研究揭示SARS-CoV-2突刺蛋白介導的受體結合和活化
作者:
小柯機器人發布時間:2020/9/21 23:06:16
英國弗朗西斯·克裡克研究所Steven J. Gamblin等研究人員合作揭示了SARS-CoV-2突刺蛋白介導的受體結合和活化。相關論文於2020年9月17日在線發表於國際學術期刊《自然》。
研究人員表示,SARS-CoV-2感染是由病毒與ACE2細胞表面受體結合而引發的,然後病毒與細胞膜融合後將病毒基因組釋放到細胞中。受體結合和膜融合活性均由病毒突刺糖蛋白S介導。與其他I類膜融合蛋白一樣,S在翻譯後被弗林蛋白酶切割成S1和S2組分,這些組分在切割後仍保持關聯。受體結合後的融合激活被認為涉及暴露第二個蛋白水解位點(S2』),其切割是融合肽釋放所必需的。
研究人員通過冷凍電鏡揭示了ACE2與SARS-CoV-2 S的弗林蛋白酶切割形式的結合。研究人員對十個不同的分子種類進行了分類,包括未結合的、封閉的突刺三聚體、完全開放的ACE2結合三聚體以及與ACE2結合的解離單體S1。十個結構描述了ACE2結合事件,該事件使突刺三聚體不穩定,進而逐漸打開和釋放單個S1組分。開放過程減少了S1的接觸並解除了三聚體S2核的保護,引發了ACE2結合的S1單體的融合活化和解離。
該結構還揭示了ACE2結合後S1亞結構域的重摺疊,從而破壞了與S2的相互作用,特別是Asp614的相互作用,最終導致鄰近二級(S2')切割位點的S2結構不穩定。
附:英文原文
Title: Receptor binding and priming of the spike protein of SARS-CoV-2 for membrane fusion
Author: Donald J. Benton, Antoni G. Wrobel, Pengqi Xu, Chlo Roustan, Stephen R. Martin, Peter B. Rosenthal, John J. Skehel, Steven J. Gamblin
Issue&Volume: 2020-09-17
Abstract: SARS-CoV-2 infection is initiated by virus binding to ACE2 cell surface receptors1–4, followed by fusion of virus and cell membranes to release the virus genome into the cell. Both receptor binding and membrane fusion activities are mediated by the virus Spike glycoprotein, S5–7. As with other class I membrane fusion proteins, S is post-translationally cleaved, in this case by furin, into S1 and S2 components that remain associated following cleavage8–10. Fusion activation following receptor binding is proposed to involve the exposure of a second proteolytic site (S2』), cleavage of which is required for the fusion peptide release11,12. We have investigated the binding of ACE2 to the furin-cleaved form of SARS-CoV-2 S by cryoEM. We classify ten different molecular species including the unbound, closed spike trimer, the fully open ACE2-bound trimer, and dissociated monomeric S1 bound to ACE2. The ten structures describe ACE2 binding events which destabilise the spike trimer, progressively opening up, and out, the individual S1 components. The opening process reduces S1 contacts and un-shields the trimeric S2 core, priming fusion activation and dissociation of ACE2-bound S1 monomers. The structures also reveal refolding of an S1 subdomain following ACE2 binding, that disrupts interactions with S2, notably involving Asp61413–15, leading to destabilisation of the structure of S2 proximal to the secondary (S2』) cleavage site.
DOI: 10.1038/s41586-020-2772-0
Source: https://www.nature.com/articles/s41586-020-2772-0