title: HLA-DM targets the hydrogen bond between the histidine at position beta81 and peptide to dissociate HLA-DR-peptide complexes.
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 beta-chain (DR1betaH81N) to perturb an important hydrogen bond between MHC class II and peptide. Peptide-DR1betaH81N 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-DR1betaH81N complexes. Reintroduction of an appropriate hydrogen bond (DR1betaH81N betaV85H) restored DM-mediated peptide dissociation. Thus, DR1betaH81N 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 betaHis81 and bound peptide.
authors.affiliation: Graduate Program in Immunology, Johns Hopkins University Baltimore, Maryland 21205, USA.
authors.forename: Kedar
authors.initials: K
authors.lastname: Narayan
authors.forename: Chih-Ling
authors.initials: CL
authors.lastname: Chou
authors.forename: AeRyon
authors.initials: A
authors.lastname: Kim
authors.forename: Isamu Z
authors.initials: IZ
authors.lastname: Hartman
authors.forename: Sarat
authors.initials: S
authors.lastname: Dalai
authors.forename: Stanislav
authors.initials: S
authors.lastname: Khoruzhenko
authors.forename: Scheherazade
authors.initials: S
authors.lastname: Sadegh-Nasseri
mesh_terms: D017951:Antigen Presentation / Q000276:immunology; D006681:HLA-D Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006684:HLA-DR Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006639:Histidine / Q000378:metabolism*; D006801:Humans; D006860:Hydrogen Bonding; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D046912:Multiprotein Complexes; D010455:Peptides / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D006681:HLA-D Antigens; C084245:HLA-DM antigens; D006684:HLA-DR Antigens; D046912:Multiprotein Complexes; D010455:Peptides; D011994:Recombinant Proteins; D006639:Histidine