Analysis of SARS-CoV-2 nucleocapsid phosphoprotein N variations in the binding site to human 14-3-3 proteins

https://doi.org/10.1016/j.bbrc.2021.06.100Get rights and content

Highlights

  • Disordered regions in SARS-CoV-2 N protein contain 14-3-3 binding motifs.

  • Binding motifs for 14-3-3 proteins are evolutionary conserved.

  • Residues positively affecting the interaction with 14-3-3γ confer viral success.

Abstract

The SARS-CoV-2 N protein binds several cell host proteins including 14-3-3γ, a well-characterized regulatory protein. However, the biological function of this interaction is not completely understood. We analyzed the variability of ∼90 000 sequences of the SARS-CoV-2 N protein, particularly, its mutations in disordered regions containing binding motifs for 14-3-3 proteins. We studied how these mutations affect the binding energy to 14-3-3γ and found that changes positively affecting the predicted interaction with 14-3-3γ are the most successfully spread, with the highest prevalence in the phylogenetic tree. Although most residues are highly conserved within the 14-3-3 binding site, compensatory mutations to maintain the interaction energy of N-14-3-3γ were found, including half of the current variants of concern and interest. Our results suggest that binding of N to 14-3-3γ is beneficial for the virus, thus targeting this viral-host protein-protein interaction seems an attractive approach to explore antiviral strategies.

Keywords

Coronavirus
SARS-CoV-2
N protein
14-3-3
Interaction
Viral success

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1

Both authors contributed equally.

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