Ca(2+)-dependent mechanism of membrane insertion and destabilization by the SARS-CoV-2 fusion peptide.
Ca(2+)-dependent mechanism of membrane insertion and destabilization by the SARS-CoV-2 fusion peptide.
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DOI：
10.1016/j.bpj.2021.02.023
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发表时间：
2021-03-16
影响因子：
3.4
通讯作者：
Weinstein H
中科院分区：
文献类型：
--
作者：
Khelashvili G;Plante A;Doktorova M;Weinstein H
严重急性呼吸综合征冠状病毒2型(SARS-CoV-2)病毒被ACE2受体识别后的细胞穿透及其病毒膜与细胞膜的融合是传染性的早期步骤。病毒的Spike蛋白的一个区域，被鉴定为“融合肽”(FP)，在其N端通过与Spike的受体结合域的相互作用而发生的特定切割而释放。研究表明，所需的钙离子与冠状病毒的FP结合可以增强穿透能力，但膜插入和失稳的机制尚不清楚。通过广泛的原子分子动力学模拟和轨迹分析，我们预测了钙离子与SARS-CoV-2-FP结合的优先位置，钙离子在介导肽-膜相互作用中的作用，钙离子结合SARS-CoV-2-FP的首选插入方式，以及随后对脂质双层的影响。在钙离子结合肽模型与脂膜相互作用的系统采样中，SARS-CoV-2-FP只以两种涉及不同结构域的方式穿透双层并破坏其组织。在一种方法中，插入来自肽中间区域的疏水残基F833/I834。在另一种更普遍的模式中，渗透涉及LLF基序的L822/F823残基，这在类CoV-2病毒中是保守的，是通过钙离子与D830/D839和E819/D820残基对结合实现的。FP穿透改变了双层特定区域的分子结构，在没有钙离子的情况下，SARS-CoV-2 FP的膜结合程度显著降低。这些发现为钙离子在介导SARS-CoV-2融合中的作用提供了新的机制见解，并提供了一个详细的结构平台，以帮助正在进行的合理设计化合物以抑制SARS-CoV-2细胞进入的努力。
Cell penetration after recognition of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus by the ACE2 receptor and the fusion of its viral envelope membrane with cellular membranes are the early steps of infectivity. A region of the Spike protein of the virus, identified as the “fusion peptide” (FP), is liberated at its N-terminal site by a specific cleavage occurring in concert with the interaction of the receptor-binding domain of the Spike. Studies have shown that penetration is enhanced by the required binding of Ca2+ ions to the FPs of coronaviruses, but the mechanisms of membrane insertion and destabilization remain unclear. We have predicted the preferred positions of Ca2+ binding to the SARS-CoV-2-FP, the role of Ca2+ ions in mediating peptide-membrane interactions, the preferred mode of insertion of the Ca2+-bound SARS-CoV-2-FP, and consequent effects on the lipid bilayer from extensive atomistic molecular dynamics simulations and trajectory analyses. In a systematic sampling of the interactions of the Ca2+-bound peptide models with lipid membranes, SARS-CoV-2-FP penetrated the bilayer and disrupted its organization only in two modes involving different structural domains. In one, the hydrophobic residues F833/I834 from the middle region of the peptide are inserted. In the other, more prevalent mode, the penetration involves residues L822/F823 from the LLF motif, which is conserved in CoV-2-like viruses, and is achieved by the binding of Ca2+ ions to the D830/D839 and E819/D820 residue pairs. FP penetration is shown to modify the molecular organization in specific areas of the bilayer, and the extent of membrane binding of the SARS-CoV-2 FP is significantly reduced in the absence of Ca2+ ions. These findings provide novel mechanistic insights regarding the role of Ca2+ in mediating SARS-CoV-2 fusion and provide a detailed structural platform to aid the ongoing efforts in rational design of compounds to inhibit SARS-CoV-2 cell entry.
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超越屏蔽：聚糖在SARS-COV-2尖峰蛋白中的作用。
影响因子：
18.2
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
通讯作者：
Amaro RE
影响因子：
64.8
作者：
Li W;Moore MJ;Vasilieva N;Sui J;Wong SK;Berne MA;Somasundaran M;Sullivan JL;Luzuriaga K;Greenough TC;Choe H;Farzan M
通讯作者：
Farzan M
DOI：
10.1038/nrmicro.2016.81
发表时间：
2016-08
期刊：
Nature reviews. Microbiology
影响因子：
--
作者：
de Wit E;van Doremalen N;Falzarano D;Munster VJ
通讯作者：
Munster VJ
影响因子：
56.9
作者：
Cai, Yongfei;Zhang, Jun;Chen, Bing
通讯作者：
Chen, Bing
影响因子：
168.9
作者：
Huang, Chaolin;Wang, Yeming;Cao, Bin
通讯作者：
Cao, Bin