HLA-DO acts as a substrate mimic to inhibit HLA-DM by a competitive mechanism
AuthorsGuce, Abigail I.
Mortimer, Sarah E.
Painter, Corrie A.
Mellins, Elizabeth D.
Stern, Lawrence J.
UMass Chan AffiliationsDepartment of Pathology
Department of Biochemistry and Molecular Pharmacology
Document TypeJournal Article
MetadataShow full item record
AbstractMammalian 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.
SourceNat Struct Mol Biol. 2013 Jan;20(1):90-8. doi: 10.1038/nsmb.2460. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/30008
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