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

  1. Yitong Li
  2. Vijaya Kumar Balakrishnan
  3. Michael Rowse
  4. Cheng-Guo Wu
  5. Anastasia Phoebe Bravos
  6. Vikash K Yadav
  7. YIva Ivarsson
  8. Stefan Strack
  9. Irina V Novikova
  10. Yongna Xing  Is a corresponding author
  1. University of Wisconsin-Madison, United States
  2. Indiana University - Purdue University Columbus, United States
  3. Uppsala University, Sweden
  4. University of Iowa, United States
  5. 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.

Article and author information

Author details

  1. Yitong Li

    Department of Oncology, University of Wisconsin-Madison, Madison, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Vijaya Kumar Balakrishnan

    Department of Oncology, University of Wisconsin-Madison, Madison, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Michael Rowse

    Indiana University - Purdue University Columbus, Columbus, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5572-5258
  4. Cheng-Guo Wu

    Department of Oncology, University of Wisconsin-Madison, Madison, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Anastasia Phoebe Bravos

    Department of Oncology, University of Wisconsin-Madison, Madison, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Vikash K Yadav

    5Department of Chemistry, Uppsala University, Uppsala, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  7. YIva Ivarsson

    5Department of Chemistry, Uppsala University, Uppsala, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  8. Stefan Strack

    Department of Neuroscience and Pharmacology, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Irina V Novikova

    Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Yongna Xing

    Department of Oncology, University of Wisconsin-Madison, Madison, United States
    For correspondence
    xing@oncology.wisc.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9834-528X

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.

Reviewing Editor

  1. Jungsan Sohn, Johns Hopkins University School of Medicine, United States

Publication history

  1. Received: April 25, 2022
  2. Accepted: August 3, 2022
  3. Accepted Manuscript published: August 4, 2022 (version 1)

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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  1. Yitong Li
  2. Vijaya Kumar Balakrishnan
  3. Michael Rowse
  4. Cheng-Guo Wu
  5. Anastasia Phoebe Bravos
  6. Vikash K Yadav
  7. YIva Ivarsson
  8. Stefan Strack
  9. Irina V Novikova
  10. Yongna Xing
(2022)
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

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