Coupling to short linear motifs creates versatile PME-1 activities in PP2A holoenzyme demethylation and inhibition
- University of Wisconsin-Madison, United States
- Indiana University - Purdue University Columbus, United States
- Uppsala University, Sweden
- University of Iowa, United States
- Pacific Northwest National Laboratory, United States
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 cryo-EM 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 multi-partite 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.
Data availability
All data are available in the main text or in the supplementary materials. The cryo-EM map and the refined atomic model of PP2A-B56γ1-PME-1 complex has been deposited at EMDB (https://www.ebi.ac.uk/https://www.ebi.ac.uk/) and RCSB (https://www.rcsb.org/) under the accession codes of EMD-25363 and 7SOY, respectively.
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Funding
National Institute of General Medical Sciences (GM137090-01 (Y.X.))
- Yongna Xing
American Cancer Society (RSG-10-153-01-DMC (Y.X.))
- Yongna Xing
Jordan's Guardian Angels Foundation and Jordan's Syndrome research consortium fund from the State of California (A19-3376-5007 (Y.X.))
- Yongna Xing
National Institute of General Medical Sciences (GM096060-01 (Y.X.))
- Yongna Xing
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
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Coupling to short linear motifs creates versatile PME-1 activities in PP2A holoenzyme demethylation and inhibition
eLife 11:e79736.
https://doi.org/10.7554/eLife.79736
