title: HLA-DO acts as a substrate mimic to inhibit HLA-DM by a competitive mechanism.
abstract: Mammalian class II major histocompatibility (MHCII) proteins bind peptide antigens in endosomal compartments of antigen-presenting cells. The nonclassical MHCII protein HLA-DM chaperones peptide-free MHCII, protecting it against inactivation, and catalyzes peptide exchange on loaded MHCII. Another nonclassical MHCII protein, HLA-DO, binds HLA-DM and influences the repertoire of peptides presented by MHCII proteins. However, the mechanism by which HLA-DO functions is unclear. Here we have used X-ray crystallography, enzyme kinetics and mutagenesis approaches to investigate human HLA-DO structure and function. In complex with HLA-DM, HLA-DO adopts a classical MHCII structure, with alterations near the α subunit's 3₁₀ helix. HLA-DO binds to HLA-DM at the same sites implicated in MHCII interaction, and kinetic analysis showed that HLA-DO acts as a competitive inhibitor. These results show that HLA-DO inhibits HLA-DM function by acting as a substrate mimic, and the findings also limit the possible functional roles for HLA-DO in antigen presentation.
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Abigail I
authors.initials: AI
authors.lastname: Guce
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Mortimer
authors.forename: Taejin
authors.initials: T
authors.lastname: Yoon
authors.forename: Corrie A
authors.initials: CA
authors.lastname: Painter
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Mellins
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Stern
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D000938:Antigen-Presenting Cells; D001665:Binding Sites; D002460:Cell Line; D018360:Crystallography, X-Ray; D004331:Drosophila melanogaster; D006681:HLA-D Antigens / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D018832:Molecular Chaperones / Q000276:immunology / Q000378:metabolism; D009154:Mutation; D011487:Protein Conformation
chemical_list: D006681:HLA-D Antigens; C084245:HLA-DM antigens; C046148:HLA-DO antigens; D018832:Molecular Chaperones