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

Kedar Narayan, Chih Ling Chou, Ae Ryon Kim, Isamu Z. Hartman, Sarat Dalai, Stanislav Khoruzhenko, Scheherazade Sadegh-Nasseri

Research output: Contribution to journalArticle

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 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.

Original languageEnglish (US)
Pages (from-to)92-100
Number of pages9
JournalNature Immunology
Volume8
Issue number1
DOIs
StatePublished - Jan 1 2007

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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