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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Gergo Gogl & Kristina V. Tugaeva & Pascal Eberling & Camille Kostmann & Gilles Trave & Nikolai N. Sluchanko, 2021. "Hierarchized phosphotarget binding by the seven human 14-3-3 isoforms," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21908-8
    DOI: 10.1038/s41467-021-21908-8
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    Cited by:

    1. Gergo Gogl & Boglarka Zambo & Camille Kostmann & Alexandra Cousido-Siah & Bastien Morlet & Fabien Durbesson & Luc Negroni & Pascal Eberling & Pau Jané & Yves Nominé & Andras Zeke & Søren Østergaard & , 2022. "Quantitative fragmentomics allow affinity mapping of interactomes," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    2. Trendelina Rrustemi & Katrina Meyer & Yvette Roske & Bora Uyar & Altuna Akalin & Koshi Imami & Yasushi Ishihama & Oliver Daumke & Matthias Selbach, 2024. "Pathogenic mutations of human phosphorylation sites affect protein–protein interactions," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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