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

Nat Commun. 2021 Mar 15;12(1):1677. doi: 10.1038/s41467-021-21908-8.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 14-3-3 Proteins / chemistry*
  • 14-3-3 Proteins / metabolism
  • Amino Acid Sequence
  • Crystallography, X-Ray
  • Humans
  • Papillomaviridae
  • Phosphoproteins
  • Phosphorylation
  • Protein Binding
  • Protein Isoforms* / metabolism

Substances

  • 14-3-3 Proteins
  • Phosphoproteins
  • Protein Isoforms