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Dual Specificity PDZ- and 14-3-3-Binding Motifs: A Structural and Interactomics Study

Abstract : Protein-protein interaction motifs are often alterable by post-translational modifications. For example, 19% of predicted human PDZ domain-binding motifs (PBMs) have been experimentally proven to be phosphorylated, and up to 82% are theoretically phosphorylatable. Phosphorylation of PBMs may drastically rewire their interactomes, by altering their affinities for PDZ domains and 14-3-3 proteins. The effect of phosphorylation is often analyzed by performing "phosphomimetic" mutations. Here, we focused on the PBMs of HPV16-E6 viral oncoprotein and human RSK1 kinase. We measured the binding affinities of native, phosphorylated, and phosphomimetic variants of both PBMs toward the 266 human PDZ domains. We co-crystallized all the motif variants with a selected PDZ domain to characterize the structural consequence of the different modifications. Finally, we elucidated the structural basis of PBM capture by 14-3-3 proteins. This study provides novel atomic and interactomic insights into phosphorylatable dual specificity motifs and the differential effects of phosphorylation and phosphomimetic approaches.
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https://hal.archives-ouvertes.fr/hal-02545805
Contributor : Célia Caillet-Saguy Connect in order to contact the contributor
Submitted on : Friday, April 17, 2020 - 1:25:22 PM
Last modification on : Wednesday, June 29, 2022 - 3:52:34 AM

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Gergo Gogl, Pau Jane, Célia Caillet-Saguy, Camille Kostmann, Goran Bich, et al.. Dual Specificity PDZ- and 14-3-3-Binding Motifs: A Structural and Interactomics Study. Structure, Elsevier (Cell Press), 2020, ⟨10.1016/j.str.2020.03.010⟩. ⟨hal-02545805⟩

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