In situ structural analysis of SARS-CoV-2 spike reveals flexibility mediated by three hinges.
In situ structural analysis of SARS-CoV-2 spike reveals flexibility mediated by three hinges.
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DOI：
10.1126/science.abd5223
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发表时间：
2020-10-09
期刊：
影响因子：
--
通讯作者：
Beck M
中科院分区：
文献类型：
--
作者：
Turoňová B;Sikora M;Schürmann C;Hagen WJH;Welsch S;Blanc FEC;von Bülow S;Gecht M;Bagola K;Hörner C;van Zandbergen G;Landry J;de Azevedo NTD;Mosalaganti S;Schwarz A;Covino R;Mühlebach MD;Hummer G;Krijnse Locker J;Beck M
严重急性呼吸综合征冠状病毒2 （SARS-CoV-2）刺突蛋白通过与血管紧张素转换酶2 （ACE2）受体结合，使病毒进入宿主细胞，是中和抗体的主要靶点。病毒粒子表面大约有20到40个尖刺。Turoňová等人现在表明，刺突通过三个铰链灵活地连接到病毒表面，这些铰链受到糖基化位点的良好保护。这些铰链所赋予的灵活性可能解释了多个刺突如何协同作用以接触宿主细胞的平面。被冠状病毒刺突蛋白中聚糖屏蔽的柔性铰链可能允许扫描宿主细胞表面。严重急性呼吸综合征冠状病毒2 （SARS-CoV-2）的刺突蛋白(S)是细胞进入所必需的，也是疫苗开发的主要重点。在这项研究中，我们结合了低温电子断层扫描、亚层析平均和分子动力学模拟来分析原位S的结构。与重组S相比，病毒S的糖基化程度更重，且主要发生在封闭预融合构象中。我们证明了S的柄域包含三个铰链，这给了头部意想不到的方向自由。我们提出铰链允许S扫描宿主细胞表面，通过广泛的聚糖外壳屏蔽抗体。本地S的结构有助于我们对SARS-CoV-2感染的理解，并有可能开发安全的疫苗。
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein enables viral entry into host cells by binding to the angiotensin-converting enzyme 2 (ACE2) receptor and is a major target for neutralizing antibodies. About 20 to 40 spikes decorate the surface of virions. Turoňová et al. now show that the spike is flexibly connected to the viral surface by three hinges that are well protected by glycosylation sites. The flexibility imparted by these hinges may explain how multiple spikes act in concert to engage onto the flat surface of a host cell. Science, this issue p. 203 Flexible hinges shielded by glycans in the coronavirus spike protein may allow scanning of the host cell surface. The spike protein (S) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is required for cell entry and is the primary focus for vaccine development. In this study, we combined cryo–electron tomography, subtomogram averaging, and molecular dynamics simulations to structurally analyze S in situ. Compared with the recombinant S, the viral S was more heavily glycosylated and occurred mostly in the closed prefusion conformation. We show that the stalk domain of S contains three hinges, giving the head unexpected orientational freedom. We propose that the hinges allow S to scan the host cell surface, shielded from antibodies by an extensive glycan coat. The structure of native S contributes to our understanding of SARS-CoV-2 infection and potentially to the development of safe vaccines.
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