SARS-CoV-2 S glycoprotein (sf9, His)

The SARS-CoV-2 S glycoprotein plays a crucial role in infection by attaching the virion to the host cell membrane through interaction with the primary receptor, host ACE2. Upon cleavage of S2/S2', binding to the ACE2 receptor initiates either direct fusion at the cell membrane or internalization of the virus via endocytosis, leading to fusion of the virion membrane with the host endosomal membrane. Additionally, the glycoprotein may utilize NRP1/NRP2 and integrin as alternative entry receptors, possibly explaining the virus's tropism in human olfactory epithelial cells. The stalk domain of S exhibits three hinges, providing unexpected orientational freedom to the head. Acting as a class I viral fusion protein, the glycoprotein undergoes an extensive and irreversible conformational change during virus entry, triggered by host TMPRSS2 or CSTL, leading to fusion of the viral envelope with the cellular cytoplasmic membrane and release of viral genomic RNA into the host cell cytoplasm. The glycoprotein exhibits at least three conformational states: pre-fusion native, pre-hairpin intermediate, and post-fusion hairpin, with the coiled coil regions adopting a trimer-of-hairpins structure during fusion, facilitating the apposition and subsequent fusion of viral and target cell membranes.