Beyond Shielding: The Roles of Glycans in the SARS-CoV-2 Spike Protein.
Beyond Shielding: The Roles of Glycans in the SARS-CoV-2 Spike Protein.
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超越屏蔽：聚糖在SARS-COV-2尖峰蛋白中的作用。
DOI：
10.1021/acscentsci.0c01056
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发表时间：
2020-10-28
影响因子：
18.2
通讯作者：
Amaro RE
中科院分区：
文献类型：
--
作者：
Casalino L;Gaieb Z;Goldsmith JA;Hjorth CK;Dommer AC;Harbison AM;Fogarty CA;Barros EP;Taylor BC;McLellan JS;Fadda E;Amaro RE
由严重急性呼吸系统综合征冠状病毒2型（SARS-CoV-2）引起的COVID-19大流行至今已导致全球超过28，000，000例感染和900，000例死亡。抗体开发工作主要围绕广泛糖基化的SARS-CoV-2刺突（S）蛋白，该蛋白通过与血管紧张素转换酶2（ACE 2）结合介导宿主细胞进入。与许多其他病毒融合蛋白类似，SARS-CoV-2刺突利用聚糖屏蔽来阻碍宿主免疫反应。在这里，我们建立了糖基化SARS-CoV-2 S蛋白的全长模型，包括开放和闭合状态，增加了可用的结构和生物学数据。多微秒长，全原子分子动力学模拟被用来提供一个原子的角度聚糖的作用和蛋白质的结构和动力学。我们揭示了N-聚糖在N165和N234位点调节刺突受体结合结构域（RBD）构象动力学的重要结构作用，该结构域负责ACE 2识别。这一发现得到了生物层干涉实验的证实，该实验表明，通过N165 A和N234 A突变缺失这些聚糖显著降低了与ACE 2的结合，这是RBD构象向“向下”状态转变的结果。此外，端到端的可及性分析概述了SARS-CoV-2 S蛋白聚糖盾的脆弱性的完整概述，这可能会被利用在针对这种分子机器的治疗努力。总的来说，这项工作提出了迄今未见的功能和结构的见解SARS-CoV-2 S蛋白及其聚糖外壳，提供了一种策略，以控制构象可塑性的RBD，可以利用疫苗的开发。聚糖盾是一种糖屏障，可以帮助病毒SARS-CoV-2避开免疫系统。除了屏蔽作用外，还发现刺突的两个聚糖可以引发病毒感染。
The ongoing COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in more than 28,000,000 infections and 900,000 deaths worldwide to date. Antibody development efforts mainly revolve around the extensively glycosylated SARS-CoV-2 spike (S) protein, which mediates host cell entry by binding to the angiotensin-converting enzyme 2 (ACE2). Similar to many other viral fusion proteins, the SARS-CoV-2 spike utilizes a glycan shield to thwart the host immune response. Here, we built a full-length model of the glycosylated SARS-CoV-2 S protein, both in the open and closed states, augmenting the available structural and biological data. Multiple microsecond-long, all-atom molecular dynamics simulations were used to provide an atomistic perspective on the roles of glycans and on the protein structure and dynamics. We reveal an essential structural role of N-glycans at sites N165 and N234 in modulating the conformational dynamics of the spike’s receptor binding domain (RBD), which is responsible for ACE2 recognition. This finding is corroborated by biolayer interferometry experiments, which show that deletion of these glycans through N165A and N234A mutations significantly reduces binding to ACE2 as a result of the RBD conformational shift toward the “down” state. Additionally, end-to-end accessibility analyses outline a complete overview of the vulnerabilities of the glycan shield of the SARS-CoV-2 S protein, which may be exploited in the therapeutic efforts targeting this molecular machine. Overall, this work presents hitherto unseen functional and structural insights into the SARS-CoV-2 S protein and its glycan coat, providing a strategy to control the conformational plasticity of the RBD that could be harnessed for vaccine development. The glycan shield is a sugary barrier that helps the viral SARS-CoV-2 spikes to evade the immune system. Beyond shielding, two of the spike’s glycans are discovered to prime the virus for infection.
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