Cargando…

SARS-CoV-2 S Mutations: A Lesson from the Viral World to Understand How Human Furin Works

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the etiological agent responsible for the worldwide pandemic and has now claimed millions of lives. The virus combines several unusual characteristics and an extraordinary ability to spread among humans. In particular, the dependence of...

Descripción completa

Detalles Bibliográficos
Autores principales: Cassari, Leonardo, Pavan, Angela, Zoia, Giulia, Chinellato, Monica, Zeni, Elena, Grinzato, Alessandro, Rothenberger, Sylvia, Cendron, Laura, Dettin, Monica, Pasquato, Antonella
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10003014/
https://www.ncbi.nlm.nih.gov/pubmed/36902222
http://dx.doi.org/10.3390/ijms24054791
_version_ 1784904508897230848
author Cassari, Leonardo
Pavan, Angela
Zoia, Giulia
Chinellato, Monica
Zeni, Elena
Grinzato, Alessandro
Rothenberger, Sylvia
Cendron, Laura
Dettin, Monica
Pasquato, Antonella
author_facet Cassari, Leonardo
Pavan, Angela
Zoia, Giulia
Chinellato, Monica
Zeni, Elena
Grinzato, Alessandro
Rothenberger, Sylvia
Cendron, Laura
Dettin, Monica
Pasquato, Antonella
author_sort Cassari, Leonardo
collection PubMed
description Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the etiological agent responsible for the worldwide pandemic and has now claimed millions of lives. The virus combines several unusual characteristics and an extraordinary ability to spread among humans. In particular, the dependence of the maturation of the envelope glycoprotein S from Furin enables the invasion and replication of the virus virtually within the entire body, since this cellular protease is ubiquitously expressed. Here, we analyzed the naturally occurring variation of the amino acids sequence around the cleavage site of S. We found that the virus grossly mutates preferentially at P positions, resulting in single residue replacements that associate with gain-of-function phenotypes in specific conditions. Interestingly, some combinations of amino acids are absent, despite the evidence supporting some cleavability of the respective synthetic surrogates. In any case, the polybasic signature is maintained and, as a consequence, Furin dependence is preserved. Thus, no escape variants to Furin are observed in the population. Overall, the SARS-CoV-2 system per se represents an outstanding example of the evolution of substrate–enzyme interaction, demonstrating a fast-tracked optimization of a protein stretch towards the Furin catalytic pocket. Ultimately, these data disclose important information for the development of drugs targeting Furin and Furin-dependent pathogens.
format Online
Article
Text
id pubmed-10003014
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-100030142023-03-11 SARS-CoV-2 S Mutations: A Lesson from the Viral World to Understand How Human Furin Works Cassari, Leonardo Pavan, Angela Zoia, Giulia Chinellato, Monica Zeni, Elena Grinzato, Alessandro Rothenberger, Sylvia Cendron, Laura Dettin, Monica Pasquato, Antonella Int J Mol Sci Article Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the etiological agent responsible for the worldwide pandemic and has now claimed millions of lives. The virus combines several unusual characteristics and an extraordinary ability to spread among humans. In particular, the dependence of the maturation of the envelope glycoprotein S from Furin enables the invasion and replication of the virus virtually within the entire body, since this cellular protease is ubiquitously expressed. Here, we analyzed the naturally occurring variation of the amino acids sequence around the cleavage site of S. We found that the virus grossly mutates preferentially at P positions, resulting in single residue replacements that associate with gain-of-function phenotypes in specific conditions. Interestingly, some combinations of amino acids are absent, despite the evidence supporting some cleavability of the respective synthetic surrogates. In any case, the polybasic signature is maintained and, as a consequence, Furin dependence is preserved. Thus, no escape variants to Furin are observed in the population. Overall, the SARS-CoV-2 system per se represents an outstanding example of the evolution of substrate–enzyme interaction, demonstrating a fast-tracked optimization of a protein stretch towards the Furin catalytic pocket. Ultimately, these data disclose important information for the development of drugs targeting Furin and Furin-dependent pathogens. MDPI 2023-03-01 /pmc/articles/PMC10003014/ /pubmed/36902222 http://dx.doi.org/10.3390/ijms24054791 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Cassari, Leonardo
Pavan, Angela
Zoia, Giulia
Chinellato, Monica
Zeni, Elena
Grinzato, Alessandro
Rothenberger, Sylvia
Cendron, Laura
Dettin, Monica
Pasquato, Antonella
SARS-CoV-2 S Mutations: A Lesson from the Viral World to Understand How Human Furin Works
title SARS-CoV-2 S Mutations: A Lesson from the Viral World to Understand How Human Furin Works
title_full SARS-CoV-2 S Mutations: A Lesson from the Viral World to Understand How Human Furin Works
title_fullStr SARS-CoV-2 S Mutations: A Lesson from the Viral World to Understand How Human Furin Works
title_full_unstemmed SARS-CoV-2 S Mutations: A Lesson from the Viral World to Understand How Human Furin Works
title_short SARS-CoV-2 S Mutations: A Lesson from the Viral World to Understand How Human Furin Works
title_sort sars-cov-2 s mutations: a lesson from the viral world to understand how human furin works
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10003014/
https://www.ncbi.nlm.nih.gov/pubmed/36902222
http://dx.doi.org/10.3390/ijms24054791
work_keys_str_mv AT cassarileonardo sarscov2smutationsalessonfromtheviralworldtounderstandhowhumanfurinworks
AT pavanangela sarscov2smutationsalessonfromtheviralworldtounderstandhowhumanfurinworks
AT zoiagiulia sarscov2smutationsalessonfromtheviralworldtounderstandhowhumanfurinworks
AT chinellatomonica sarscov2smutationsalessonfromtheviralworldtounderstandhowhumanfurinworks
AT zenielena sarscov2smutationsalessonfromtheviralworldtounderstandhowhumanfurinworks
AT grinzatoalessandro sarscov2smutationsalessonfromtheviralworldtounderstandhowhumanfurinworks
AT rothenbergersylvia sarscov2smutationsalessonfromtheviralworldtounderstandhowhumanfurinworks
AT cendronlaura sarscov2smutationsalessonfromtheviralworldtounderstandhowhumanfurinworks
AT dettinmonica sarscov2smutationsalessonfromtheviralworldtounderstandhowhumanfurinworks
AT pasquatoantonella sarscov2smutationsalessonfromtheviralworldtounderstandhowhumanfurinworks