Molecular mechanism of activation-triggered subunit exchange in Ca2+/calmodulin-dependent protein kinase II

  1. Moitrayee Bhattacharyya
  2. Margaret M Stratton
  3. Catherine C Going
  4. Ethan D McSpadden
  5. Yongjian Huang
  6. Anna C Susa
  7. Anna Elleman
  8. Yumeng Melody Cao
  9. Nishant Pappireddi
  10. Pawel Burkhardt
  11. Christine L Gee
  12. Tiago Barros
  13. Howard Schulman
  14. Evan R Williams
  15. John Kuriyan  Is a corresponding author
  1. University of California, Berkeley, United States
  2. University of Massachusetts at Amherst, United States
  3. Stanford University, United States
  4. Smith College, United States
  5. Marine Biological Association, United States
  6. Allosteros Therapeutics, United States

Abstract

Activation triggers the exchange of subunits in Ca2+/calmodulin-dependent protein kinase II (CaMKII), an oligomeric enzyme that is critical for learning, memory, and cardiac function. The mechanism by which subunit exchange occurs remains elusive. We show that the human CaMKII holoenzyme exists in dodecameric and tetradecameric forms, and that the calmodulin(CaM)-binding element of CaMKII can bind to the hub of the holoenzyme and destabilize it to release dimers. The structures of CaMKII from two distantly diverged organisms suggest that the CaM-binding element of activated CaMKII acts as a wedge by docking at intersubunit interfaces in the hub. This converts the hub into a spiral form that can release or gain CaMKII dimers. Our data reveal a three-way competition for the CaM-binding element, whereby phosphorylation biases it towards the hub interface, away from the kinase domain and calmodulin, thus unlocking the ability of activated CaMKII holoenzymes to exchange dimers with unactivated ones.

Article and author information

Author details

  1. Moitrayee Bhattacharyya

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  2. Margaret M Stratton

    Department of Biochemistry and Molecular Biology, University of Massachusetts at Amherst, Amherst, United States
    Competing interests
    No competing interests declared.
  3. Catherine C Going

    Department of Chemistry, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  4. Ethan D McSpadden

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  5. Yongjian Huang

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  6. Anna C Susa

    Department of Chemistry, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  7. Anna Elleman

    Department of Chemistry, Stanford University, Palo Alto, United States
    Competing interests
    No competing interests declared.
  8. Yumeng Melody Cao

    Department of Physics, Smith College, Northampton, United States
    Competing interests
    No competing interests declared.
  9. Nishant Pappireddi

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  10. Pawel Burkhardt

    The Laboratory, Marine Biological Association, Plymouth, United States
    Competing interests
    No competing interests declared.
  11. Christine L Gee

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  12. Tiago Barros

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  13. Howard Schulman

    Allosteros Therapeutics, Sunnyvale, United States
    Competing interests
    No competing interests declared.
  14. Evan R Williams

    Department of Chemistry, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  15. John Kuriyan

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    For correspondence
    kuriyan@berkeley.edu
    Competing interests
    John Kuriyan, Senior editor, eLife.

Reviewing Editor

  1. Andrea Musacchio, Max Planck Institute of Molecular Physiology, Germany

Version history

  1. Received: November 30, 2015
  2. Accepted: March 3, 2016
  3. Accepted Manuscript published: March 7, 2016 (version 1)
  4. Version of Record published: May 6, 2016 (version 2)

Copyright

© 2016, Bhattacharyya 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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  1. Moitrayee Bhattacharyya
  2. Margaret M Stratton
  3. Catherine C Going
  4. Ethan D McSpadden
  5. Yongjian Huang
  6. Anna C Susa
  7. Anna Elleman
  8. Yumeng Melody Cao
  9. Nishant Pappireddi
  10. Pawel Burkhardt
  11. Christine L Gee
  12. Tiago Barros
  13. Howard Schulman
  14. Evan R Williams
  15. John Kuriyan
(2016)
Molecular mechanism of activation-triggered subunit exchange in Ca2+/calmodulin-dependent protein kinase II
eLife 5:e13405.
https://doi.org/10.7554/eLife.13405

Share this article

https://doi.org/10.7554/eLife.13405

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