Major histocompatibility complex class I (MHC I) molecules are central to adaptive immunity. Their assembly, epitope selection, and antigen presentation are controlled by the MHC I glycan through a sophisticated network of chaperones and modifying enzymes. However, the mechanistic integration of the corresponding processes remains poorly understood. Here, we determine the multi-chaperone-client interaction network of the peptide loading complex (PLC) and report the PLC editing module structure by cryogenic electron microscopy at 3.7 Å resolution. Combined with epitope-proofreading studies of the PLC in near-native lipid environment, these data show that peptide-receptive MHC I molecules are stabilized by multivalent chaperone interactions including the calreticulin-engulfed mono-glucosylated MHC I glycan, which only becomes accessible for processing by α-glucosidase II upon loading of optimal epitopes. Our work reveals allosteric coupling between peptide-MHC I assembly and glycan processing. This inter-process communication defines the onset of an adaptive immune response and provides a prototypical example of the tightly coordinated events in endoplasmic reticulum quality control.

主要组织相容性复合物 I 类 (MHC I) 分子是适应性免疫的核心。它们的组装、表位选择和抗原呈递由 MHC I 聚糖通过复杂的分子伴侣和修饰酶网络控制。然而，相应过程的机械集成仍然知之甚少。在这里，我们确定了肽加载复合物 (PLC) 的多伴侣-客户端交互网络，并通过低温电子显微镜以 3.7 Å 的分辨率报告了 PLC 编辑模块结构。结合近天然脂质环境中 PLC 的表位校对研究，这些数据表明肽受体 MHC I 分子通过多价伴侣相互作用稳定，包括钙网蛋白吞噬的单糖基化 MHC I 聚糖，只有在加载最佳表位后才能被 α-葡萄糖苷酶 II 处理。我们的工作揭示了肽-MHC I 组装和聚糖加工之间的变构耦合。这种进程间通信定义了适应性免疫反应的开始，并提供了内质网质量控制中紧密协调事件的典型示例。