Functional analysis of polymorphisms at the S1/S2 site of SARS-CoV-2 spike protein

Several SARS-CoV-2 variants emerged that harbor mutations in the surface unit of the viral spike (S) protein that enhance infectivity and transmissibility. Here, we analyzed whether ten naturally-occurring mutations found within the extended loop harboring the S1/S2 cleavage site of the S protein, a...

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Bibliographic Details
Published in:PloS one 2022-03, Vol.17 (3), p.e0265453-e0265453
Main Authors: Arora, Prerna, Sidarovich, Anzhalika, Graichen, Luise, Hörnich, Bojan, Hahn, Alexander, Hoffmann, Markus, Pöhlmann, Stefan
Format: Article
Language:English
Subjects:
ACE2
Analysis
Angiotensin-converting enzyme 2
Animals
Biology and life sciences
Cathepsin L
Cell fusion
Chlorocebus aethiops
Cleavage
Coronaviruses
COVID-19
Functional analysis
Genetic polymorphisms
HEK293 Cells - virology
Humans
Immunoblotting
Infectivity
Medicine and health sciences
Mutation
Pathogenicity
Pathogens
Plasmids
Polymorphism, Genetic - genetics
Proteins
Research and analysis methods
RNA
SARS-CoV-2 - genetics
Severe acute respiratory syndrome
Severe acute respiratory syndrome coronavirus 2
Spike Glycoprotein, Coronavirus - genetics
Spike protein
Tropism
Vero Cells - virology
Viruses
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Summary:Several SARS-CoV-2 variants emerged that harbor mutations in the surface unit of the viral spike (S) protein that enhance infectivity and transmissibility. Here, we analyzed whether ten naturally-occurring mutations found within the extended loop harboring the S1/S2 cleavage site of the S protein, a determinant of SARS-CoV-2 cell tropism and pathogenicity, impact S protein processing and function. None of the mutations increased but several decreased S protein cleavage at the S1/S2 site, including S686G and P681H, the latter of which is found in variants of concern B.1.1.7 (Alpha variant) and B.1.1.529 (Omicron variant). None of the mutations reduced ACE2 binding and cell-cell fusion although several modulated the efficiency of host cell entry. The effects of mutation S686G on viral entry were cell-type dependent and could be linked to the availability of cathepsin L for S protein activation. These results show that polymorphisms at the S1/S2 site can modulate S protein processing and host cell entry.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0265453