期刊
NATURE STRUCTURAL & MOLECULAR BIOLOGY
卷 20, 期 1, 页码 90-U118出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.2460
关键词
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资金
- Offices of Biological and Environmental Research and of Basic Energy Sciences of the US Department of Energy
- National Center for Research Resources (NCRR) of the US National Institutes of Health (NIH)
- NIH [AI-38996, AI-48833, T32 AI07349, F32 AI072984, AI-095813, AI-075253]
- NIH/NCRR Clinical and Translational Science Award at Stanford University [UL1 RR025744]
- Lucile Packard Foundation for Children's Health
Mammalian class II major histocompatibility (MHCII) proteins bind peptide antigens in endosomal compartments of antigenpresenting 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 a 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.
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