Phosphorylation-independent interaction between 14-3-3 and exoenzyme S: from structure to pathogenesis |
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| Authors: | Ottmann Christian Yasmin Lubna Weyand Michael Veesenmeyer Jeffrey L Diaz Maureen H Palmer Ruth H Francis Matthew S Hauser Alan R Wittinghofer Alfred Hallberg Bengt |
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| Affiliation: | Department of Structural Biology, Max-Planck-Institute for Molecular Physiology, Dortmund, Germany. |
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| Abstract: | 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. |
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