Molecular mechanism of activation-triggered subunit exchange in Ca2+/calmodulin-dependent protein kinase II
- University of California, Berkeley, United States
- University of Massachusetts at Amherst, United States
- Stanford University, United States
- Smith College, United States
- Marine Biological Association, United States
- 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
Reviewing Editor
- Andrea Musacchio, Max Planck Institute of Molecular Physiology, Germany
Version history
- Received: November 30, 2015
- Accepted: March 3, 2016
- Accepted Manuscript published: March 7, 2016 (version 1)
- 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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Molecular mechanism of activation-triggered subunit exchange in Ca2+/calmodulin-dependent protein kinase II
eLife 5:e13405.
https://doi.org/10.7554/eLife.13405
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