Furin cleavage sites naturally occur in coronaviruses

Wu, Yiran; Zhao, Suwen

doi:10.1016/j.scr.2020.102115

Cited by 88 publications

(67 citation statements)

References 43 publications

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“…Most of the studies focused on the rapid spread of the SARS-CoV-2 due to its S1-RBD diversity to binds with the human ACE2 receptor and the presence of a specific furin cleavage site (FCS) 4,[29][30][31][32][33][34][35] . However, the furin cleavage site is not only present in SARS-CoV-2, but also present in MERS-CoV, HKU1, and HCoV-OC43 4,32,34,36 , and the SARS-CoV-2 without FCS also can infect target cells efficiently in the presence of trypsin or human airway trypsin-like protease (HAT) 37 . Further, the S1-RBD for the human ACE2 is also present in SARS-CoV-1; however, SARS-CoV-2 has improved binding to ACE2 receptor than SARS-CoV-1 38,39 .…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 gained the unique spike protein S1-N-Terminal Domain from the promising pangolins mixing vessel: A novel clue for the pandemic outbreak

Desingu¹,

Nagarajan²

2021

Preprint

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The clue behind the emergence of SARS-CoV-2 remains a huge debate among the virologist, policymakers, and general public, while the gain-of-function hypothesizes mostly focused on the furin cleavage site and receptor-binding domain (RBD) of the spike (S) protein. Here, we report that the SARS-CoV-2 gained the novel human-specific spike protein S1-N-Terminal Domain (S1-NTD) (Type-I) which is present only in SARS-CoV-2. Interestingly, SARS-CoV-2-rB-CoV showed unique bat-specific Type-II and Type-III-S1-NTD, which is not present in other SARS coronaviruses, including SARS-CoV-2 variants. We also found widespread recombination and selection pressure in the S1-NTDs of the bat viruses. In addition, the Pangolin/GX/2018 and Pangolin/Guangdong/2019 lineages showed close identity (73-79%) with the Type-I-S1-NTD and Type-II-S1-NTD respectively. This justifies that the pangolin is the mixing vessel (intermediate host) to exchange the bat-specific Type-II-S1-NTD in the SARS-CoV-2-rB-CoV into Type-I-like-S1-NTD in pangolin through recombination. Furthermore, the pangolin virus with Type-I-like-S1-NTD jumped into humans which then transformed into SARS-CoV-2 with Type-I-S1-NTD by host selection pressure. Remarkably, we characterized the bat/Cambodia virus as a recombinant SARS-CoV-2/RatG13 with the S1-NTD of bat-SARS-like viruses; while only bat/RatG13 with Type-I-S1-NTD established a huge pandemic outbreak. Additionally, recent SARS-CoV-2 S1-NTD specific neutralizing antibody-based studies support the role of S1-NTD in the post-attachment of the virus; fusion, virus dissemination, and cell-cell fusion thereby prevent the onset of infection; and most of the SARS-CoV-2 variants with increased transmissibility were linked to the S1-NTD mutations. Collectively, our results strongly suggest that the gain of Type-I-S1-NTD in the SARS-CoV-2 is the reason for the pandemic outbreak.

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Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 gained the unique spike protein S1-N-Terminal Domain from the promising pangolins mixing vessel: A novel clue for the pandemic outbreak

Desingu¹,

Nagarajan²

2021

Preprint

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“…Although there may be minuscule variations in the LCRs length and/or amino acid composition, the segments described in this work fall well into the low complexity category, suggesting that their biased composition may confer adaptive advantages to the Delta variant. For instance, the polybasic Spike LCR-3, which includes several arginines in its N-terminus, is a highly conserved sequence located precisely in the furin cleavage site at spike S1/S2, which is essential for membrane fusion, and plays a key role in viral infection and transmission 43,44 .…”

Section: Discussionmentioning

confidence: 99%

Two Short Low Complexity Regions (LCRs) are Hallmark Sequences of the Delta SARS-CoV- 2 Variant Spike Protein

Becerra

Muñoz-Velasco

Aguilar-Cámara

et al. 2021

Preprint

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Low complexity regions (LCRs) are protein sequences formed by a set of compositionally biased residues. LCRs are extremely abundant in cellular proteins and have also been reported in viruses, where they may partake in evasion of the host immune system. Here we report four novel extremely conserved LCRs in the spike proteins of several SARS-CoV-2 variants. With the exception of Iota, where it is absent, the Spike LCR-1 is present in the signal peptide of 80.57% of the Delta variant, and in other variants of concern and interest. The Spike LCR-2 is highly prevalent (79.87%) in Iota. Two distinctive LCRs are present in the Delta spike protein. The Delta Spike LCR-3 is present in 99.19% of the analyzed sequences, and the Delta Spike LCR-4 in 98.3% of the same set of proteins. These two LCRs are present in the furin cleavage site and HR1 domain, respectively, and may be considered hallmark traits of the Delta variant. The presence of two medically-important point mutations, P681R and D950N, in these LCRs, combined with the extraordinary conservation of these regions, suggests that they may be a trait associated with the rapid spread of the highly contagious Delta lineage.

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“…Additionally, its insertion causes a peculiar split of one of the codons, serine (TCA) when compared with the close relatives MP789 and RaTG13 (Segreto and Deigin 2020). The recent acquisition of the FCS by SARS-CoV-2 via a natural insert was proposed by Wu and Zhao (2021) on the basis of the existence of FCS in other, more distant Betacoronaviruses with different loop positions to SARS-CoV-2 and the existence of a partial natural insert in the same region in RmYN02 (Zhou et al 2020a). The reliability of the conclusions of Zhou et al (2020a) has been questioned by Deigin and Segreto (2020), who particularly challenge the claim that RmYN02 has an insertion around the site of the FCS insertion in SARS-CoV-2 and instead point to a two amino acid deletion in RmYN02 at that locus.…”

Section: Furin Cleavage Sitementioning

confidence: 99%