Specificity of 14-3-3 isoform dimer interactions and phosphorylation

Abstract

Proteins that interact with 14-3-3 isoforms are involved in regulation of the cell cycle, intracellular trafficking/targeting, signal transduction, cytoskeletal structure and transcription. Recent novel roles for 14-3-3 isoforms include nuclear trafficking the direct interaction with cruciform DNA and with a number of receptors, small G-proteins and their regulators. Recent findings also show that the mechanism of interaction is also more complex than the initial finding of the novel phosphoserine/threonine motif. Non-phosphorylated binding motifs that can also be of high affinity may show a more isoform-dependent interaction and binding of a protein through two distinct binding motifs to a dimeric 14-3-3 may also be essential for full interaction. Phosphorylation of specific 14-3-3 isoforms can also regulate interactions. In many cases, they show a distinct preference for a particular isoform(s) of 14-3-3. A specific repertoire of dimer formation may influence which of the 14-3-3-interacting proteins could be brought together. Mammalian and yeast 14-3-3 isoforms show a preference for dimerization with specific partners in vivo.

Adenomatous polyposis coli plays a key role, in vivo, in coordinating assembly of the neuronal nicotinic postsynaptic complex

“…Several lines of evidence support this concept. 14-3-3 isoforms function as homo-and heterodimers that link their binding partners (Yaffe et al, 1997;Aitken et al, 2002). 14-3-3 isoforms (sigma and zeta) bind to APC (Jin et al, 2004;Meek et al, 2004).…”

“…Finally, 14-3-3 linking α3*nAChRs to APC would tether the receptors to the postsynaptic cytoskeleton and provide an additional mechanism by which 14-3-3 interactions promote the stable retention of α3*nAChRs at postsynaptic sites. Because 14-3-3 binding to its target proteins is often phosphorylation-dependent (Muslin et al, 1996;Aitken et al, 2002), the decreases in 14-3-3 synaptic accumulation in APC::EB1-dn expressing neurons may reflect changes in signaling events at the synapse. The reduced levels of functional α3*nAChRs may cause decreases in activity-dependent downstream signaling cascades.…”

“…14-3-3 adapter proteins are known to function as dimers that link their binding partners (Aitken et al, 2002;Yaffe, 2002). APC binds to 14-3-3 ( Fig.…”

TTK/Mps1 controls nuclear targeting of c-Abl by 14-3-3-coupled phosphorylation in response to oxidative stress

“…We also found that c-Abl is tethered in the cytoplasm by binding to 14-3-3 proteins and that the c-Abl-14-3-3 complexes are disrupted after genotoxic stress or oxidative stress. Functional binding analyses demonstrated that this binding depends on phosphorylation of c-Abl at Thr735, which is included within the 14-3-3 binding motif RSXpS/TXP (Aitken et al, 2002). Importantly, Thr735 is located between the second and third nuclear localization signals in the C terminus of c-Abl, suggesting that binding of 14-3-3 to phosphorylated Thr735 masks the c-Abl nuclear localization signals and prevents its nuclear entry.…”

The crystal structure of the non-liganded 14-3-3σ protein: insights into determinants of isoform specific ligand binding and dimerization

“…Two canonical 14-3-3-binding motifs have been identified as R(S/X)XpSXP and RXXXpSXP, where pS repre-sents phospho-serine or phospho-threonine and X any amino-acid [12]. Association with 14-3-3 proteins regulates the function of ligands by inter-and intra-compartmental sequestration, activation/inactivation of enzymatic activity and promotion/inhibition of protein-interactions; thereby, numerous cellular processes in all multi-cellular species analyzed are regulated by 14-3-3 proteins (reviewed in [1,13,14]). In part this regulation is mediated by conformational changes of the ligand after association with 14-3-3 proteins [15].…”