HLA-DM targets the hydrogen bond between the histidine at position beta81 and peptide to dissociate HLA-DR-peptide complexes.
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.
Narayan
Kedar
K
Graduate Program in Immunology, Johns Hopkins University Baltimore, Maryland 21205, USA.
Chou
Chih-Ling
CL
Kim
AeRyon
A
Hartman
Isamu Z
IZ
Dalai
Sarat
S
Khoruzhenko
Stanislav
S
Sadegh-Nasseri
Scheherazade
S
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
D006681:HLA-D Antigens; C084245:HLA-DM antigens; D006684:HLA-DR Antigens; D046912:Multiprotein Complexes; D010455:Peptides; D011994:Recombinant Proteins; D006639:Histidine