Journal Article

HLA-DO acts as a substrate mimic to inhibit HLA-DM by a competitive mechanism

Mortimer, Sarah E, Yoon, Taejin, Mellins, Elizabeth D, Jiang, Wei, Stern, Lawrence J, Guce, Abigail I, Painter, Corrie A

2013

Overview

HLA-DM interacts with MHCII and promotes peptide exchange. This activity of HLA-DM is regulated by HLA-DO. The crystal structure of the HLA-DO–HLA-DM complex along with mutagenesis and kinetic analyses reveal that HLA-DO adopts a classical MHCII structure and competitively inhibits HLA-DM's activity on MHCII. 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 α subunit's 3 10 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/250/21/324/1508 / 631/45/535 / 631/57/2272/1590 / Animals / Antigen Presentation / Antigen-Presenting Cells / Antigens / Binding Sites / Biochemistry / Biological Microscopy / Cell Line / Cellular biology / Crystallography / Crystallography, X-Ray / Drosophila melanogaster / Enzymes / HLA-D Antigens - chemistry / HLA-D Antigens - immunology / HLA-D Antigens - metabolism / Humans / Inactivation / Kinetics / Life Sciences / Major histocompatibility complex / Mammals / Membrane Biology / Molecular chaperones / Molecular Chaperones - immunology / Molecular Chaperones - metabolism / Mutagenesis / Mutation / Peptides / Properties / Protein Conformation / Protein Structure / Proteins / Structure / Substrates (Biochemistry)