Coupling to short linear motifs creates versatile PME-1 activities in PP2A holoenzyme demethylation and inhibition

Journal article


Li, Y., Balakrishnan, Vijaya Kumar . K., Rowse, M., Wu, C, G., Bravos, A. P., Yadav, VK, Ivarsson, Y., Strack, S., Novikova, I. V. and Xing, Y. 2022. Coupling to short linear motifs creates versatile PME-1 activities in PP2A holoenzyme demethylation and inhibition. Elife. 11, pp. 1-26. https://doi.org/10.7554/eLife.79736
AuthorsLi, Y., Balakrishnan, Vijaya Kumar . K., Rowse, M., Wu, C, G., Bravos, A. P., Yadav, VK, Ivarsson, Y., Strack, S., Novikova, I. V. and Xing, Y.
Abstract

Protein phosphatase 2A (PP2A) holoenzymes target broad substrates by recognizing short motifs via regulatory subunits. PP2A methylesterase 1 (PME-1) is a cancer-promoting enzyme and undergoes methylesterase activation upon binding to the PP2A core enzyme. Here, we showed that PME-1 readily demethylates different families of PP2A holoenzymes and blocks substrate recognition in vitro. The high-resolution cryoelectron microscopy structure of a PP2A-B56 holoenzyme–PME-1 complex reveals that PME-1 disordered regions, including a substrate-mimicking motif, tether to the B56 regulatory subunit at remote sites. They occupy the holoenzyme substrate-binding groove and allow large structural shifts in both holoenzyme and PME-1 to enable multipartite contacts at structured cores to activate the methylesterase. B56 interface mutations selectively block PME-1 activity toward PP2A-B56 holoenzymes and affect the methylation of a fraction of total cellular PP2A. The B56 interface mutations allow us to uncover B56-specific PME-1 functions in p53 signaling. Our studies reveal multiple mechanisms of PME-1 in suppressing holoenzyme functions and versatile PME-1 activities derived from coupling substrate-mimicking motifs to dynamic structured cores.

KeywordsPhosphatases; Motifs; Protein interactions; cell signaling
Year2022
JournalElife
Journal citation11, pp. 1-26
PublishereLife Sciences Publications
ISSN 2050-084X
Digital Object Identifier (DOI)https://doi.org/10.7554/eLife.79736
Web address (URL)https://elifesciences.org/articles/79736
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Open
Output statusPublished
Publication dates
Online04 Aug 2022
Publication process dates
Accepted03 Aug 2022
Deposited16 Dec 2022
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