SARS-CoV-2 Fusion Peptide has a Greater Membrane Perturbating Effect than SARS-CoV with Highly Specific Dependence on Ca(2).
SARS-CoV-2 Fusion Peptide has a Greater Membrane Perturbating Effect than SARS-CoV with Highly Specific Dependence on Ca(2).
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DOI：
10.1016/j.jmb.2021.166946
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发表时间：
2021-05-14
影响因子：
5.6
通讯作者：
Freed JH
中科院分区：
文献类型：
--
作者：
Lai AL;Freed JH
冠状病毒是一种主要的传染病威胁，包括人畜共患病的人类病原体SARS-CoV-2、SARS-CoV和MERS-CoV(SARS-2、SARS-1和MERS)。冠状病毒进入宿主细胞是由尖峰蛋白(S)介导的。在我们以往的ESR研究中，一致地观察到包括SARS-1和MERS的S在内的各种病毒糖蛋白的融合肽(FP)的局部膜有序效应。我们先前确定S2‘裂解位点下游的序列是真正的SARS-1 FP。在本研究中，我们用序列比对的方法对SARS-2 FP进行了鉴定，并研究了它的膜有序效应。虽然只有三个残基的差异，但SARS-2 FP比SARS-1 FP诱导更大的膜有序性，可能是由于其更大的疏水性。这可能是SARS-2更能感染宿主细胞的一个原因。此外，SARS-2的膜结合热较大。SARS-2和SARS-1 FFP的膜有序性都依赖于钙离子，但SARS-2的膜有序性对存在的钙离子有更大的反应。与SARS-1FP一样，这两个FP都结合了两个钙离子，但SARS-2的两个钙结合部位表现出更大的协同性。SARS-2FP对钙离子的依赖是离子特异性的。这些结果表明，Ca~(2+)是与SARS-2 FP相互作用的重要调节因子，因此在SARS-2病毒进入过程中起着重要作用。这可能导致针对FP-钙相互作用或阻断钙通道的治疗方案。
Coronaviruses are a major infectious disease threat, and include the zoonotic-origin human pathogens SARS-CoV-2, SARS-CoV, and MERS-CoV (SARS-2, SARS-1, and MERS). Entry of coronaviruses into host cells is mediated by the spike (S) protein. In our previous ESR studies, the local membrane ordering effect of the fusion peptide (FP) of various viral glycoproteins including the S of SARS-1 and MERS has been consistently observed. We previously determined that the sequence immediately downstream from the S2′ cleavage site is the bona fide SARS-1 FP. In this study, we used sequence alignment to identify the SARS-2 FP, and studied its membrane ordering effect. Although there are only three residue differences, SARS-2 FP induces even greater membrane ordering than SARS-1 FP, possibly due to its greater hydrophobicity. This may be a reason that SARS-2 is better able to infect host cells. In addition, the membrane binding enthalpy for SARS-2 is greater. Both the membrane ordering of SARS-2 and SARS-1 FPs are dependent on Ca2+, but that of SARS-2 shows a greater response to the presence of Ca2+. Both FPs bind two Ca2+ ions as does SARS-1 FP, but the two Ca2+ binding sites of SARS-2 exhibit greater cooperativity. This Ca2+ dependence by the SARS-2 FP is very ion-specific. These results show that Ca2+ is an important regulator that interacts with the SARS-2 FP and thus plays a significant role in SARS-2 viral entry. This could lead to therapeutic solutions that either target the FP-calcium interaction or block the Ca2+ channel.
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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：
3.4
作者：
GE, MT;BUDIL, DE;FREED, JH
通讯作者：
FREED, JH
影响因子：
3.4
作者：
Khelashvili G;Plante A;Doktorova M;Weinstein H
通讯作者：
Weinstein H
影响因子：
3.4
作者：
Georgieva, Elka R.;Xiao, Shifeng;Eliezer, David
通讯作者：
Eliezer, David
影响因子：
16.8
作者：
Bhalla, A;Chicka, MC;Chapman, ER
通讯作者：
Chapman, ER