1. Biochemistry and Chemical Biology
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Breakage of the oligomeric CaMKII hub by the regulatory segment of the kinase

  1. Deepti Karandur
  2. Moitrayee Bhattacharyya
  3. Zijie Xia
  4. Young Kwang Lee
  5. Serena Muratcioglu
  6. Darren McAffee
  7. Ethan D McSpadden
  8. Baiyu Qiu
  9. Jay T Groves
  10. Evan R Williams  Is a corresponding author
  11. John Kuriyan  Is a corresponding author
  1. Howard Hughes Medical Institute, University of California, Berkeley, United States
  2. University of California, Berkeley, United States
  3. San Diego State University, United States
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Cite this article as: eLife 2020;9:e57784 doi: 10.7554/eLife.57784

Abstract

Ca2+/calmodulin dependent protein kinase II (CaMKII) is an oligomeric enzyme with crucial roles in neuronal signaling and cardiac function. Previously, we showed that activation of CaMKII triggers the exchange of subunits between holoenzymes, potentially increasing the spread of the active state (Stratton et al. 2014; Bhattacharyya et al. 2016). Using mass spectrometry, we show now that unphosphorylated and phosphorylated peptides derived from the CaMKII-α regulatory segment bind to the CaMKII-α hub and break it into smaller oligomers. Molecular dynamics simulations show that the regulatory segments dock spontaneously at the interface between hub subunits, trapping large fluctuations in hub structure. Single-molecule fluorescence intensity analysis of CaMKII-α expressed in mammalian cells shows that activation of CaMKII-α results in the destabilization of the holoenzyme. Our results suggest that release of the regulatory segment by activation and phosphorylation allows it to destabilize the hub, producing smaller assemblies that might reassemble to form new holoenzymes.

Article and author information

Author details

  1. Deepti Karandur

    Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6949-6337
  2. Moitrayee Bhattacharyya

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2168-1541
  3. Zijie Xia

    Department of Chemistry, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  4. Young Kwang Lee

    Department of Molecular and Cell Biology, San Diego State University, San Diego, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0056-6357
  5. Serena Muratcioglu

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  6. Darren McAffee

    Department of Molecular and Cell Biology, Department of Chemistry, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  7. Ethan D McSpadden

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  8. Baiyu Qiu

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  9. Jay T Groves

    QB3, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  10. Evan R Williams

    Department of Chemistry, University of California, Berkeley, Berkeley, United States
    For correspondence
    erw@berkeley.edu
    Competing interests
    No competing interests declared.
  11. John Kuriyan

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    For correspondence
    jkuriyan@mac.com
    Competing interests
    John Kuriyan, Senior editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4414-5477

Funding

National Institute of General Medical Sciences (K99 GM 126145)

  • Moitrayee Bhattacharyya

National Science Foundation (CHE-1609866)

  • Zijie Xia

National Science Foundation (CHE-1609866)

  • Evan R Williams

Howard Hughes Medical Institute

  • John Kuriyan

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

Reviewing Editor

  1. Leslie C Griffith, Brandeis University, United States

Publication history

  1. Received: April 15, 2020
  2. Accepted: September 8, 2020
  3. Accepted Manuscript published: September 9, 2020 (version 1)
  4. Accepted Manuscript updated: September 10, 2020 (version 2)

Copyright

© 2020, Karandur 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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