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

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.

Pubmed ID: 9428519

Authors

  • Yaffe MB
  • Rittinger K
  • Volinia S
  • Caron PR
  • Aitken A
  • Leffers H
  • Gamblin SJ
  • Smerdon SJ
  • Cantley LC

Journal

Cell

Publication Data

December 26, 1997

Associated Grants

  • Agency: NIGMS NIH HHS, Id: GM56203
  • Agency: NIGMS NIH HHS, Id: R01 GM056203

Mesh Terms

  • 14-3-3 Proteins
  • Crystallography, X-Ray
  • Enzyme Inhibitors
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Peptide Library
  • Phosphopeptides
  • Phosphorylation
  • Phosphoserine
  • Protein Binding
  • Protein Conformation
  • Proteins
  • Substrate Specificity
  • Tyrosine 3-Monooxygenase