The Free Fatty Acid-Binding Pocket is a Conserved Hallmark in Pathogenic β-Coronavirus Spike Proteins from SARS-CoV to Omicron

Toelzer, C.; Gupta, K.; Yadav, S. K. N.; Hodgson, L.; Kavanagh Williamson, M.; Buzas, D.; Borucu, U.; Powers, K.; Stenner, R.; Vasileiou, K.; Garzoni, F.; Fitzgerald, D.; Payre, C.; Lambeau, G.; Davidson, A. D.; Verkade, P.; Frank, M.; Berger, I.; Schaffitzel, C.

doi:10.1101/2022.04.22.489083

bioRxiv · 10.1101/2022.04.22.489083

The Free Fatty Acid-Binding Pocket is a Conserved Hallmark in Pathogenic β-Coronavirus Spike Proteins from SARS-CoV to Omicron

Toelzer, C.·Gupta, K.·Yadav, S. K. N.·Hodgson, L.·Kavanagh Williamson, M.·Buzas, D.·Borucu, U.·Powers, K.·Stenner, R.·Vasileiou, K.·Garzoni, F.·Fitzgerald, D.·Payre, C.·Lambeau, G.·Davidson, A. D.·Verkade, P.·Frank, M.·Berger, I.·Schaffitzel, C.

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Abstract

As COVID-19 persists, severe acquired respiratory syndrome coronavirus-2 (SARS-CoV-2) Variants of Concern (VOCs) emerge, accumulating spike (S) glycoprotein mutations. S receptor-binding domain (RBD) comprises a free fatty acid (FFA)-binding pocket. FFA-binding stabilizes a locked S conformation, interfering with virus infectivity. We provide evidence that the pocket is conserved in pathogenic {beta}-coronaviruses ({beta}-CoVs) infecting humans. SARS-CoV, MERS-CoV, SARS-CoV-2 and VOCs bind the essential FFA linoleic acid (LA), while binding is abolished by one mutation in common cold-causing HCoV-HKU1. In the SARS-CoV S structure, LA stabilizes the locked conformation while the open, infectious conformation is LA-free. Electron tomography of SARS-CoV-2 infected cells reveals that LA-treatment inhibits viral replication, resulting in fewer, deformed virions. Our results establish FFA-binding as a hallmark of pathogenic {beta}-CoV infection and replication, highlighting potential antiviral strategies. One-Sentence SummaryFree fatty acid-binding is conserved in pathogenic {beta}-coronavirus S proteins and suppresses viral infection and replication.

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Toelzer, C., Gupta, K., Yadav, S. K. N., Hodgson, L., Kavanagh Williamson, M., Buzas, D., Borucu, U., Powers, K., Stenner, R., Vasileiou, K., Garzoni, F., Fitzgerald, D., Payre, C., Lambeau, G., Davidson, A. D., Verkade, P., Frank, M., Berger, I., Schaffitzel, C.. 2022-04-22. The Free Fatty Acid-Binding Pocket is a Conserved Hallmark in Pathogenic β-Coronavirus Spike Proteins from SARS-CoV to Omicron. https://doi.org/10.1101/2022.04.22.489083

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