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Receptor binding and priming of the spike protein of SARS-CoV-2 for membrane fusion

机译：SARS-COV-2的受体结合和引发膜融合的SARS-COV-2

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摘要

Cryo-electron microscopy structures of consecutive binding events of ACE2 in complex with the spike protein of SARS-CoV-2 reveal the mechanisms of receptor binding by the spike protein and activation for membrane fusion by the spike protein of SARS-CoV-2.Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is initiated by virus binding to the ACE2 cell-surface receptors(1-4), followed by fusion of the 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(5-7). As with other class-I membrane-fusion proteins, the spike protein is post-translationally cleaved, in this case by furin, into the S1 and S2 components that remain associated after cleavage(8-10). Fusion activation after receptor binding is proposed to involve the exposure of a second proteolytic site (S2 '), cleavage of which is required for the release of the fusion peptide(11,12). Here we analyse the binding of ACE2 to the furin-cleaved form of the SARS-CoV-2 spike protein using cryo-electron microscopy. 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 that destabilize the spike trimer, progressively opening up, and out, the individual S1 components. The opening process reduces S1 contacts and unshields the trimeric S2 core, priming the protein for fusion activation and dissociation of ACE2-bound S1 monomers. The structures also reveal refolding of an S1 subdomain after ACE2 binding that disrupts interactions with S2, which involves Asp614(13-15) and leads to the destabilization of the structure of S2 proximal to the secondary (S2 ') cleavage site.
机译：Cryo-Collect-Electron显微镜结构与SARS-COV-2的尖峰蛋白质的ACE2中连续结合事件的结构揭示了SARS-COV-2.尖刺蛋白的穗蛋白和膜融合的受体结合的机制由于严重的急性呼吸综合征冠状病毒2（SARS-COV-2）由与ACE2细胞表面受体（1-4）的病毒结合引发，然后融合病毒和细胞膜以将病毒基因组释放到细胞中。受体结合和膜融合活性均由病毒穗糖蛋白（5-7）介导。与其他类-I膜 - 融合蛋白一样，尖峰蛋白在这种情况下被翻译成裂解成在裂解后保留相关的S1和S2组分（8-10）。提出了受体结合后的融合激活，涉及涉及第二蛋白水解位点（S2'）的暴露，其裂解融合肽（11,12）。在这里，我们使用冷冻电子显微镜分析ACE2与SARS-COV-2刺蛋白的Furin切割形式的结合。我们分类十种不同的分子物种，包括未结合的闭式三角形，完全打开的Ace2结合的三聚体和与ACE2结合的离解的单体S1。十个结构描述了一种稳定地破坏尖刺三聚体的ACE2结合事件，逐渐打开，并且单独的S1部件。开口过程可减少S1触点和遮挡三聚体S2核，促使蛋白质用于融合活化和ACE2结合的S1单体的解离。该结构还揭示了acce2结合后扰乱与S2的相互作用后的S1子域的重折叠，这涉及ASP614（13-15）并导致S2近端的S2结构的稳定性（S2'）切割位点。

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  • 来源
    《Nature》 |2020年第7837期|327-330|共4页
  • 作者

    Benton Donald J.; Wrobel Antoni G.; Xu Pengqi; Roustan Chloe; Martin Stephen R.; Rosenthal Peter B.; Skehel John J.; Gamblin Steven J.;

  • 作者单位

    Francis Crick Inst Strutural Biol Dis Proc Lab London England;

    Francis Crick Inst Strutural Biol Dis Proc Lab London England;

    Sun Yat Sen Univ Affiliated Hosp 7 Precis Med Ctr Shenzhen Peoples R China|Francis Crick Inst London England;

    Francis Crick Inst Struct Biol Sci Technol Platform London England;

    Francis Crick Inst Strutural Biol Dis Proc Lab London England;

    Francis Crick Inst Struct Biol Cells & Viruses Lab London England;

    Francis Crick Inst Strutural Biol Dis Proc Lab London England;

    Francis Crick Inst Strutural Biol Dis Proc Lab London England;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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