Author Correction: SARS-CoV-2 and bat RaTG13 spike glycoprotein structures inform on virus evolution and furin-cleavage effects.
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ABSTRACT:
SUBMITTER: Wrobel AG
PROVIDER: S-EPMC7448700 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:SARS-CoV-2 is thought to have emerged from bats, possibly via a secondary host. Here, we investigate the relationship of spike (S) glycoprotein from SARS-CoV-2 with the S protein of a closely related bat virus, RaTG13. We determined cryo-EM structures for RaTG13 S and for both furin-cleaved and uncleaved SARS-CoV-2 S; we compared these with recently reported structures for uncleaved SARS-CoV-2 S. We also biochemically characterized their relative stabilities and affinities for the SARS-CoV-2 receptor ACE2. Although the overall structures of human and bat virus S proteins are similar, there are key differences in their properties, including a more stable precleavage form of human S and about 1,000-fold tighter binding of SARS-CoV-2 to human receptor. These observations suggest that cleavage at the furin-cleavage site decreases the overall stability of SARS-CoV-2 S and facilitates the adoption of the open conformation that is required for S to bind to the ACE2 receptor.
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Project description:The furin cleavage site in the spike glycoprotein of the SARS-CoV-2 coronavirus is considered important for the virus to enter the host cells. By analyzing 45828 SARS-CoV-2 genome sequences, we identified 103 strains of SARS-CoV-2 with various DNA mutations including 18 unique non-synonymous point mutations, one deletion, and six gains of premature stop codon that may affect the furin cleavage site. Our results revealed that the furin cleavage site might not be required for SARS-CoV-2 to enter human cells in vivo. The identified mutants may represent a new subgroup of SARS-CoV-2 coronavirus with reduced tropism and transmissibility as potential live-attenuated vaccine candidates.
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Project description:In recognizing the host cellular receptor and mediating fusion of virus and cell membranes, the spike (S) glycoprotein of coronaviruses is the most critical viral protein for cross-species transmission and infection. Here we determined the cryo-EM structures of the spikes from bat (RaTG13) and pangolin (PCoV_GX) coronaviruses, which are closely related to SARS-CoV-2. All three receptor-binding domains (RBDs) of these two spike trimers are in the "down" conformation, indicating they are more prone to adopt the receptor-binding inactive state. However, we found that the PCoV_GX, but not the RaTG13, spike is comparable to the SARS-CoV-2 spike in binding the human ACE2 receptor and supporting pseudovirus cell entry. We further identified critical residues in the RBD underlying different activities of the RaTG13 and PCoV_GX/SARS-CoV-2 spikes. These results collectively indicate that tight RBD-ACE2 binding and efficient RBD conformational sampling are required for the evolution of SARS-CoV-2 to gain highly efficient infection.
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Project description:The fusogenic potential of Class I viral envelope glycoproteins is activated by proteloytic cleavage of the precursor glycoprotein to generate the mature receptor-binding and transmembrane fusion subunits. Although the coronavirus (CoV) S glycoproteins share membership in this class of envelope glycoproteins, cleavage to generate the respective S1 and S2 subunits appears absent in a subset of CoV species, including that responsible for the severe acute respiratory syndrome (SARS). To determine whether proteolytic cleavage of the S glycoprotein might be important for the newly emerged SARS-CoV, we introduced a furin recognition site at single basic residues within the putative S1-S2 junctional region. We show that furin cleavage at the modified R667 position generates discrete S1 and S2 subunits and potentiates membrane fusion activity. This effect on the cell-cell fusion activity by the S glycoprotein is not, however, reflected in the infectivity of pseudotyped lentiviruses bearing the cleaved glycoprotein. The lack of effect of furin cleavage on virion infectivity mirrors that observed in the normally cleaved S glycoprotein of the murine coronavirus and highlights an additional level of complexity in coronavirus entry.
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Project description:Bat coronavirus RaTG13 Raw sequence reads
| PRJNA606165 | ENA
Project description:The furin cleavage site (FCS) in SARS-CoV-2 is unique within the Severe acute respiratory syndrome-related coronavirus (SrC) species. We re-assessed diverse SrC from European horseshoe bats and analyzed the spike-encoding genomic region harboring the FCS in SARS-CoV-2. We reveal molecular features in SrC such as purine richness and RNA secondary structures that resemble those required for FCS acquisition in avian influenza viruses. We discuss the potential acquisition of FCS through molecular mechanisms such as nucleotide substitution, insertion, or recombination, and show that a single nucleotide exchange in two European bat-associated SrC may suffice to enable furin cleavage. Furthermore, we show that FCS occurrence is variable in bat- and rodent-borne counterparts of human coronaviruses. Our results suggest that furin cleavage sites can be acquired in SrC via conserved molecular mechanisms known in other reservoir-bound RNA viruses and thus support a natural origin of SARS-CoV-2.
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Project description:Bats and rodents comprise two of the world's largest orders of mammals and the order Chiroptera (bats) has been implicated as a major reservoir of coronaviruses in nature and a source of zoonotic transfer to humans. However, the order Rodentia (rodents) also harbors coronaviruses, with two human coronaviruses (HCoV-OC43 and HCoV-HKU1) considered to have rodent origins. The coronavirus spike protein mediates viral entry and is a major determinant of viral tropism; importantly, the spike protein is activated by host cell proteases at two distinct sites, designated as S1/S2 and S2'. SARS-CoV-2, which is considered to be of bat origin, contains a cleavage site for the protease furin at S1/S2, absent from the rest of the currently known betacoronavirus lineage 2b coronaviruses (Sarbecoviruses). This cleavage site is thought to be critical to its replication and pathogenesis, with a notable link to virus transmission. Here, we examine the spike protein across coronaviruses identified in both bat and rodent species and address the role of furin as an activating protease. Utilizing two publicly available furin prediction algorithms (ProP and PiTou) and based on spike sequences reported in GenBank, we show that the S1/S2 furin cleavage site is typically not present in bat virus spike proteins but is common in rodent-associated sequences, and suggest this may have implications for zoonotic transfer. We provide a phylogenetic history of the Embecoviruses (betacoronavirus lineage 2a), including context for the use of furin as an activating protease for the viral spike protein. From a One Health perspective, continued rodent surveillance should be an important consideration in uncovering novel circulating coronaviruses.
| S-EPMC8216856 | biostudies-literature
Project description:In 2019, a new coronavirus (2019-nCoV) infecting Humans has emerged in Wuhan, China. Its genome has been sequenced and the genomic information promptly released. Despite a high similarity with the genome sequence of SARS-CoV and SARS-like CoVs, we identified a peculiar furin-like cleavage site in the Spike protein of the 2019-nCoV, lacking in the other SARS-like CoVs. In this article, we discuss the possible functional consequences of this cleavage site in the viral cycle, pathogenicity and its potential implication in the development of antivirals.
| S-EPMC7114094 | biostudies-literature
Project description:Compared with other SARS-related coronaviruses (SARSr-CoVs), SARS-CoV-2 possesses a unique furin cleavage site (FCS) in its spike. This has stimulated discussion pertaining to the origin of SARS-CoV-2 because the FCS has been observed to be under strong selective pressure in humans and confers the enhanced ability to infect some cell types and induce cell-cell fusion. Furthermore, scientists have demonstrated interest in studying novel cleavage sites by introducing them into SARSr-CoVs. We review what is known about the SARS-CoV-2 FCS in the context of its pathogenesis, origin, and how future wildlife coronavirus sampling may alter the interpretation of existing data.
| S-EPMC8689951 | biostudies-literature
Project description: Not available
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