Large scale discovery of coronavirus-host factor protein interaction motifs reveals SARS-CoV-2 specific mechanisms and vulnerabilities

Thomas Kruse, Caroline Benz, Dimitriya H. Garvanska, Richard Lindqvist, Filip Mihalic, Fabian Coscia, Raviteja Inturi, Ahmed Sayadi, Leandro Simonetti, Emma Nilsson, Muhammad Ali, Johanna Kliche, Ainhoa Moliner Morro, Andreas Mund, Eva Andersson, Gerald McInerney, Matthias Mann, Per Jemth, Norman E. Davey, Anna K. Överby (), Jakob Nilsson () and Ylva Ivarsson ()
Additional contact information
Thomas Kruse: University of Copenhagen, Faculty of Health and Medical Sciences
Caroline Benz: Uppsala University
Dimitriya H. Garvanska: University of Copenhagen, Faculty of Health and Medical Sciences
Richard Lindqvist: Umeå University
Filip Mihalic: Uppsala University
Fabian Coscia: University of Copenhagen, Faculty of Health and Medical Sciences
Raviteja Inturi: Uppsala University
Ahmed Sayadi: Uppsala University
Leandro Simonetti: Uppsala University
Emma Nilsson: Umeå University
Muhammad Ali: Uppsala University
Johanna Kliche: Uppsala University
Ainhoa Moliner Morro: Karolinska Institutet
Andreas Mund: University of Copenhagen, Faculty of Health and Medical Sciences
Eva Andersson: Uppsala University
Gerald McInerney: Karolinska Institutet
Matthias Mann: University of Copenhagen, Faculty of Health and Medical Sciences
Per Jemth: Uppsala University
Norman E. Davey: The Institute of Cancer Research
Anna K. Överby: Umeå University
Jakob Nilsson: University of Copenhagen, Faculty of Health and Medical Sciences
Ylva Ivarsson: Uppsala University

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract Viral proteins make extensive use of short peptide interaction motifs to hijack cellular host factors. However, most current large-scale methods do not identify this important class of protein-protein interactions. Uncovering peptide mediated interactions provides both a molecular understanding of viral interactions with their host and the foundation for developing novel antiviral reagents. Here we describe a viral peptide discovery approach covering 23 coronavirus strains that provides high resolution information on direct virus-host interactions. We identify 269 peptide-based interactions for 18 coronaviruses including a specific interaction between the human G3BP1/2 proteins and an ΦxFG peptide motif in the SARS-CoV-2 nucleocapsid (N) protein. This interaction supports viral replication and through its ΦxFG motif N rewires the G3BP1/2 interactome to disrupt stress granules. A peptide-based inhibitor disrupting the G3BP1/2-N interaction dampened SARS-CoV-2 infection showing that our results can be directly translated into novel specific antiviral reagents.

Date: 2021
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DOI: 10.1038/s41467-021-26498-z

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