Journal
EMBO REPORTS
Volume 10, Issue 9, Pages 983-989Publisher
WILEY
DOI: 10.1038/embor.2009.150
Keywords
14-3-3; isothermal titration calorimetry; PKC epsilon; crystal structure
Categories
Funding
- Cancer Research-UK Peptide Synthesis Laboratory
- EU FP6 [LSHB-CT-2004-503467]
- Cancer Research UK [10747] Funding Source: researchfish
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The phosphoserine/threonine binding protein 14-3-3 stimulates the catalytic activity of protein kinase C-epsilon (PKC epsilon) by engaging two tandem phosphoserine-containing motifs located between the PKC epsilon regulatory and catalytic domains (V3 region). Interaction between 14-3-3 and this region of PKC epsilon is essential for the completion of cytokinesis. Here, we report the crystal structure of 14-3-3 zeta bound to a synthetic diphosphorylated PKC epsilon V3 region revealing how a consensus 14-3-3 site and a divergent 14-3-3 site cooperate to bind to 14-3-3 and so activate PKC epsilon. Thermodynamic data show a markedly enhanced binding affinity for two-site phosphopeptides over single-site 14-3-3 binding motifs and identifies Ser 368 as a gatekeeper phosphorylation site in this physiologically relevant 14-3-3 ligand. This dual-site intra-chain recognition has implications for other 14-3-3 targets, which seem to have only a single 14-3-3 motif, as other lower affinity and cryptic 14-3-3 gatekeeper sites might exist.
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