ACERT, Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, United States.
ACERT, Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, United States.
J Mol Biol. 2021 May 14;433(10):166946. doi: 10.1016/j.jmb.2021.166946. Epub 2021 Mar 18.
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 Ca, but that of SARS-2 shows a greater response to the presence of Ca. Both FPs bind two Ca ions as does SARS-1 FP, but the two Ca binding sites of SARS-2 exhibit greater cooperativity. This Ca dependence by the SARS-2 FP is very ion-specific. These results show that Ca 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 Ca channel.
冠状病毒是主要的传染病威胁，包括人畜共患病源性人类病原体 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刺突（S）蛋白介导的。在我们之前的 ESR 研究中，包括 SARS-1 和 MERS 的 S 在内的各种病毒糖蛋白的融合肽（FP）的局部膜有序化效应一直存在。我们之前确定，S2'切割位点下游的序列是真正的 SARS-1 FP。在这项研究中，我们使用序列比对来确定 SARS-2 FP，并研究了其膜有序化效应。尽管只有三个残基的差异，SARS-2 FP 诱导的膜有序化作用甚至比 SARS-1 FP 更强，可能是由于其更大的疏水性。这可能是 SARS-2 能够更好地感染宿主细胞的原因之一。此外，SARS-2 的膜结合焓更大。SARS-2 和 SARS-1 FP 的膜有序化都依赖于 Ca，但 SARS-2 的膜有序化对 Ca 的存在反应更大。两种 FP 都像 SARS-1 FP 一样结合两个 Ca 离子，但 SARS-2 的两个 Ca 结合位点表现出更大的协同作用。SARS-2 FP 的这种 Ca 依赖性非常特异。这些结果表明，Ca 是与 SARS-2 FP 相互作用的重要调节剂，因此在 SARS-2 病毒进入中起着重要作用。这可能导致针对 FP-钙相互作用的治疗解决方案，或者阻止钙通道。
