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

eLife

Isha Nasa¹  Arminja N Kettenbach²  Wolfgang Peti³  Rebecca Page³  Xinru Wang³  Yumi Ueki⁴  Jakob Nilsson⁴  Gang Zhang⁴  Dimitriya H Garvanska⁴ 

[1] Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, United States;Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, United States;Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Medical Center Drive, Lebanon, United States;Department of Chemistry and Biochemistry, University of Arizona, Tucson, United States;The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark;

关键词: protein phosphatase;    PP2A-B56;    intrinsically disordered protein;    dynamic, charge-charge interactions;    KIF4A;    structural and cell biology;    E. coli;    Human;   

DOI  :  10.7554/eLife.55966

来源: publisher

【 摘 要 】

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.

【 授权许可】

CC BY