2O02 : Phosphorylation independent interactions between 14-3-3 and Exoenzyme S: from structure to pathogenesis

  • Christian Ottmann (Contributor)
  • Lubna Yasmin (Contributor)
  • Michael Weyand (Contributor)
  • Alan R Hauser (Contributor)
  • Alfred Wittinghofer (Contributor)
  • Bengt Hallberg (Contributor)



Experimental Technique/Method:X-RAY DIFFRACTION
Release Date:2007-11-27
Deposition Date:2006-11-27
Revision Date:2011-07-13#2017-10-18
Molecular Weight:55612.74
Macromolecule Type:Protein
Residue Count:488
Atom Site Count:4161

14-3-3 proteins are phosphoserine/phosphothreonine-recognizing adapter proteins that regulate the activity of a vast array of targets. There are also examples of 14-3-3 proteins binding their targets via unphosphorylated motifs. Here we present a structural and biological investigation of the phosphorylation-independent interaction between 14-3-3 and exoenzyme S (ExoS), an ADP-ribosyltransferase toxin of Pseudomonas aeruginosa. ExoS binds to 14-3-3 in a novel binding mode mostly relying on hydrophobic contacts. The 1.5 A crystal structure is supported by cytotoxicity analysis, which reveals that substitution of the corresponding hydrophobic residues significantly weakens the ability of ExoS to modify the endogenous targets RAS/RAP1 and to induce cell death. Furthermore, mutation of key residues within the ExoS binding site for 14-3-3 impairs virulence in a mouse pneumonia model. In conclusion, we show that ExoS binds 14-3-3 in a novel reversed orientation that is primarily dependent on hydrophobic residues. This interaction is phosphorylation independent and is required for the function of ExoS.
Date made available2007

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