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Potential coupling between SARS-CoV-2 replicative fitness and interactions of its nucleoprotein with human 14-3-3 proteins

Kristina V. Tugaeva, Andrey A. Sysoev, Jake L. R. Smith, View ORCID ProfileRichard B. Cooley, View ORCID ProfileAlfred A. Antson, View ORCID ProfileNikolai N. Sluchanko
doi: https://doi.org/10.1101/2021.12.23.474009
Kristina V. Tugaeva
1A.N. Bach Institute of Biochemistry, Federal Research Center of Biotechnology of the Russian Academy of Sciences, 119071, Moscow, Russia
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Andrey A. Sysoev
1A.N. Bach Institute of Biochemistry, Federal Research Center of Biotechnology of the Russian Academy of Sciences, 119071, Moscow, Russia
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Jake L. R. Smith
2York Structural Biology Laboratory, Department of Chemistry, University of York, York YO10 5DD, United Kingdom
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Richard B. Cooley
3Department of Biochemistry and Biophysics, Oregon State University, Corvallis, OR, 97331, USA
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Alfred A. Antson
2York Structural Biology Laboratory, Department of Chemistry, University of York, York YO10 5DD, United Kingdom
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  • For correspondence: nikolai.sluchanko@mail.ru fred.antson@york.ac.uk
Nikolai N. Sluchanko
1A.N. Bach Institute of Biochemistry, Federal Research Center of Biotechnology of the Russian Academy of Sciences, 119071, Moscow, Russia
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  • For correspondence: nikolai.sluchanko@mail.ru fred.antson@york.ac.uk
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Abstract

The SARS-CoV-2 nucleocapsid protein (N) is responsible for the viral genome packaging and virion assembly. Being highly abundant in the host cell, N interacts with numerous human proteins and undergoes multisite phosphorylation in vivo. When phosphorylated within its Ser/Arg-rich region, a tract highly prone to mutations as exemplified in the Omicron and Delta variants, N recruits human 14-3-3 proteins, potentially hijacking their functions. Here, we show that in addition to phosphorylated Ser197, an alternative, less conserved phosphosite at Thr205, absent in SARS-CoV N, binds 14-3-3 with micromolar affinity and is in fact the preferred binding site. Fluorescence anisotropy reveals a distinctive pT205/pS197 binding selectivity towards the seven human 14-3-3 isoforms. While explaining the structural basis for the discovered selectivity towards SARS-CoV-2 N phosphopeptides, our crystal structures enable prediction of N interactions with 14-3-3, suggesting a link between the strength of this interaction and replicative fitness of emerging coronavirus variants.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted December 25, 2021.
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Potential coupling between SARS-CoV-2 replicative fitness and interactions of its nucleoprotein with human 14-3-3 proteins
Kristina V. Tugaeva, Andrey A. Sysoev, Jake L. R. Smith, Richard B. Cooley, Alfred A. Antson, Nikolai N. Sluchanko
bioRxiv 2021.12.23.474009; doi: https://doi.org/10.1101/2021.12.23.474009
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Potential coupling between SARS-CoV-2 replicative fitness and interactions of its nucleoprotein with human 14-3-3 proteins
Kristina V. Tugaeva, Andrey A. Sysoev, Jake L. R. Smith, Richard B. Cooley, Alfred A. Antson, Nikolai N. Sluchanko
bioRxiv 2021.12.23.474009; doi: https://doi.org/10.1101/2021.12.23.474009

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