University of Massachusetts Medical School Faculty Publications
Title
HLA-DO acts as a substrate mimic to inhibit HLA-DM by a competitive mechanism
UMMS Affiliation
Department of Biochemistry and Molecular Pharmacology; Department of Pathology
Publication Date
1-2013
Document Type
Article
Subjects
Animals; Antigen Presentation; Antigen-Presenting Cells; Binding Sites; Cell Line; Crystallography, X-Ray; Drosophila melanogaster; HLA-D Antigens; Humans; Molecular Chaperones; Mutation; Protein Conformation
Disciplines
Immunopathology | Molecular Biology | Structural Biology
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 alpha subunit's 3(1)(0) 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.
DOI of Published Version
10.1038/nsmb.2460
Source
Nat Struct Mol Biol. 2013 Jan;20(1):90-8. doi: 10.1038/nsmb.2460. Link to article on publisher's site
Related Resources
Journal/Book/Conference Title
Nature structural and molecular biology
PubMed ID
23222639
Repository Citation
Guce, Abigail I.; Mortimer, Sarah E.; Yoon, Taejin; Painter, Corrie A.; Jiang, Wei; Mellins, Elizabeth D.; and Stern, Lawrence J., "HLA-DO acts as a substrate mimic to inhibit HLA-DM by a competitive mechanism" (2013). University of Massachusetts Medical School Faculty Publications. 242.
https://escholarship.umassmed.edu/faculty_pubs/242