Journal
NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/s41467-021-21908-8
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Funding
- Russian Science Foundation [19-74-10031]
- Swiss Light Source synchrotron (P. Scherrer Institute, Villigen, Switzerland)
- Ligue contre le cancer
- Agence Nationale de la Recherche [UBE3A ANR-18-CE92-0017]
- French Infrastructure for Integrated Structural Biology (FRISBI)
- Instruct-ERIC
- Post-doctorants en France program of the Fondation ARC
- Russian Science Foundation [19-74-10031] Funding Source: Russian Science Foundation
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The 14-3-3 proteins can recognize phosphorylated motifs within various protein partners, and display different affinities when binding to E6 oncoproteins, but follow a conserved affinity ranking. This knowledge allows predicting the proportions of 14-3-3 isoforms engaged with phosphoproteins in different tissues.
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. 14-3-3 proteins recognize phosphorylated motifs within numerous protein partners. Here, the authors characterize the binding of all human 14-3-3 isoforms to four E6 oncoproteins, and identify a fixed order of 14-3-3 binding affinities that is conserved in 14-3-3:phosphoprotein interactions across the proteome.
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