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Dual Specificity PDZ- and 14-3-3-Binding Motifs: A Structural and Interactomics Study.
Structure ( IF 4.4 ) Pub Date : 2020-04-14 , DOI: 10.1016/j.str.2020.03.010
Gergo Gogl 1 , Pau Jane 1 , Célia Caillet-Saguy 2 , Camille Kostmann 1 , Goran Bich 1 , Alexandra Cousido-Siah 1 , Laszlo Nyitray 3 , Renaud Vincentelli 4 , Nicolas Wolff 2 , Yves Nomine 1 , Nikolai N Sluchanko 5 , Gilles Trave 1
Affiliation  

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.



中文翻译:

双重特异性PDZ-和14-3-3-结合基序:结构和相互作用研究。

蛋白质-蛋白质相互作用基序通常可以通过翻译后修饰来改变。例如,已通过实验证明19%的预测人PDZ域结合基序(PBM)被磷酸化,理论上高达82%可磷酸化。PBM的磷酸化可能会通过改变其对PDZ域和14-3-3蛋白的亲和力而彻底改变其相互作用组。通常通过进行“拟膦酸”突变来分析磷酸化的作用。在这里,我们集中于HPV16-E6病毒癌蛋白和人RSK1激酶的PBM。我们测量了两个PBM对266个人PDZ域的天然,磷酸化和磷酸化变体的结合亲和力。我们用选定的PDZ结构域共结晶所有基序变体,以表征不同修饰的结构结果。最后,我们阐明了14-3-3蛋白捕获PBM的结构基础。这项研究提供了新的原子和相互作用的见解,可磷酸化的双特异性基序以及磷酸化和拟膦酸方法的不同影响。

更新日期:2020-04-14
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