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

2013-1

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

Link to Article in PubMed

Journal/Book/Conference Title

Nature structural and molecular biology

PubMed ID

23222639

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