{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T04:26:52Z","timestamp":1768710412055,"version":"3.49.0"},"reference-count":85,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2023,3,1]],"date-time":"2023-03-01T00:00:00Z","timestamp":1677628800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"EU Research Framework Programme H2020\/Marie Sk\u0142odowska-Curie Actions","award":["101024974"],"award-info":[{"award-number":["101024974"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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\u2013enzyme 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.<\/jats:p>","DOI":"10.3390\/ijms24054791","type":"journal-article","created":{"date-parts":[[2023,3,2]],"date-time":"2023-03-02T03:29:00Z","timestamp":1677727740000},"page":"4791","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["SARS-CoV-2 S Mutations: A Lesson from the Viral World to Understand How Human Furin Works"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3034-4771","authenticated-orcid":false,"given":"Leonardo","family":"Cassari","sequence":"first","affiliation":[{"name":"Department of Industrial Engineering, University of Padova, Via Marzolo 9, 35131 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8692-9712","authenticated-orcid":false,"given":"Angela","family":"Pavan","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Padua, Viale G. Colombo 3, 35131 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giulia","family":"Zoia","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Padua, Viale G. Colombo 3, 35131 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monica","family":"Chinellato","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Padua, Viale G. Colombo 3, 35131 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Zeni","sequence":"additional","affiliation":[{"name":"Department of Industrial Engineering, University of Padova, Via Marzolo 9, 35131 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6307-3053","authenticated-orcid":false,"given":"Alessandro","family":"Grinzato","sequence":"additional","affiliation":[{"name":"European Synchrotron Radiation Facility, 71, Avenue des Martyrs, 38000 Grenoble, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8633-2994","authenticated-orcid":false,"given":"Sylvia","family":"Rothenberger","sequence":"additional","affiliation":[{"name":"Institute of Microbiology, University Hospital Center and University of Lausanne, Rue du Bugnon 48, 1011 Lausanne, Switzerland"},{"name":"Spiez Laboratory, Federal Office for Civil Protection, Austrasse, 3700 Spiez, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0125-0461","authenticated-orcid":false,"given":"Laura","family":"Cendron","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Padua, Viale G. Colombo 3, 35131 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6823-3375","authenticated-orcid":false,"given":"Monica","family":"Dettin","sequence":"additional","affiliation":[{"name":"Department of Industrial Engineering, University of Padova, Via Marzolo 9, 35131 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonella","family":"Pasquato","sequence":"additional","affiliation":[{"name":"Department of Industrial Engineering, University of Padova, Via Marzolo 9, 35131 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Coronaviridae Study Group of the International Committee on Taxonomy of Viruses (2020). The Species Severe Acute Respiratory Syndrome-Related Coronavirus: Classifying 2019-NCoV and Naming It SARS-CoV-2. Nat. 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