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.
UMass Chan Affiliations
Department of PathologyDepartment of Biochemistry and Molecular Pharmacology
Document Type
Journal ArticlePublication Date
2013-01-01Keywords
AnimalsAntigen Presentation
Antigen-Presenting Cells
Binding Sites
Cell Line
Crystallography, X-Ray
Drosophila melanogaster
HLA-D Antigens
Humans
Molecular Chaperones
Mutation
Protein Conformation
Immunopathology
Molecular Biology
Structural Biology
Metadata
Show full item recordAbstract
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.Source
Nat Struct Mol Biol. 2013 Jan;20(1):90-8. doi: 10.1038/nsmb.2460. Link to article on publisher's siteDOI
10.1038/nsmb.2460Permanent Link to this Item
http://hdl.handle.net/20.500.14038/30008PubMed ID
23222639Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1038/nsmb.2460