Structural insights into hepatitis C virus receptor binding and entry.
Structural insights into hepatitis C virus receptor binding and entry.
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DOI：
10.1038/s41586-021-03913-5
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发表时间：
2021-10
期刊：
影响因子：
64.8
通讯作者：
Marcotrigiano J
中科院分区：
文献类型：
--
作者：
Kumar A;Hossain RA;Yost SA;Bu W;Wang Y;Dearborn AD;Grakoui A;Cohen JI;Marcotrigiano J
丙型肝炎病毒（HCV）感染是人类慢性肝病、肝硬化和肝细胞癌的病因，全球有7000多万人受其困扰。HCV包膜糖蛋白E1和E2负责与宿主细胞结合，但确切的进入过程仍未确定。大多数广泛中和抗体阻止HCV E2与细胞受体CD81的大胞外环（LEL）之间的相互作用。我们观察到低pH值增强CD81 - LEL与E2的结合，并确定了E2/Fab 2A12/CD81 - LEL、E2/Fab 2A12和CD81 - LEL的晶体结构。在与CD81结合时，E2的418 - 422位残基发生位移，使得内部环（520 - 539位残基）得以伸展。将E2/CD81 - LEL复合物对接至嵌入膜中的全长CD81上时，E2的Tyr529和Trp531靠近膜。脂质体浮选试验表明，低pH值和CD81 - LEL增加E2与膜的相互作用，而基于结构的E2氨基末端的Tyr529、Trp531和Ile422突变体则消除膜结合。这些数据支持一种模型，即酸化和受体结合导致E2发生构象变化，为膜融合做准备。
Hepatitis C virus (HCV) infection is a causal agent of chronic liver disease, cirrhosis, and hepatocellular carcinoma in humans, afflicting more than 70 million people worldwide. HCV envelope glycoproteins E1 and E2 are responsible for host cell binding, but the exact entry process remains undetermined. The majority of broadly neutralizing antibodies preclude interaction between HCV E2 and the large extracellular loop (LEL) of the cellular receptor CD81. We observed that low pH enhances CD81-LEL binding to E2 and determined the crystal structures of E2/Fab 2A12/CD81-LEL, E2/Fab 2A12, and CD81-LEL. Upon binding CD81, E2 residues 418–422 are displaced, allowing for the extension of an internal loop, residues 520–539. Docking of the E2/CD81-LEL complex onto a membrane embedded, full length CD81 places Tyr529 and Trp531 of E2 proximal to the membrane. Liposome flotation assays demonstrate that low pH and CD81-LEL increase E2 interaction with membranes, while structure-based mutants of Tyr529, Trp531, and Ile422 of the E2 amino terminus abolish membrane binding. These data support a model that acidification and receptor binding result in a conformation change in E2 in preparation for membrane fusion.
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期刊：
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DOI：
10.1107/s0907444909042073
发表时间：
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期刊：
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影响因子：
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