Structure of the human MHC-I peptide-loading complex
Structure of the human MHC-I peptide-loading complex
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DOI：
10.1038/nature24627
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发表时间：
2017-11-23
期刊：
影响因子：
64.8
通讯作者：
Tampe, Robert
中科院分区：
文献类型：
--
作者：
Blees, Andreas;Januliene, Dovile;Tampe, Robert
肽负载复合物（PLC）是内质网中的一种瞬时多亚基膜复合物，对于建立分级免疫应答至关重要。PLC通过装载和编辑主要组织相容性复合体I类（MHC-I）分子来协调肽移位到内质网中。在PLC中最终校正后，稳定的肽-MHC-I复合物被释放到细胞表面，以引起针对感染或恶性细胞的T细胞应答（1，2）。不同MHC-I同种异型物的取样需要在单个大分子组装体中七个不同亚基的精确协调，包括与抗原加工相关的转运蛋白（TAP 1和TAP 2，统称为TAP）、氧化还原酶ERp 57、MHC-I异源二聚体以及伴侣tapasin和钙网蛋白（3，4）。PLC中发生的分子组织和机械事件是未知的，由于复杂的异质性组合物和内在的动态性质。在这里，我们使用工程病毒抑制剂作为诱饵从伯基特淋巴瘤细胞中分离出人PLC，并通过电子冷冻显微镜确定天然PLC的结构。由tapasin、钙网蛋白、ERp 57和MHC-I组成的两个内质网驻留编辑模块以假对称方向围绕TAP。编辑模块内部和跨编辑模块的多价伴侣网络在MHC-I分子的两个侧向结合平台上建立了校对功能。钙网蛋白的凝集素样结构域感知MHC-I聚糖，而P结构域越过MHC-I肽结合口袋到达ERp 57。这种排列允许tapasin通过夹持MHC-I来促进肽编辑。TAP的转运途径打开进入一个大的内质网内腔，由Tapasin和MHC-I的膜进入点限制。两个侧窗将抗原肽引导至MHC-I。在不同的组装状态下捕获的PLC结构提供了对MHC-I的募集和释放的机械见解。我们的工作定义了ABC转运蛋白和内质网伴侣网络在MHC-I组装中的分子共生关系，并提供了对适应性免疫反应发生的深入了解。
The peptide-loading complex (PLC) is a transient, multisubunit membrane complex in the endoplasmic reticulum that is essential for establishing a hierarchical immune response. The PLC coordinates peptide translocation into the endoplasmic reticulum with loading and editing of major histocompatibility complex class I (MHC-I) molecules. After final proofreading in the PLC, stable peptide-MHC-I complexes are released to the cell surface to evoke a T-cell response against infected or malignant cells(1,2). Sampling of different MHC-I allomorphs requires the precise coordination of seven different subunits in a single macromolecular assembly, including the transporter associated with antigen processing (TAP1 and TAP2, jointly referred to as TAP), the oxidoreductase ERp57, the MHC-I heterodimer, and the chaperones tapasin and calreticulin(3,4). The molecular organization of and mechanistic events that take place in the PLC are unknown owing to the heterogeneous composition and intrinsically dynamic nature of the complex. Here, we isolate human PLC from Burkitt's lymphoma cells using an engineered viral inhibitor as bait and determine the structure of native PLC by electron cryo-microscopy. Two endoplasmic reticulum-resident editing modules composed of tapasin, calreticulin, ERp57, and MHC-I are centred around TAP in a pseudo-symmetric orientation. A multivalent chaperone network within and across the editing modules establishes the proofreading function at two lateral binding platforms for MHC-I molecules. The lectin-like domain of calreticulin senses the MHC-I glycan, whereas the P domain reaches over the MHC-I peptide-binding pocket towards ERp57. This arrangement allows tapasin to facilitate peptide editing by clamping MHC-I. The translocation pathway of TAP opens out into a large endoplasmic reticulum lumenal cavity, confined by the membrane entry points of tapasin and MHC-I. Two lateral windows channel the antigenic peptides to MHC-I. Structures of PLC captured at distinct assembly states provide mechanistic insight into the recruitment and release of MHC-I. Our work defines the molecular symbiosis of an ABC transporter and an endoplasmic reticulum chaperone network in MHC-I assembly and provides insight into the onset of the adaptive immune response.