1. Biochemistry and Chemical Biology
  2. Microbiology and Infectious Disease
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A widespread family of serine/threonine protein phosphatases shares a common regulatory switch with proteasomal proteases

  1. Niels Bradshaw
  2. Vladimir M Levdikov
  3. Christina M Zimanyi
  4. Rachelle Gaudet
  5. Anthony J Wilkinson
  6. Richard Losick  Is a corresponding author
  1. Harvard University, United States
  2. University of York, United Kingdom
  3. New York Structural Biology Center, United States
Research Article
  • Cited 6
  • Views 2,012
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Cite this article as: eLife 2017;6:e26111 doi: 10.7554/eLife.26111

Abstract

PP2C phosphatases control biological processes including stress responses, development, and cell division in all kingdoms of life. Diverse regulatory domains adapt PP2C phosphatases to specific functions, but how these domains control phosphatase activity was unknown. We present structures representing active and inactive states of the PP2C phosphatase SpoIIE from Bacillus subtilis. Based on structural analyses and genetic and biochemical experiments, we identify an α-helical switch that shifts a carbonyl oxygen into the active site to coordinate a metal cofactor. Our analysis indicates that this switch is widely conserved among PP2C family members, serving as a platform to control phosphatase activity in response to diverse inputs. Remarkably, the switch is shared with proteasomal proteases, which we identify as evolutionary and structural relatives of PP2C phosphatases. Although these proteases use an unrelated catalytic mechanism, rotation of equivalent helices controls protease activity by movement of the equivalent carbonyl oxygen into the active site.

Article and author information

Author details

  1. Niels Bradshaw

    Department of Molecular and Cellular Biology, Harvard University, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6845-4717
  2. Vladimir M Levdikov

    Structural Biology Laboratory, Department of Chemistry, University of York, York, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Christina M Zimanyi

    New York Structural Biology Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Rachelle Gaudet

    Department of Molecular and Cellular Biology, Harvard University, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9177-054X
  5. Anthony J Wilkinson

    Structural Biology Laboratory, Department of Chemistry, University of York, York, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Richard Losick

    Department of Molecular and Cellular Biology, Harvard University, Cambridge, United States
    For correspondence
    losick@mcb.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5130-6582

Funding

National Institutes of Health (GM18568)

  • Richard Losick

Wellcome (82829)

  • Anthony J Wilkinson

Damon Runyon Cancer Research Foundation (DRG 2051-10)

  • Niels Bradshaw

Jane Coffin Childs Memorial Fund for Medical Research

  • Christina M Zimanyi

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Michael T Laub, Massachusetts Institute of Technology, United States

Publication history

  1. Received: February 17, 2017
  2. Accepted: May 18, 2017
  3. Accepted Manuscript published: May 20, 2017 (version 1)
  4. Version of Record published: June 12, 2017 (version 2)

Copyright

© 2017, Bradshaw et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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