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...
Autores principales: | , , , , , , , , , |
---|---|
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 |