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Review
.2004 Jul 15;381(Pt 2):329-42.
doi: 10.1042/BJ20031332.

Dynamic interactions between 14-3-3 proteins and phosphoproteins regulate diverse cellular processes

Affiliations
Review

Dynamic interactions between 14-3-3 proteins and phosphoproteins regulate diverse cellular processes

Carol Mackintosh. Biochem J..

Abstract

14-3-3 proteins exert an extraordinarily widespread influence on cellular processes in all eukaryotes. They operate by binding to specific phosphorylated sites on diverse target proteins, thereby forcing conformational changes or influencing interactions between their targets and other molecules. In these ways, 14-3-3s 'finish the job' when phosphorylation alone lacks the power to drive changes in the activities of intracellular proteins. By interacting dynamically with phosphorylated proteins, 14-3-3s often trigger events that promote cell survival--in situations from preventing metabolic imbalances caused by sudden darkness in leaves to mammalian cell-survival responses to growth factors. Recent work linking specific 14-3-3 isoforms to genetic disorders and cancers, and the cellular effects of 14-3-3 agonists and antagonists, indicate that the cellular complement of 14-3-3 proteins may integrate the specificity and strength of signalling through to different cellular responses.

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Figures

Figure 1
Figure 1. Crystal structure of a 14-3-3 dimer bound to phosphorylated AANAT
Structure of the 14-3-3–pAANAT complex, indicating the pThr31 of AANAT (brown/yellow), the proline twist C-terminal to pThr31, and the loop in AANAT (α1/α2 in brown) whose movement is restricted by the 14-3-3 dimer (green). Reprinted fromCell105, Obsil, T., Ghirlando, R., Klein, D. C., Ganguly, S. and Dyda, F., “Crystal structure of the 14-3-3ζ:serotonin N-acetyltransferase complex: a role for scaffolding in enzyme regulation”, pp. 257–267, © 2001, with permission from Elsevier.
Figure 2
Figure 2. Model of 14-3-3-dependent conformational change upon twosite binding
14-3-3 binding relies initially upon interaction of a gatekeeper residue with one monomeric subunit (1). Binding of weaker secondary sites (2) facilitates a ligand conformation that is unfavourable in the unbound state, exposing one or more regions of the protein (shaded circle) that are inaccessible in the free or monomer-bound form. Reprinted by permission of the Federation of the European Biochemical Societies from “How do 14-3-3 proteins work? – Gatekeeper phosphorylation and the molecular anvil hypothesis”, by Yaffe, M. B., FEBS Letters513, pp. 53–57, © 2002.
Figure 3
Figure 3. 14-3-3s inhibit phosphorylated NR in leaves in the dark
When leaves are actively photosynthesizing, NR is in an active, dephosphorylated state. When photosynthesis is blocked (depicted here as a cloud blocking the sun), NR becomes phosphorylated (on Ser543 on the spinach enzyme), which creates a phosphopeptide motif that binds directly to 14-3-3s in the presence of bivalent metal ions. 14-3-3 binding inhibits NR activity. AMPK, AMP-activated kinase; Fdred, reduced ferredoxin.
Figure 4
Figure 4. Many proteins bind to 14-3-3s after phosphorylation by the growth-factor- and insulin-stimulated PKB/Akt
Activation of receptor tyrosine kinases (or other receptors, such as G-protein-coupled receptors, not shown) recruits PI3K family lipid kinases to the plasma membrane where they convert PtdIns(4,5)P2 into PtdIns(3,4,5)P3. PtdIns(3,4,5)P3 recruits PH (pleckstrin homology) domain-containing proteins to the lipid bilayer, including PKB and PDK (phosphoinositide-dependent kinase) 1, and PKB becomes activated. Proteins that bind to 14-3-3s after phosphorylation by PKB are shown. These interactions contribute to the anti-apoptotic and metabolic effects of PKB. fru 2,6-P2, fructose 2,6-bisphosphate.
Figure 5
Figure 5. Structure of the fungal toxin fusicoccin
Fusicoccin permanently activates the plant plasma membrane (H+)-ATPase by filling a cavity that forms when a 14-3-3 dimer binds to the C-terminus of the proton pump [93]. Pathologically, activation of the plant plasma membrane (H+)-ATPase promotes permanent opening of guard cells. This Figure was kindly supplied by Claudia Oecking.
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References

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