Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305.
HHMI, Stanford University School of Medicine, Stanford, CA 94305.
Proc Natl Acad Sci U S A. 2024 May 7;121(19):e2403031121. doi: 10.1073/pnas.2403031121. Epub 2024 Apr 30.
The loading of processed peptides on to major histocompatibility complex II (MHC-II) molecules for recognition by T cells is vital to cell-mediated adaptive immunity. As part of this process, MHC-II associates with the invariant chain (Ii) during biosynthesis in the endoplasmic reticulum to prevent premature peptide loading and to serve as a scaffold for subsequent proteolytic processing into MHC-II-CLIP. Cryo-electron microscopy structures of full-length Human Leukocyte Antigen-DR (HLA-DR) and HLA-DQ complexes associated with Ii, resolved at 3.0 to 3.1 Å, elucidate the trimeric assembly of the HLA/Ii complex and define atomic-level interactions between HLA, Ii transmembrane domains, loop domains, and class II-associated invariant chain peptides (CLIP). Together with previous structures of MHC-II peptide loading intermediates DO and DM, our findings complete the structural path governing class II antigen presentation.
加工后的肽加载到主要组织相容性复合体 II (MHC-II) 分子上，以便 T 细胞识别，这对细胞介导的适应性免疫至关重要。在这个过程中，MHC-II 在内质网中与不变链 (Ii) 结合，以防止过早的肽加载，并作为随后的蛋白水解处理成 MHC-II-CLIP 的支架。全长人类白细胞抗原-DR (HLA-DR) 和 HLA-DQ 复合物与 Ii 相关的冷冻电镜结构，分辨率为 3.0 到 3.1 Å，阐明了 HLA/Ii 复合物的三聚体组装，并定义了 HLA、Ii 跨膜结构域、环结构域和 II 类相关不变链肽 (CLIP) 之间的原子水平相互作用。与之前 MHC-II 肽加载中间物 DO 和 DM 的结构一起，我们的发现完成了指导 II 类抗原呈递的结构途径。
