HLA-DM targets the hydrogen bond between the histidine at position β81 and peptide to dissociate HLA-DR -peptide complexes

• Published in: Nature immunology Vol. 8; no. 1; pp. 92 - 100
• Main Authors: Kim, AeRyon, Khoruzhenko, Stanislav, Dalai, Sarat, Chou, Chih-Ling, Sadegh-Nasseri, Scheherazade, Hartman, Isamu Z, Narayan, Kedar
• Format: Journal Article
• Language: English
• Published: Nature Publishing Group 01-01-2007
• Subjects: Histocompatibility antigens; HLA histocompatibility antigens; Ir genes; Physiological aspects; United States
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/ni1414

The peptide editor HLA-DM (DM) mediates exchange of peptides bound to major histocompatibility (MHC) class II molecules during antigen processing; however, the mechanism by which DM displaces peptides remains unclear. Here we generated a soluble mutant HLA-DR1 with a histidine-to-asparagine substitution at position 81 of the β-chain (DR1βH81N) to perturb an important hydrogen bond between MHC class II and peptide. Peptide–DR1βH81N complexes dissociated at rates similar to the dissociation rates of DM-induced peptide–wild-type DR1, and DM did not enhance the dissociation of peptide–DR1βH81N complexes. Reintroduction of an appropriate hydrogen bond (DR1βH81N βV85H) restored DM-mediated peptide dissociation. Thus, DR1βH81N might represent a `post-DM effect' conformation. We suggest that DM may mediate peptide dissociation by a `hit-and-run' mechanism that results in conformational changes in MHC class II molecules and disruption of hydrogen bonds between βHis81 and bound peptide.