Coupling to short linear motifs creates versatile PME-1 activities in PP2A holoenzyme demethylation and inhibition
Journal article
Authors | 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. |
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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. |
Keywords | Phosphatases; Motifs; Protein interactions; cell signaling |
Year | 2022 |
Journal | Elife |
Journal citation | 11, pp. 1-26 |
Publisher | eLife Sciences Publications |
ISSN | 2050-084X |
Digital Object Identifier (DOI) | https://doi.org/10.7554/eLife.79736 |
Web address (URL) | https://elifesciences.org/articles/79736 |
Publisher's version | License File Access Level Open |
Output status | Published |
Publication dates | |
Online | 04 Aug 2022 |
Publication process dates | |
Accepted | 03 Aug 2022 |
Deposited | 16 Dec 2022 |
https://repository.derby.ac.uk/item/9vqy4/coupling-to-short-linear-motifs-creates-versatile-pme-1-activities-in-pp2a-holoenzyme-demethylation-and-inhibition
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