School of Computer Science and Engineering, Sichuan University of Science & Engineering, Zigong, 643002, China.
School of Life Science and Food Engineering, Yibin University, Yibin, 644000, China.
Immunol Res. 2021 Dec;69(6):496-519. doi: 10.1007/s12026-021-09224-1. Epub 2021 Aug 19.
The SARS-CoV-2 S protein on the membrane of infected cells can promote receptor-dependent syncytia formation, relating to extensive tissue damage and lymphocyte elimination. In this case, it is challenging to obtain neutralizing antibodies and prevent them through antibodies effectively. Considering that, in the current study, structural domain search methods are adopted to analyze the SARS-CoV-2 S protein to find the fusion mechanism. The results show that after the EF-hand domain of S protein bound to calcium ions, S2 protein had CaMKII protein activities. Besides, the CaMKII_AD domain of S2 changed S2 conformation, facilitating the formation of HR1-HR2 six-helix bundles. Apart from that, the Ca-ATPase of S2 pumped calcium ions from the virus cytoplasm to help membrane fusion, while motor structures of S drove the CaATP_NAI and CaMKII_AD domains to extend to the outside and combined the viral membrane and the cell membrane, thus forming a calcium bridge. Furthermore, the phospholipid-flipping-ATPase released water, triggering lipid mixing and fusion and generating fusion pores. Then, motor structures promoted fusion pore extension, followed by the cytoplasmic contents of the virus being discharged into the cell cytoplasm. After that, the membrane of the virus slid onto the cell membrane along the flowing membrane on the gap of the three CaATP_NAI. At last, the HR1-HR2 hexamer would fall into the cytoplasm or stay on the cell membrane. Therefore, the CaMKII_like system of S protein facilitated membrane fusion for further inducing syncytial multinucleated giant cells.
受感染细胞膜上的 SARS-CoV-2 S 蛋白可促进受体依赖性合胞体形成，与广泛的组织损伤和淋巴细胞消除有关。在这种情况下，很难获得中和抗体并通过抗体有效地预防它们。考虑到这一点，在目前的研究中，采用结构域搜索方法来分析 SARS-CoV-2 S 蛋白以寻找融合机制。结果表明，S 蛋白的 EF 手结构域与钙离子结合后，S2 蛋白具有 CaMKII 蛋白活性。此外，S2 的 CaMKII_AD 结构域改变了 S2 的构象，促进了 HR1-HR2 六螺旋束的形成。除此之外，S2 的 Ca-ATPase 将钙离子从病毒细胞质中泵出，有助于膜融合，而 S 的运动结构将 CaATP_NAI 和 CaMKII_AD 结构域驱动到外部，并将病毒膜和细胞膜结合起来，从而形成钙桥。此外，磷脂翻转-ATPase 释放水，引发脂质混合和融合并产生融合孔。然后，运动结构促进融合孔的延伸，随后病毒的细胞质内容物被排入细胞细胞质中。之后，病毒的膜沿着三个 CaATP_NAI 间隙中的流动膜滑到细胞膜上。最后，HR1-HR2 六聚体要么落入细胞质中，要么留在细胞膜上。因此，S 蛋白的 CaMKII 样系统促进了膜融合，以进一步诱导合胞体多核巨细胞的形成。
