期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2005
卷号：102
期号：18
页码：6443-6448
DOI：10.1073/pnas.0500853102
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：B lymphocytes express the nonclassical class II molecule HLA-DO, which modulates the peptide loading activity of HLA-DM in the endocytic pathway. Binding to HLA-DM is required for HLA-DO to egress from the endoplasmic reticulum (ER). To gain insights into the mode of action of DO and on the role of DM in ER release, we sought to identify DM-binding residues on DO. Our results show that DO{alpha} encompasses the binding site for HLA-DM. More specifically, mutation of residue DO{alpha}41 on an exposed lateral loop of the {alpha}1 domain affects the binding to DM, ER egress, and activity of DO. Using a series of chimeric DR/DO molecules, we confirmed the role of the {alpha} chain and established that a second DM-binding region is located C-terminal to the DO{alpha}80 residue, most probably in the {alpha}2 domain. Interestingly, after mutation of a buried proline ({alpha}11) on the floor of the putative peptide-binding groove, HLA-DO remained functional but became independent of HLA-DM for ER egress and intracellular trafficking. Collectively, these results suggest that the binding of HLA-DM to DO{alpha} allows the complex to egress from the ER by stabilizing intramolecular contacts between the N-terminal antiparallel {beta}-strands of the DO{alpha}{beta} heterodimer.
