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Activation of the SARS coronavirus spike protein via sequential proteolytic cleavage at two distinct sites
Open accessAbstract
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.
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Metadata
- Authors
- Belouzard, S., Chu, V. C., & Whittaker, G. R.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2009-04-07
- Volume
- 106
- Issue
- 14
- Pages
- 5871-5876
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W1965531501
- Cited by
- 1,073
- References
- 3
- FWCI
- 7.54
- Type
- journal article
- Language
- en
- Open access
- bronze
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