| Title: |
Coupling to short linear motifs creates versatile PME-1 activities in PP2A holoenzyme demethylation and inhibition |
| Authors: |
Li, Yitong; Balakrishnan, Vijaya Kumar; Rowse, Michael; Wu, Cheng-Guo; Bravos, Anastasia Phoebe; Yadav, Vikash K; Ivarsson, Ylva; Strack, Stefan; Novikova, Irina V; Xing, Yongna |
| Contributors: |
National Institute of General Medical Sciences; American Cancer Society; Jordan's Guardian Angels Foundation and Jordan's Syndrome research consortium fund from the State of California |
| Source: |
eLife ; volume 11 ; ISSN 2050-084X |
| Publisher Information: |
eLife Sciences Publications, Ltd |
| Publication Year: |
2022 |
| Collection: |
eLife (E-Journal - via CrossRef) |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.7554/elife.79736 |
| Availability: |
https://doi.org/10.7554/elife.79736; https://cdn.elifesciences.org/articles/79736/elife-79736-v2.pdf; https://cdn.elifesciences.org/articles/79736/elife-79736-v2.xml; https://elifesciences.org/articles/79736 |
| Rights: |
http://creativecommons.org/publicdomain/zero/1.0/ ; http://creativecommons.org/publicdomain/zero/1.0/ ; http://creativecommons.org/publicdomain/zero/1.0/ |
| Accession Number: |
edsbas.C8877A47 |
| Database: |
BASE |