Abstract
Coronavirus-cell entry programs involve virus-cell membrane fusions mediated by viral spike (S) proteins. Coronavirus S proteins acquire membrane fusion competence by receptor interactions, proteolysis, and acidification in endosomes. This review describes our current understanding of the S proteins, their interactions with and their responses to these entry triggers. We focus on receptors and proteases in prompting entry and highlight the type II transmembrane serine proteases (TTSPs) known to activate several virus fusion proteins. These and other proteases are essential cofactors permitting coronavirus infection, conceivably being in proximity to cell-surface receptors and thus poised to split entering spike proteins into the fragments that refold to mediate membrane fusion. The review concludes by noting how understanding of coronavirus entry informs antiviral therapies.
Highlights
Coronaviruses (CoVs) are enveloped RNA viruses causing respiratory and enteric diseases
CoV diversity is reflected in the variable S proteins, which have evolved into forms differing in their receptor interactions and their response to various environmental triggers of virus-cell membrane fusion
This review focuses on the S: receptor interactions and events leading to membrane fusion and successful cell entry
Summary
Coronaviruses (CoVs) are enveloped RNA viruses causing respiratory and enteric diseases. Models depicting the S-mediated membrane fusion event have extended from knowledge of S protein structures and functions In part, these models are deemed reasonable because the postfusion 6HB conformations in SARS and MHV S proteins are so strikingly similar to postfusion forms of influenza HA2, paramyxovirus F2, Ebolavirus GP2 and HIV gp41 [16]. Along with measured fusion activities of site-directed S mutants, suggest that the FPs are near or immediately N-terminal to the HR1 ([17,18]; see Figure 1 for proposed FP location) At this stage in which the FP is in the target cell membrane and the transmembrane (TM) span is in the virion membrane, the S proteins are considered to be in “fusion intermediate” conformations. The part of the S protein nearest to the virus membrane refolds onto a heptad repeat 1 (HR1) core to form the six-helix bundle (6-HB), which is the final postfusion configuration of the S2 protein
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