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研究揭示膜融合pH下HA结构转变
2020-05-29 15:48

英国弗朗西斯·克里克研究所John J. SkehelDonald J. Benton研究组合作取得一项新成果。他们揭示了膜融合pH下流感血凝素(HA)的结构转变。相关论文于2020527日发表在《自然》杂志上。

为了进一步研究融合过程,他们将HApH 5.0下孵育了不同的时间,并使用单粒子冷冻电镜直接扫描结构变化。他们描述了三种不同的,以前未描述的HA形式,最著名的是HA2150Å长的三螺旋线圈,它可以在病毒膜和内体膜之间架起桥梁。这些结构的比较揭示了HA介导膜融合的一致的构象重排。

据介绍,包膜病毒的感染涉及其脂质包膜与细胞膜的融合,从而将病毒基因组释放到细胞中。对于HIV、埃博拉病毒、流感病毒和许多其他病毒,包膜糖蛋白将感染的病毒体与细胞表面受体结合并介导膜融合。在流感的情况下,受体结合糖蛋白是HA,在被内吞作用受体介导摄取结合病毒后,HA介导了病毒包膜与内体膜的融合。三聚体HA的每个亚基由两个二硫键连接的多肽HA1HA2组成。较大的病毒膜远端HA1介导受体结合。较小的膜近端HA2HA锚定在包膜中,并包含融合肽,该区域直接参与膜相互作用。内体的低pH值通过促进糖蛋白中不可逆的构象变化来激活融合。研究人员通过电镜和X射线晶体学研究了中性pH下初始HA的结构和融合pH下最终HA的结构。

附:英文原文

Title: Structural transitions in influenza haemagglutinin at membrane fusion pH

Author: Donald J. Benton, Steven J. Gamblin, Peter B. Rosenthal, John J. Skehel

Issue&Volume: 2020-05-27

Abstract: Infection by enveloped viruses involves fusion of their lipid envelopes with cellular membranes to release the viral genome into cells. For HIV, Ebola, influenza and numerous other viruses, envelope glycoproteins bind the infecting virion to cell-surface receptors and mediate membrane fusion. In the case of influenza, the receptor-binding glycoprotein is the haemagglutinin (HA), and following receptor-mediated uptake of the bound virus by endocytosis1, it is the HA that mediates fusion of the virus envelope with the membrane of the endosome2. Each subunit of the trimeric HA consists of two disulfide-linked polypeptides, HA1 and HA2. The larger, virus-membrane-distal, HA1 mediates receptor binding; the smaller, membrane-proximal, HA2 anchors HA in the envelope and contains the fusion peptide, a region that is directly involved in membrane interaction3. The low pH of endosomes activates fusion by facilitating irreversible conformational changes in the glycoprotein. The structures of the initial HA at neutral pH and the final HA at fusion pH have been investigated by electron microscopy4,5 and X-ray crystallography6,7,8. Here, to further study the process of fusion, we incubate HA for different times at pH 5.0 and directly image structural changes using single-particle cryo-electron microscopy. We describe three distinct, previously undescribed forms of HA, most notably a 150 -long triple-helical coil of HA2, which may bridge between the viral and endosomal membranes. Comparison of these structures reveals concerted conformational rearrangements through which the HA mediates membrane fusion.

DOI: 10.1038/s41586-020-2333-6

Source: https://www.nature.com/articles/s41586-020-2333-6

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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