Download MendeleyHierarchized phosphotarget binding by the seven human 14-3-3 isoforms.
Gogl, G., Tugaeva, K.V., Eberling, P., Kostmann, C., Trave, G., Sluchanko, N.N.(2021) Nat Commun 12: 1677-1677
- PubMed: 33723253
- DOI: https://doi.org/10.1038/s41467-021-21908-8
- Primary Citation of Related Structures:
6ZFD, 6ZFG - PubMed Abstract:
The seven 14-3-3 isoforms are highly abundant human proteins encoded by similar yet distinct genes. 14-3-3 proteins recognize phosphorylated motifs within numerous human and viral proteins. Here, we analyze by X-ray crystallography, fluorescence polarization, mutagenesis and fusicoccin-mediated modulation the structural basis and druggability of 14-3-3 binding to four E6 oncoproteins of tumorigenic human papillomaviruses. 14-3-3 isoforms bind variant and mutated phospho-motifs of E6 and unrelated protein RSK1 with different affinities, albeit following an ordered affinity ranking with conserved relative K D ratios. Remarkably, 14-3-3 isoforms obey the same hierarchy when binding to most of their established targets, as supported by literature and a recent human complexome map. This knowledge allows predicting proportions of 14-3-3 isoforms engaged with phosphoproteins in various tissues. Notwithstanding their individual functions, cellular concentrations of 14-3-3 may be collectively adjusted to buffer the strongest phosphorylation outbursts, explaining their expression variations in different tissues and tumors.
Organizational Affiliation:
Equipe Labellisee Ligue 2015, Department of Integrated Structural Biology, Institut de Genetique et de Biologie Moleculaire et Cellulaire (IGBMC), INSERM U1258/CNRS UMR 7104/Universite de Strasbourg, Illkirch, France. [email protected].
