Abstract
The SARS-CoV-2 (SARS2) is the cause of the coronavirus disease 2019 (COVID-19) pandemic. One unique structural feature of the SARS2 spike protein is the presence of a furin-like cleavage site (FLC) which is associated with both viral pathogenesis and host tropism. Specifically, SARS2 spike protein binds to the host ACE-2 receptor which in-turn is cleaved by furin proteases at the FLC site, suggesting that SARS2 FLC structural variations may have an impact on viral infectivity. However, this has not yet been fully elucidated. This study designed and analyzed a COVID-19 genomic epidemiology network for December 2019 to July 2020, and subsequently generated and analyzed representative SARS2 spike protein models from significant node clusters within the network. To distinguish possible structural variations, a model quality assessment was performed before further protein model analyses and superimposition of the protein models, particularly in both the receptor-binding domain (RBD) and FLC. Mutant spike models were generated with the unique 681PRRA684 amino acid sequence found within the deleted FLC. We found 9 SARS2 FLC structural patterns that could potentially correspond to nine node clusters encompassing various countries found within the COVID-19 genomic epidemiology network. Similarly, we associated this with the rapid evolution of the SARS2 genome. Furthermore, we observed that either in the presence or absence of the unique 681PRRA684 amino acid sequence no structural changes occurred within the SARS2 RBD, which we believe would mean that the SARS2 FLC has no structural influence on SARS2 RBD and may explain why host tropism was maintained.
Highlights
Coronaviruses (CoV) are enveloped positive-stranded RNA viruses that have the largest genome among all known RNA viruses and, at present, there are seven known CoVs capable of infecting humans [1,2,3,4,5,6,7]
With regards to the homotrimeric spike protein, the SARS2 spike protein follows the same mechanism of viral entry used by SARS-CoV-1, wherein, the SARS2 spike protein binds to a functional receptor human angiotensin-converting enzyme 2 (ACE2) via the 6-residue (L455, F486, Q493, S494, N501, Y505) receptor-binding domain (RBD) [10, 14]
Considering that the SARS2 furin-like cleavage site (FLC) is crucial for viral pathogenesis and host tropism [17,18,19], which we believe would imply that the SARS2 FLC is a conserved structural feature [18], we postulate that the SARS2 FLC could be a common structural feature among the node clusters
Summary
Coronaviruses (CoV) are enveloped positive-stranded RNA viruses that have the largest genome among all known RNA viruses and, at present, there are seven known CoVs capable of infecting humans [1,2,3,4,5,6,7]. One notable structural feature of the SARS2 spike protein is the presence of a polybasic (furin-like) cleavage site (682RRAR685) which has been found to be disordered [15, 16] and, likewise, linked to effective furin cleavage that could help determine viral pathogenesis and host tropism [17,18,19]. Aside from the presence of the polybasic cleavage site (682RRAR685), SARS2 likewise has an inserted leading proline (P681), which is suggested to improve protease active site accessibility by furin proteases but other proteases as well [21]. This would mean that the inserted sequence unique for SARS2 is the 681PRRA684 sequence [18]
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