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Modulation of the interaction of regulatory 14-3-3 proteins to their physiological partners through small cell-permeant molecules is a promising strategy to control cellular processes where 14-3-3s are engaged. Here, we show that the fungal phytotoxin fusicoccin (FC), known to stabilize 14-3-3 association to the plant plasma membrane H(+) -ATPase, is able to stabilize 14-3-3 interaction to several client proteins with a mode III binding motif. Isothermal titration calorimetry analysis of the interaction between 14-3-3s and different peptides reproducing a mode III binding site demonstrated the FC ability to stimulate 14-3-3 the association. Moreover, molecular docking studies provided the structural rationale for the differential FC effect, which exclusively depends on the biochemical properties of the residue in peptide C-terminal position. Our study proposes FC as a promising tool to control cellular processes regulated by 14-3-3 proteins, opening new perspectives on its potential pharmacological applications., (© 2014 International Union of Biochemistry and Molecular Biology.)

The study of the structure and dynamics of protein-protein interaction networks has become overwhelming in all biological systems. Most of the biological events are the consequence of several protein-protein interactions finely regulated by covalent modifications and physiological effectors. Moreover, several studies have shown that the complex interactome responsible for the progress and control of vital processes is disturbed in diseases. Besides the basic information on the mechanisms involved in the processes driven by protein-protein interactions, it appears nowadays extremely challenging to study possible regulators of the lifespan of protein networks. Small molecules able to stabilize or to inhibit protein complexes could easily find applications as potential innovative drugs. In this article, we hypothesize that a natural product, the fungal phytotoxin fusicoccin, can play a role as a stabilizer of interactions between 14-3-3 proteins and specific natural targets. A very specific stabilizer molecule is the ideal starting point for the development of a family of structurally related drugs able to selectively tune 14-3-3 interaction with their targets., (Copyright © 2013 International Union of Biochemistry and Molecular Biology, Inc.)

Phosphatidic acid is a phospholipid second messenger implicated in various cellular processes in eukaryotes. In plants, production of phosphatidic acid is triggered in response to a number of biotic and abiotic stresses. Here, we show that phosphatidic acid binds to 14-3-3 proteins, a family of regulatory proteins which bind client proteins in a phosphorylation-dependent manner. Binding of phosphatidic acid involves the same 14-3-3 region engaged in protein target binding. Consequently, micromolar phosphatidic acid concentrations significantly hamper the interaction of 14-3-3 proteins with the plasma membrane H(+)-ATPase, a well characterized plant 14-3-3 target, thus inhibiting the phosphohydrolitic enzyme activity. Moreover, the proton pump is inhibited when endogenous PA production is triggered by phospholipase D and the G protein agonist mastoparan-7. Hence, our data propose a possible mechanism involving PA that regulates 14-3-3-mediated cellular processes in response to stress., (Copyright © 2012 International Union of Biochemistry and Molecular Biology, Inc.)

14-3-3 proteins are a class of highly conserved proteins wide-spread in eukaryotes. They regulate several cellular processes through phosphorylation-dependent interaction with their targets. Since their discovery in plants, a number of peculiar functions have been ascertained, such as regulation of primary metabolism, ion transport, cellular trafficking, chloroplast and mitochondrial enzyme activities and gene transcription. The still increasing body of evidence suggests that 14-3-3s may function as versatile proteins able to move from cytosol to different cellular organelles. This review will focus on the broad range of regulatory tasks carried out by 14-3-3s in the different compartments.