The Free Fatty Acid-Binding Pocket is a Conserved Hallmark in Pathogenic β-Coronavirus Spike Proteins from SARS-CoV to Omicron - Archive ouverte HAL Accéder directement au contenu
Pré-Publication, Document De Travail Année : 2022

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

Christine Toelzer
  • Fonction : Auteur
Kapil Gupta
  • Fonction : Auteur
Sathish K.N. Yadav
  • Fonction : Auteur
Lorna Hodgson
  • Fonction : Auteur
Maia Kavanagh Williamson
  • Fonction : Auteur
Dora Buzas
  • Fonction : Auteur
Ufuk Borucu
  • Fonction : Auteur
Kyle Powers
  • Fonction : Auteur
Richard Stenner
  • Fonction : Auteur
Kate Vasileiou
  • Fonction : Auteur
Frederic Garzoni
  • Fonction : Auteur
Daniel Fitzgerald
  • Fonction : Auteur
Christine Payré
  • Fonction : Auteur
Andrew Davidson
  • Fonction : Auteur
Paul Verkade
Martin Frank
  • Fonction : Auteur
Imre Berger
  • Fonction : Auteur
Christiane Schaffitzel
  • Fonction : Auteur

Résumé

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 β-coronaviruses (β-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 β-CoV infection and replication, highlighting potential antiviral strategies. One-Sentence Summary Free fatty acid-binding is conserved in pathogenic β-coronavirus S proteins and suppresses viral infection and replication.

Dates et versions

hal-03861183 , version 1 (19-11-2022)

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Citer

Christine Toelzer, Kapil Gupta, Sathish K.N. Yadav, Lorna Hodgson, Maia Kavanagh Williamson, et al.. The Free Fatty Acid-Binding Pocket is a Conserved Hallmark in Pathogenic β-Coronavirus Spike Proteins from SARS-CoV to Omicron. 2022. ⟨hal-03861183⟩
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