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- Title
HLA-DO acts as a substrate mimic to inhibit HLA-DM by a competitive mechanism.
- Authors
Guce, Abigail I; Mortimer, Sarah E; Yoon, Taejin; Painter, Corrie A; Jiang, Wei; Mellins, Elizabeth D; Stern, Lawrence J
- 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 ? 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.
- Subjects
HLA class II antigens; MAJOR histocompatibility complex; PROTEIN binding; RADIOLIGAND assay; X-ray crystallography
- Publication
Nature Structural & Molecular Biology, 2013, Vol 20, Issue 1, p90
- ISSN
1545-9993
- Publication type
Article
- DOI
10.1038/nsmb.2460