Activation of the SARS coronavirus spike protein via sequential proteolytic cleavage at two distinct sites.
Identifieur interne : 002B90 ( Main/Exploration ); précédent : 002B89; suivant : 002B91Activation of the SARS coronavirus spike protein via sequential proteolytic cleavage at two distinct sites.
Auteurs : Sandrine Belouzard [États-Unis] ; Victor C. Chu ; Gary R. WhittakerSource :
- Proceedings of the National Academy of Sciences of the United States of America [ 1091-6490 ] ; 2009.
Descripteurs français
- KwdFr :
- Furine, Fusion cellulaire, Glycoprotéine de spicule des coronavirus, Glycoprotéines membranaires (métabolisme), Glycoprotéines membranaires (physiologie), Hydrolyse, Mutagenèse dirigée, Protéines de l'enveloppe virale (métabolisme), Protéines de l'enveloppe virale (physiologie), Pénétration virale, Sites de fixation, Trypsine (métabolisme), Virus du SRAS (pathogénicité).
- MESH :
- métabolisme : Glycoprotéines membranaires, Protéines de l'enveloppe virale, Trypsine.
- pathogénicité : Virus du SRAS.
- physiologie : Glycoprotéines membranaires, Protéines de l'enveloppe virale.
- Furine, Fusion cellulaire, Glycoprotéine de spicule des coronavirus, Hydrolyse, Mutagenèse dirigée, Pénétration virale, Sites de fixation.
English descriptors
- KwdEn :
- Binding Sites, Cell Fusion, Furin, Hydrolysis, Membrane Glycoproteins (metabolism), Membrane Glycoproteins (physiology), Mutagenesis, Site-Directed, SARS Virus (pathogenicity), Spike Glycoprotein, Coronavirus, Trypsin (metabolism), Viral Envelope Proteins (metabolism), Viral Envelope Proteins (physiology), Virus Internalization.
- MESH :
- chemical , metabolism : Membrane Glycoproteins, Trypsin, Viral Envelope Proteins.
- chemical , physiology : Membrane Glycoproteins, Viral Envelope Proteins.
- chemical : Furin, Spike Glycoprotein, Coronavirus.
- pathogenicity : SARS Virus.
- Binding Sites, Cell Fusion, Hydrolysis, Mutagenesis, Site-Directed, Virus Internalization.
Abstract
The coronavirus spike protein (S) plays a key role in the early steps of viral infection, with the S1 domain responsible for receptor binding and the S2 domain mediating membrane fusion. In some cases, the S protein is proteolytically cleaved at the S1-S2 boundary. In the case of the severe acute respiratory syndrome coronavirus (SARS-CoV), it has been shown that virus entry requires the endosomal protease cathepsin L; however, it was also found that infection of SARS-CoV could be strongly induced by trypsin treatment. Overall, in terms of how cleavage might activate membrane fusion, proteolytic processing of the SARS-CoV S protein remains unclear. Here, we identify a proteolytic cleavage site within the SARS-CoV S2 domain (S2', R797). Mutation of R797 specifically inhibited trypsin-dependent fusion in both cell-cell fusion and pseudovirion entry assays. We also introduced a furin cleavage site at both the S2' cleavage site within S2 793-KPTKR-797 (S2'), as well as at the junction of S1 and S2. Introduction of a furin cleavage site at the S2' position allowed trypsin-independent cell-cell fusion, which was strongly increased by the presence of a second furin cleavage site at the S1-S2 position. Taken together, these data suggest a novel priming mechanism for a viral fusion protein, with a critical proteolytic cleavage event on the SARS-CoV S protein at position 797 (S2'), acting in concert with the S1-S2 cleavage site to mediate membrane fusion and virus infectivity.
DOI: 10.1073/pnas.0809524106
PubMed: 19321428
Affiliations:
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Le document en format XML
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<term>Membrane Glycoproteins (physiology)</term>
<term>Mutagenesis, Site-Directed</term>
<term>SARS Virus (pathogenicity)</term>
<term>Spike Glycoprotein, Coronavirus</term>
<term>Trypsin (metabolism)</term>
<term>Viral Envelope Proteins (metabolism)</term>
<term>Viral Envelope Proteins (physiology)</term>
<term>Virus Internalization</term>
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<term>Fusion cellulaire</term>
<term>Glycoprotéine de spicule des coronavirus</term>
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<term>Glycoprotéines membranaires (physiologie)</term>
<term>Hydrolyse</term>
<term>Mutagenèse dirigée</term>
<term>Protéines de l'enveloppe virale (métabolisme)</term>
<term>Protéines de l'enveloppe virale (physiologie)</term>
<term>Pénétration virale</term>
<term>Sites de fixation</term>
<term>Trypsine (métabolisme)</term>
<term>Virus du SRAS (pathogénicité)</term>
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<term>Viral Envelope Proteins</term>
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<term>Viral Envelope Proteins</term>
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<term>Protéines de l'enveloppe virale</term>
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<term>Hydrolysis</term>
<term>Mutagenesis, Site-Directed</term>
<term>Virus Internalization</term>
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<term>Fusion cellulaire</term>
<term>Glycoprotéine de spicule des coronavirus</term>
<term>Hydrolyse</term>
<term>Mutagenèse dirigée</term>
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<front><div type="abstract" xml:lang="en">The coronavirus spike protein (S) plays a key role in the early steps of viral infection, with the S1 domain responsible for receptor binding and the S2 domain mediating membrane fusion. In some cases, the S protein is proteolytically cleaved at the S1-S2 boundary. In the case of the severe acute respiratory syndrome coronavirus (SARS-CoV), it has been shown that virus entry requires the endosomal protease cathepsin L; however, it was also found that infection of SARS-CoV could be strongly induced by trypsin treatment. Overall, in terms of how cleavage might activate membrane fusion, proteolytic processing of the SARS-CoV S protein remains unclear. Here, we identify a proteolytic cleavage site within the SARS-CoV S2 domain (S2', R797). Mutation of R797 specifically inhibited trypsin-dependent fusion in both cell-cell fusion and pseudovirion entry assays. We also introduced a furin cleavage site at both the S2' cleavage site within S2 793-KPTKR-797 (S2'), as well as at the junction of S1 and S2. Introduction of a furin cleavage site at the S2' position allowed trypsin-independent cell-cell fusion, which was strongly increased by the presence of a second furin cleavage site at the S1-S2 position. Taken together, these data suggest a novel priming mechanism for a viral fusion protein, with a critical proteolytic cleavage event on the SARS-CoV S protein at position 797 (S2'), acting in concert with the S1-S2 cleavage site to mediate membrane fusion and virus infectivity.</div>
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