小柯机器人

美国国立卫生研究院Joseph Marcotrigiano课题组揭示丙型肝炎病毒受体结合和进入的结构基础。该项研究成果于2021年9月15日在线发表在《自然》杂志上。

据研究人员介绍，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原体，全世界有7000多万人受到困扰。HCV包膜糖蛋白E1和E2负责病毒与宿主细胞的结合，但确切的进入过程仍未确定。大多数广义中和抗体阻断了HCV E2和细胞受体CD81的大胞外环（CD81-LEL）之间的相互作用。

研究人员发现，低pH值会增强CD81-LEL与E2的结合，并确定了E2与抗原结合片段（2A12）和CD81-LEL（E2-2A12-CD81-LEL）；E2与2A12（E2-2A12）；以及CD81-LEL单独复合物的晶体结构。在与CD81结合后，E2中的残基第418-422被移位，这使得由残基第520-539组成的内环得以延伸。E2-CD81-LEL复合物与膜包埋的全长CD81对接，使E2的残基Tyr529和Trp531靠近膜。

脂质体漂浮试验显示，低pH值和CD81-LEL增加了E2与膜的相互作用，而E2氨基末端的Tyr529、Trp531和Ile422的结构突变体则废除了膜结合。这些数据支持一种模型，即酸化和受体结合导致E2的构象变化，进而为膜融合做准备。

附：英文原文

Title: Structural insights into hepatitis C virus receptor binding and entry

Author: Kumar, Ashish, Hossain, Reafa A., Yost, Samantha A., Bu, Wei, Wang, Yuanyuan, Dearborn, Altaira D., Grakoui, Arash, Cohen, Jeffrey I., Marcotrigiano, Joseph

Issue&Volume: 2021-09-15

Abstract: Hepatitis C virus (HCV) infection is a causal agent of chronic liver disease, cirrhosis and hepatocellular carcinoma in humans, and afflicts more than 70million people worldwide. The HCV envelope glycoproteins E1 and E2 are responsible for the binding of the virus to the host cell, but the exact entry process remains undetermined1. The majority of broadly neutralizing antibodies block interaction between HCV E2 and the large extracellular loop (LEL) of the cellular receptor CD81 (CD81-LEL)2. Here we show that low pH enhances the binding of CD81-LEL to E2, and we determine the crystal structure of E2 in complex with an antigen-binding fragment (2A12) and CD81-LEL (E2–2A12–CD81-LEL); E2 in complex with 2A12 (E2–2A12); and CD81-LEL alone. After binding CD81, residues 418–422 in E2 are displaced, which allows for the extension of an internal loop consisting of residues 520–539. Docking of the E2–CD81-LEL complex onto a membrane-embedded, full-length CD81 places the residues Tyr529 and Trp531 of E2 proximal to the membrane. Liposome flotation assays show that low pH and CD81-LEL increase the interaction of E2 with membranes, whereas structure-based mutants of Tyr529, Trp531 and Ile422 in the amino terminus of E2 abolish membrane binding. These data support a model in which acidification and receptor binding result in a conformational change in E2 in preparation for membrane fusion.

DOI: 10.1038/s41586-021-03913-5

Source: https://www.nature.com/articles/s41586-021-03913-5

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html