Biological and Medicinal Chemistry

COVID-19: The CaMKII_Like System of S Protein Drives Membrane Fusion and Induces Syncytial Multinucleated Giant Cells

liu wenzhong Sichuan University of Science & Engineering


COVID-19 is a unique disease characterized by extensive pulmonary thrombosis and infected syncytial multinucleated giant cells, relating to extensive tissue damage. The SARS-CoV-2 S protein on the membrane of infected cells can initiate receptor-dependent syncytia formation. To study the membrane fusion on S protein, we adopted structural domain search methods to analyze the structural and non-structural proteins of the SARS-COV-2 virus in this study. The results showed that the surface glycoprotein (S) had conserved domains of CaMKII: CaMKII_AD, CaATP_NAI, DUF4440, EF-hand, Protein kinase, and SnoaL-like. Comparing to SARS-COV and MERS, only the CaATP_NAI of SARS-COV-2 is in the contact position of the viral membrane and cell membrane. We believed that when the EF-hand domain (“YEQYIKWPWYIWLGF”) of S protein bound to calcium ions, S2 protein had CaMKII protein activities. After the S protein fusion peptide was inserted into the infected cell membrane and fixed the S2 protein on the cell membrane, the CaMKII_AD prompted the S2 protein to form HR1-HR2 six-helix bundles. The HR1-HR2 hexamer had three CaATP_NAI domains (“APAICHDGKAHFPRE”) near the viral membrane (contact position), the CaATPase activated by magnesium ions, and released energy through ATP phosphorylation. The CaATPase drove the HR1-HR2 hexamer fold irreversibly toward the viral membrane. Then the CaATP_NAI and CaMKII_AD domains extended to the outside and combined the viral membrane and the cell membrane so that the contact position formed a thin barrel structure. The hydrated calcium ions are gathered in the barrel structure to create a calcium bridge. The release action of water in contact position caused the instability of the double membrane, triggering lipid mixing and fusion of the membrane. CaATPases disassembled the barrel structure, and HR1-HR2 hexamer is fell into the cytoplasm. The viral membrane fused with the cell membrane on a large scale. The cytoplasmic contents of the virus mixed with the cell. The S protein of the infected cell may bind to the ACE2 receptor of another cell (or also an infected cell) and then achieved membrane fusion through a similar principle, forming cell syncytia, includes syncytial multinucleated giant cells. The membrane fusion could disrupt the calcium homeostasis in human body, and increased the risk of coagulation and vascular calcification.


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