PP2A-B′ holoenzyme substrate recognition, regulation and role in cytokinesis

作者：Cheng-Guo Wu, Hui Chen, Feng Guo, Vikash Kumar Yadav, Sean J. McIlwain, Michael Rowse, Alka Choudhary, Ziqing Lin, Yitong Li, Ting‐Jia Gu, Aiping Zheng, Qingge Xu, Woo‐Jong Lee, Eduard Resch, Benjamin M. Johnson, Jenny Day, Ying Ge, Irene M. Ong, Mark E. Burkard, Ylva Ivarsson, Yongna Xing · 发表于：Cell Discovery · 年份：2017 · DOI：10.1038/celldisc.2017.27 · 被引用次数：95 · 研究领域：Microtubule and mitosis dynamics、Cellular transport and secretion、Glycosylation and Glycoproteins Research

Protein phosphatase 2A (PP2A) is a major Ser/Thr phosphatase; it forms diverse heterotrimeric holoenzymes that counteract kinase actions. Using a peptidome that tiles the disordered regions of the human proteome, we identified proteins containing [LMFI]xx[ILV]xEx motifs that serve as interaction sites for B'-family PP2A regulatory subunits and holoenzymes. The B'-binding motifs have important roles in substrate recognition and in competitive inhibition of substrate binding. With more than 100 novel ligands identified, we confirmed that the recently identified LxxIxEx B'α-binding motifs serve as common binding sites for B' subunits with minor variations, and that S/T phosphorylation or D/E residues at positions 2, 7, 8 and 9 of the motifs reinforce interactions. Hundreds of proteins in the human proteome harbor intrinsic or phosphorylation-responsive B'-interaction motifs, and localize at distinct cellular organelles, such as midbody, predicting kinase-facilitated recruitment of PP2A-B' holoenzymes for tight spatiotemporal control of phosphorylation at mitosis and cytokinesis. Moroever, Polo-like kinase 1-mediated phosphorylation of Cyk4/RACGAP1, a centralspindlin component at the midbody, facilitates binding of both RhoA guanine nucleotide exchange factor (epithelial cell transforming sequence 2 (Ect2)) and PP2A-B' that in turn dephosphorylates Cyk4 and disrupts Ect2 binding. This feedback signaling loop precisely controls RhoA activation and specifies a restricted region for...