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A dynamic charge-charge interaction modulates PP2A:B56 substrate recruitment.

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Garvanska, Dimitriya H 
Ueki, Yumi 


The recruitment of substrates by the ser/thr protein phosphatase 2A (PP2A) is poorly understood, limiting our understanding of PP2A-regulated signaling. Recently, the first PP2A:B56 consensus binding motif, LxxIxE, was identified. However, most validated LxxIxE motifs bind PP2A:B56 with micromolar affinities, suggesting that additional motifs exist to enhance PP2A:B56 binding. Here, we report the requirement of a positively charged motif in a subset of PP2A:B56 interactors, including KIF4A, to facilitate B56 binding via dynamic, electrostatic interactions. Using molecular and cellular experiments, we show that a conserved, negatively charged groove on B56 mediates dynamic binding. We also discovered that this positively charged motif, in addition to facilitating KIF4A dephosphorylation, is essential for condensin I binding, a function distinct and exclusive from PP2A-B56 binding. Together, these results reveal how dynamic, charge-charge interactions fine-tune the interactions mediated by specific motifs, providing a new framework for understanding how PP2A regulation drives cellular signaling.



E. coli, KIF4A, PP2A-B56, biochemistry, chemical biology, dynamic, charge-charge interactions, human, intrinsically disordered protein, molecular biophysics, protein phosphatase, structural and cell biology, structural biology, Amino Acid Sequence, Cloning, Molecular, Gene Expression Regulation, HeLa Cells, Humans, Kinesins, Models, Molecular, Mutation, Protein Conformation, Protein Phosphatase 2, RNA Interference, Substrate Specificity

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eLife Sciences Publications, Ltd
National Institute of General Medical Sciences (R35GM119455)
National Institute of General Medical Sciences (P20GM113132)
National Institute of General Medical Sciences (R01GM098482)
National Institute of Neurological Disorders and Stroke (R01NS091336)
National Institute of General Medical Sciences (R01GM134683)
Novo Nordisk (NNF14CC0001)
Independent Research Fund Denmark (DFF-7016-00086)