Abstract
Viruses are obligate intracellular parasites, and host cell entry is the first step in the viral life cycle. The SARS-CoV-2 (COVID-19) entry process into susceptible host tissue cells is complex requiring (1) attachment of the virus via the conserved spike (S) protein receptor-binding motif (RBM) to the host cell angiotensin-converting-enzyme 2 (ACE2) receptor, (2) S protein proteolytic processing, and (3) membrane fusion. Spike protein processing occurs at two cleavage sites, i.e., S1/S2 and S2′. Cleavage at the S1/S2 and S2′ sites ultimately gives rise to generation of competent fusion elements important in the merging of the host cell and viral membranes. Following cleavage, shedding of the S1 crown results in significant conformational changes and fusion peptide repositioning for target membrane insertion and fusion. Identification of specific protease involvement has been difficult due to the many cell types used and studied. However, it appears that S protein proteolytic cleavage is dependent on (1) furin and (2) serine protease transmembrane protease serine 2 proteases acting in tandem. Although at present not clear, increased SARS-CoV-2 S receptor-binding motif binding affinity and replication efficiency may in part account for observed differences in infectivity. Cleavage of the ACE2 receptor appears to be yet another layer of complexity in addition to forfeiture and/or alteration of ACE2 function which plays an important role in cardiovascular and immune function.
Highlights
Coronaviruses (CoVs) are enveloped, single-stranded RNA viruses that cause gastrointestinal, respiratory, and neurological symptoms in several mammalian species and birds [1]
Prior to the outbreak of the severe acute respiratory syndrome coronavirus (SARS-CoV) in Southern China in 2002-2003 which caused a fatal pneumonia in approximately 10% of those infected, CoVs in large part were considered harmless in humans [2, 3]
TMPRSS-2 and the metalloprotease have been shown to cleave the angiotensin-converting-enzyme 2 (ACE2) receptor close to its transmembrane domain [7, 92, 93]. is cleavage supposedly results in ACE2 receptor shedding and suggests that the transmembrane serine protease (TTSP) and other proteases can impact S protein driven entry by ways other than S protein priming/activation [93, 94]
Summary
Coronaviruses (CoVs) are enveloped, single-stranded RNA viruses that cause gastrointestinal, respiratory, and neurological symptoms in several mammalian species and birds [1]. Initial SARS-CoV-2 proteolytic processing in human cells has been associated with recognition of a polybasic (several arginine residues, i.e., -RRAR685↓-) furin site at the S1/S2 cleavage site [42] implicating involvement of multiple proteases affecting viral infectivity and host range. TMPRSS-2 processing of SARS-CoV S is principally at the cell membrane, whereas furin-mediated processing occurs at the cell surface and in the early endosome [35, 41, 56] It appears that redundancy is built into the CoV S protein with both furin and related proprotein convertase recognition of polybasic cleavage sites [56]. Class I fusion proteins adopt a well-defined coiled structure referred to as a “6-helix bundle” or 6HB
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