The polybasic insert, the RBD of the SARS-CoV-2 spike protein, and the feline coronavirus - evolved or yet to evolve

Recent research on the SARS-CoV-2 pandemic has exploded around the furin-cleavable polybasic insert PRRAR↓S, found within the spike protein. The insert and the receptor-binding domain, (RBD), are vital clues in the Sherlock Holmes-like investigation into the origin of the virus and in its zoonotic c...

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Main Authors: Budhraja, Anshul, Pandey, Sakshi, Kannan, Srinivasaraghavan, Verma, Chandra Shekhar, Venkatraman, Prasanna
Other Authors: School of Biological Sciences
Format: Article
Language:English
Published: 2021
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Online Access:https://hdl.handle.net/10356/146866
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spelling sg-ntu-dr.10356-1468662023-02-28T16:58:54Z The polybasic insert, the RBD of the SARS-CoV-2 spike protein, and the feline coronavirus - evolved or yet to evolve Budhraja, Anshul Pandey, Sakshi Kannan, Srinivasaraghavan Verma, Chandra Shekhar Venkatraman, Prasanna School of Biological Sciences Bioinformatics Institute, A*STAR Science::Biological sciences Spike Protein Furin Recent research on the SARS-CoV-2 pandemic has exploded around the furin-cleavable polybasic insert PRRAR↓S, found within the spike protein. The insert and the receptor-binding domain, (RBD), are vital clues in the Sherlock Holmes-like investigation into the origin of the virus and in its zoonotic crossover. Based on comparative analysis of the whole genome and the sequence features of the insert and the RBD domain, the bat and the pangolin have been proposed as very likely intermediary hosts. In this study, using the various databases, in-house developed tools, sequence comparisons, structure-guided docking, and molecular dynamics simulations, we cautiously present a fresh, theoretical perspective on the SARS-CoV-2 virus activation and its intermediary host. They are a) the SARS-CoV-2 has not yet acquired a fully optimal furin binding site or this seemingly less optimal sequence, PRRARS, has been selected for survival; b) in structural models of furin complexed with peptides, PRRAR↓S binds less well and with distinct differences as compared to the all basic RRKRR↓S; c) these differences may be exploited for the design of virus-specific inhibitors; d) the novel polybasic insert of SARS-CoV-2 may be promiscuous enough to be cleaved by multiple enzymes of the human airway epithelium and tissues which may explain its unexpected broad tropism; e) the RBD domain of the feline coronavirus spike protein carries residues that are responsible for high-affinity binding of the SARS-CoV-2 to the ACE 2 receptor; f) en route zoonotic transfer, the virus may have passed through the domestic cat whose very human-like ACE2 receptor and furin may have played some role in optimizing the traits required for zoonotic transfer. Agency for Science, Technology and Research (A*STAR) National Supercomputing Centre (NSCC) Singapore Published version We thank Mahalakshmi Harish for careful reading of the manuscript and input. We thank all authors who would have contributed to the field but could not be cited here. We thank Venkatraman G. Mangasuli for initiating PV into this project. SK and CSV would like to thank Agency for Science Technology and Research (A*STAR), Singapore and National Super Computing Center (NSCC), Singapore for the support. 2021-03-12T04:28:50Z 2021-03-12T04:28:50Z 2021 Journal Article Budhraja, A., Pandey, S., Kannan, S., Verma, C. S. & Venkatraman, P. (2021). The polybasic insert, the RBD of the SARS-CoV-2 spike protein, and the feline coronavirus - evolved or yet to evolve. Biochemistry and Biophysics Reports, 25. https://dx.doi.org/10.1016/j.bbrep.2021.100907 2405-5808 0000-0003-1254-0023 https://hdl.handle.net/10356/146866 10.1016/j.bbrep.2021.100907 33521335 2-s2.0-85100054151 25 en Biochemistry and Biophysics Reports © 2021 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Science::Biological sciences
Spike Protein
Furin
spellingShingle Science::Biological sciences
Spike Protein
Furin
Budhraja, Anshul
Pandey, Sakshi
Kannan, Srinivasaraghavan
Verma, Chandra Shekhar
Venkatraman, Prasanna
The polybasic insert, the RBD of the SARS-CoV-2 spike protein, and the feline coronavirus - evolved or yet to evolve
description Recent research on the SARS-CoV-2 pandemic has exploded around the furin-cleavable polybasic insert PRRAR↓S, found within the spike protein. The insert and the receptor-binding domain, (RBD), are vital clues in the Sherlock Holmes-like investigation into the origin of the virus and in its zoonotic crossover. Based on comparative analysis of the whole genome and the sequence features of the insert and the RBD domain, the bat and the pangolin have been proposed as very likely intermediary hosts. In this study, using the various databases, in-house developed tools, sequence comparisons, structure-guided docking, and molecular dynamics simulations, we cautiously present a fresh, theoretical perspective on the SARS-CoV-2 virus activation and its intermediary host. They are a) the SARS-CoV-2 has not yet acquired a fully optimal furin binding site or this seemingly less optimal sequence, PRRARS, has been selected for survival; b) in structural models of furin complexed with peptides, PRRAR↓S binds less well and with distinct differences as compared to the all basic RRKRR↓S; c) these differences may be exploited for the design of virus-specific inhibitors; d) the novel polybasic insert of SARS-CoV-2 may be promiscuous enough to be cleaved by multiple enzymes of the human airway epithelium and tissues which may explain its unexpected broad tropism; e) the RBD domain of the feline coronavirus spike protein carries residues that are responsible for high-affinity binding of the SARS-CoV-2 to the ACE 2 receptor; f) en route zoonotic transfer, the virus may have passed through the domestic cat whose very human-like ACE2 receptor and furin may have played some role in optimizing the traits required for zoonotic transfer.
author2 School of Biological Sciences
author_facet School of Biological Sciences
Budhraja, Anshul
Pandey, Sakshi
Kannan, Srinivasaraghavan
Verma, Chandra Shekhar
Venkatraman, Prasanna
format Article
author Budhraja, Anshul
Pandey, Sakshi
Kannan, Srinivasaraghavan
Verma, Chandra Shekhar
Venkatraman, Prasanna
author_sort Budhraja, Anshul
title The polybasic insert, the RBD of the SARS-CoV-2 spike protein, and the feline coronavirus - evolved or yet to evolve
title_short The polybasic insert, the RBD of the SARS-CoV-2 spike protein, and the feline coronavirus - evolved or yet to evolve
title_full The polybasic insert, the RBD of the SARS-CoV-2 spike protein, and the feline coronavirus - evolved or yet to evolve
title_fullStr The polybasic insert, the RBD of the SARS-CoV-2 spike protein, and the feline coronavirus - evolved or yet to evolve
title_full_unstemmed The polybasic insert, the RBD of the SARS-CoV-2 spike protein, and the feline coronavirus - evolved or yet to evolve
title_sort polybasic insert, the rbd of the sars-cov-2 spike protein, and the feline coronavirus - evolved or yet to evolve
publishDate 2021
url https://hdl.handle.net/10356/146866
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