Article abstract
Nature Immunology 8, 92 - 100 (2006)
Published online: 3 December 2006 | doi:10.1038/ni1414
HLA-DM targets the hydrogen bond between the histidine at position 
81 and peptide to dissociate HLA-DR–peptide complexes
Kedar Narayan1,4, Chih-Ling Chou2,4, AeRyon Kim1, Isamu Z Hartman1, Sarat Dalai3, Stanislav Khoruzhenko3 & Scheherazade Sadegh-Nasseri1,2,3
Abstract
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 
-chain (DR1H81N) to perturb an important hydrogen bond between MHC class II and peptide. Peptide–DR1H81N 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–DR1H81N complexes. Reintroduction of an appropriate hydrogen bond (DR1H81N V85H) restored DM-mediated peptide dissociation. Thus, DR1H81N 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 His81 and bound peptide.
- Graduate Program in Immunology, Johns Hopkins University Baltimore, Maryland 21205, USA.
- Graduate Program in Molecular and Computational Biophysics, Johns Hopkins University, Baltimore, Maryland 21205, USA.
- Department of Pathology, Johns Hopkins University, Baltimore, Maryland 21205, USA.
- These authors contributed equally to this work.
Correspondence to: Scheherazade Sadegh-Nasseri1,2,3 e-mail: ssadegh@jhmi.edu
