Kostelecky, B and Saurin, AT and Purkiss, A and Parker, PJ and McDonald, NQ (2009) Recognition of an intra-chain tandem 14-3-3 binding site within PKCepsilon. EMBO Rep , 10 983 - 989. 10.1038/embor.2009.150.
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Abstract
The phosphoserine/threonine binding protein 14-3-3 stimulates the catalytic activity of protein kinase C-epsilon (PKCepsilon) by engaging two tandem phosphoserine-containing motifs located between the PKCepsilon regulatory and catalytic domains (V3 region). Interaction between 14-3-3 and this region of PKCepsilon is essential for the completion of cytokinesis. Here, we report the crystal structure of 14-3-3zeta bound to a synthetic diphosphorylated PKCepsilon 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 PKCepsilon. 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.
| Type: | Article |
|---|---|
| Title: | Recognition of an intra-chain tandem 14-3-3 binding site within PKCepsilon |
| DOI: | 10.1038/embor.2009.150 |
| Additional information: | The phosphoserine/threonine binding protein 14-3-3 stimulates the catalytic activity of protein kinase C-epsilon (PKCepsilon) by engaging two tandem phosphoserine-containing motifs located between the PKCepsilon regulatory and catalytic domains (V3 region). Interaction between 14-3-3 and this region of PKCepsilon is essential for the completion of cytokinesis. Here, we report the crystal structure of 14-3-3zeta bound to a synthetic diphosphorylated PKCepsilon 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 PKCepsilon. 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. |
| Keywords: | 14-3-3 Proteins Amino Acid Sequence Binding Sites Cell Line Crystallography, X-Ray Humans Models, Molecular Molecular Sequence Data Phosphoserine Protein Binding Protein Kinase C-epsilon Protein Structure, Quaternary Thermodynamics |
| UCL classification: | UCL > School of Life and Medical Sciences > Faculty of Life Sciences |
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