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

Journal article


Yadav, V. 2017. PP2A-B' holoenzyme substrate recognition, regulation and role in cytokinesis. Cell discovery. Vol 3 (2017, Article: 17027). https://doi.org/10.1038/celldisc.2017.27
AuthorsYadav, V.
Abstract

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 cleavage furrow ingression. Our results provide a framework for further investigation of diverse signaling circuits formed by PP2A-B' holoenzymes in various cellular processes.

KeywordsPP2A; Substrate Binding; Holoenzymes; Signalling
Year2017
JournalCell discovery
Journal citationVol 3 (2017, Article: 17027)
PublisherNature
ISSN2056-5968
Digital Object Identifier (DOI)https://doi.org/10.1038/celldisc.2017.27
Web address (URL)https://europepmc.org/articles/PMC5586252
Output statusPublished
Publication dates08 Aug 2017
Publication process dates
Accepted12 Jul 2017
Deposited15 Jun 2023
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