Hierarchized phosphotarget binding by the seven human 14-3-3 isoforms
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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.
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Milo, R. (2013) · BioEssays · doi:10.1002/bies.201300066 · Cited by 643 · see citing works
Paxdb, a database of protein abundance averages across all three domains of life
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Nominé, Y., Masson, M., Charbonnier, S., Zanier, K., Ristriani, T., Deryckère, F., Sibler, A.-P., Desplancq, D., Atkinson, R. A., Weiss, E., et al. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.01.024 · Cited by 177 · see citing works
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The Mechanism of SARS-CoV-2 Nucleocapsid Protein Recognition by the Human 14-3-3 Proteins
Tugaeva, K. V., Hawkins, D. E. D. P., Smith, J. L. R., Bayfield, O. W., Ker, D.-S., Sysoev, A. A., Klychnikov, O. I., Antson, A. A., & Sluchanko, N. N. (2021) · Journal of Molecular Biology · doi:10.1016/j.jmb.2021.166875 · Cited by 95 · see citing works
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- Authors
- Gogl, G., Tugaeva, K. V., Eberling, P., Kostmann, C., Trave, G., & Sluchanko, N. N.
- Affiliations
- Russian Academy of Sciences (RU)
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Sluchanko, Nikolai N.
- Venue
- Nature Communications
- Published
- 2021-03-15
- Volume
- 12
- Issue
- 1
- Pages
- 1677-1677
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC7961048
- OpenAlex
- W3138934297
- Cited by
- 91
- References
- 3
- Citations by year
- 2026: 11 · 2025: 23 · 2024: 11 · 2023: 13 · 2022: 20 · 2021: 13
- FWCI
- 4.47
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DORA PSI (Paul Scherrer Institute) (submittedVersion, cc-by)
- HAL (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Agence Nationale de la Recherche (ANR-18-CE92-0017, ANR18)
- Fondation ARC pour la Recherche sur le Cancer
- Ligue Contre le Cancer (Équipe labellisée 2015)
- Russian Science Foundation (19‐74‐10031)
- French Infrastructure for Integrated Structural Biology
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › 14-3-3 protein interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Interaction Studies and Fluorescence Analysis
- Keywords
- 14-3-3 proteins, 14-3-3 isoforms, phosphopeptide binding, phosphorylation motifs, E6 oncoprotein, human papillomavirus, RSK1, druggability, fusicoccin, tissue-specific protein expression
- MeSH terms
- Amino Acid Sequence, Humans, Phosphoproteins, Phosphorylation, Protein Binding, Crystallography, X-Ray, Protein Isoforms, Papillomaviridae, 14-3-3 Proteins
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