Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Nat Immunol. 2011 Jan;12(1):54-61. doi: 10.1038/ni.1967. Epub 2010 Dec 5.
The mechanisms of HLA-DM-catalyzed peptide exchange remain uncertain. Here we found that all stages of the interaction of HLA-DM with HLA-DR were dependent on the occupancy state of the peptide-binding groove. High-affinity peptides were protected from removal by HLA-DM through two mechanisms: peptide binding induced the dissociation of a long-lived complex of empty HLA-DR and HLA-DM, and high-affinity HLA-DR-peptide complexes bound HLA-DM only very slowly. Nonbinding covalent HLA-DR-peptide complexes were converted into efficient HLA-DM binders after truncation of an N-terminal peptide segment that emptied the P1 pocket and disrupted conserved hydrogen bonds to HLA-DR. HLA-DM thus binds only to HLA-DR conformers in which a critical part of the binding site is already vacant because of spontaneous peptide motion.
HLA-DM 催化肽交换的机制仍不清楚。在这里，我们发现 HLA-DM 与 HLA-DR 相互作用的所有阶段都依赖于肽结合槽的占据状态。高亲和力的肽通过两种机制被 HLA-DM 保护而不被清除：肽结合诱导 HLA-DR 和 HLA-DM 的长寿命复合物解离，并且高亲和力的 HLA-DR-肽复合物与 HLA-DM 的结合非常缓慢。非结合的共价 HLA-DR-肽复合物在截断 N 端肽段后被转化为有效的 HLA-DM 结合物，该肽段排空了 P1 口袋并破坏了与 HLA-DR 的保守氢键。因此，HLA-DM 仅结合由于自发肽运动而使结合位点的关键部分已经空出的 HLA-DR 构象。
