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

The SARS-CoV-2 N protein binds several cell host proteins including 14-3-3y, 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 14-3-3y and found that changes positively affecting the predicted interaction with 14-3-3y 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-14-3-3y were found, including half of the current variants of concern and interest. Our results suggest that binding of N to 14-3-3y is beneficial for the virus, thus targeting this viral-host protein-protein interaction seems an attractive approach to explore antiviral strategies. (c) 2021 Elsevier Inc. All rights reserved.