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The structural basis for 14-3-3:phosphopeptide binding specificity.

M B Yaffe·K Rittinger·S Volinia·P R Caron·A Aitken·H Leffers·S J Gamblin·S J Smerdon·L C Cantley
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Abstract

The 14-3-3 family of proteins mediates signal transduction by binding to phosphoserine-containing proteins. Using phosphoserine-oriented peptide libraries to probe all mammalian and yeast 14-3-3s, we identified two different binding motifs, RSXpSXP and RXY/FXpSXP, present in nearly all known 14-3-3 binding proteins. The crystal structure of 14-3-3zeta complexed with the phosphoserine motif in polyoma middle-T was determined to 2.6 A resolution. The bound peptide is in an extended conformation, with a tight turn created by the pS +2 Pro in a cis conformation. Sites of peptide-protein interaction in the complex rationalize the peptide library results. Finally, we show that the 14-3-3 dimer binds tightly to single molecules containing tandem repeats of phosphoserine motifs, implicating bidentate association as a signaling mechanism with molecules such as Raf, BAD, and Cbl.

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14-3-3 ProteinsCrystallography, X-RayEnzyme InhibitorsHumansModels, MolecularMolecular Sequence DataPeptide LibraryPhosphopeptidesPhosphorylationPhosphoserineProtein BindingProtein ConformationProteinsSubstrate SpecificityTyrosine 3-MonooxygenaseJournal ArticleResearch Support, Non-U.S. Gov'tResearch Support, U.S. Gov't, P.H.S.

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M B Yaffe, K Rittinger, S Volinia, P R Caron, A Aitken, H Leffers, S J Gamblin, S J Smerdon, L C Cantley. 1997-12-26. The structural basis for 14-3-3:phosphopeptide binding specificity.. https://doi.org/10.1016/s0092-8674(00)80487-0

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