementary
  • Drug Stability
  • HLA-D Antigens
  • HLA-DR Antigens
  • Histocompatibility Antigens Class II
  • Humans
  • In Vitro Techniques
  • Kinetics
  • Macromolecular Substances
  • Models, Molecular
  • Mutagenesis, Site-Directed
  • Solubility