Hierarchized phosphotarget binding by the seven human 14-3-3 isoforms

Gergo Gogl (), Kristina V. Tugaeva, Pascal Eberling, Camille Kostmann, Gilles Trave () and Nikolai N. Sluchanko ()
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Gergo Gogl: INSERM U1258/CNRS UMR 7104/Universite de Strasbourg
Kristina V. Tugaeva: Federal Research Center of Biotechnology of the Russian Academy of Sciences
Pascal Eberling: INSERM U1258/CNRS UMR 7104/Universite de Strasbourg
Camille Kostmann: INSERM U1258/CNRS UMR 7104/Universite de Strasbourg
Gilles Trave: INSERM U1258/CNRS UMR 7104/Universite de Strasbourg
Nikolai N. Sluchanko: Federal Research Center of Biotechnology of the Russian Academy of Sciences

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

Abstract: 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 KD 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.

Date: 2021
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DOI: 10.1038/s41467-021-21908-8

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