Structural dynamics in the evolution of SARS-CoV-2 spike glycoprotein.
Structural dynamics in the evolution of SARS-CoV-2 spike glycoprotein.
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DOI：
10.1038/s41467-023-36745-0
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发表时间：
2023-03-14
影响因子：
16.6
通讯作者：
Politis, Argyris
中科院分区：
文献类型：
--
作者：
Calvaresi, Valeria;Wrobel, Antoni G.;Toporowska, Joanna;Hammerschmid, Dietmar;Doores, Katie J.;Bradshaw, Richard T.;Parsons, Ricardo B.;Benton, Donald J.;Roustan, Chloe;Reading, Eamonn;Malim, Michael H.;Gamblin, Steve J.;Politis, Argyris
SARS-CoV-2刺突糖蛋白介导受体结合和随后的膜融合。它存在于一系列构象中，包括不能结合ACE 2受体的闭合状态，以及这样做但显示更多暴露的抗原表面的开放状态。关注变体（VOC）的尖峰获得与增加的毒力和免疫逃避相关的氨基酸变化。在这里，使用HDX-MS，我们确定了尖峰动力学的变化，我们与从封闭到开放构象的转变，ACE 2结合，以及VOC中的特定突变相关。我们发现，RBD相关的子域在穗开放中发挥作用，而NTD作为热点的VOC穗驱动免疫逃避的构象分歧。α、β和δ尖峰主要呈现开放构象，并且ACE 2结合增加其核心螺旋的动力学，引发尖峰融合。相反，omicron刺突中的取代导致主要的闭合构象，推测使其能够逃避抗体。同时，其核心螺旋显示出即使在没有ACE 2的情况下也被预先引发融合的特征。这些数据为SARS-CoV-2的进化和omicron变体的出现提供了信息。在本文中，作者使用氢-氘交换质谱来描述SARS-CoV-2刺突糖蛋白从最初的武汉分离株的出现到最近的omicron变体如何演变其结构动力学特征和受体结合能力。报告的研究结果揭示了SARS-CoV-2在人群中的进化以及新变体出现的机制。
SARS-CoV-2 spike glycoprotein mediates receptor binding and subsequent membrane fusion. It exists in a range of conformations, including a closed state unable to bind the ACE2 receptor, and an open state that does so but displays more exposed antigenic surface. Spikes of variants of concern (VOCs) acquired amino acid changes linked to increased virulence and immune evasion. Here, using HDX-MS, we identified changes in spike dynamics that we associate with the transition from closed to open conformations, to ACE2 binding, and to specific mutations in VOCs. We show that the RBD-associated subdomain plays a role in spike opening, whereas the NTD acts as a hotspot of conformational divergence of VOC spikes driving immune evasion. Alpha, beta and delta spikes assume predominantly open conformations and ACE2 binding increases the dynamics of their core helices, priming spikes for fusion. Conversely, substitutions in omicron spike lead to predominantly closed conformations, presumably enabling it to escape antibodies. At the same time, its core helices show characteristics of being pre-primed for fusion even in the absence of ACE2. These data inform on SARS-CoV-2 evolution and omicron variant emergence. In this paper, the authors use hydrogen-deuterium exchange mass spectrometry to describe how the SARS-CoV-2 spike glycoprotein has evolved its structural dynamics features and receptor binding capability from the emergence of the original Wuhan isolate to the recent omicron variant. The findings reported shed light on the evolution of SARS-CoV-2 in the human population and the mechanisms of emergence of new variants.
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影响因子：
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