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Nature Immunology 8, 92–100 (1 January 2007) | doi:10.1038/ni1414

HLA-DM targets the hydrogen bond between the histidine at position |[beta]|81 and peptide to dissociate HLA-DR|[ndash]|peptide complexes

Kedar Narayan , Chih-Ling Chou , AeRyon Kim , Isamu Z Hartman , Sarat Dalai , Stanislav Khoruzhenko & Scheherazade Sadegh-Nasseri

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.