CaMKII autophosphorylation can occur between holoenzymes without subunit exchange
- Humboldt-Universität zu Berlin, Germany
- Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Germany
- Freie Universität Berlin, Germany
Abstract
The dodecameric protein kinase CaMKII is expressed throughout the body. The alpha isoform is responsible for synaptic plasticity and participates in memory through its phosphorylation of synaptic proteins. Its elaborate subunit organization and propensity for autophosphorylation allow it to preserve neuronal plasticity across space and time. The prevailing hypothesis for the spread of CaMKII activity, involving shuffling of subunits between activated and naïve holoenzymes, is broadly termed subunit exchange. In contrast to the expectations of previous work, we found little evidence for subunit exchange upon activation, and no effect of restraining subunits to their parent holoenzymes. Rather, mass photometry, crosslinking mass spectrometry, single molecule TIRF microscopy and biochemical assays identify inter-holoenzyme phosphorylation (IHP) as the mechanism for spreading phosphorylation. The transient, activity-dependent formation of groups of holoenzymes is well suited to the speed of neuronal activity. Our results place fundamental limits on the activation mechanism of this kinase.
Data availability
All data generated during this study are included in the manuscript, supporting figures and supporting tables.
Article and author information
Author details
Andrew J R Plested
Funding
HORIZON EUROPE Marie Sklodowska-Curie Actions (798696)
- Iva Lučić
Deutsche Forschungsgemeinschaft (272140445)
- Andrew J R Plested
Deutsche Forschungsgemeinschaft (323514590 & 446182550)
- Andrew J R Plested
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Takeo Saneyoshi, Kyoto University, Japan
Version history
- Preprint posted: August 5, 2022 (view preprint)
- Received: January 10, 2023
- Accepted: August 10, 2023
- Accepted Manuscript published: August 11, 2023 (version 1)
- Version of Record published: August 30, 2023 (version 2)
- Version of Record updated: August 31, 2023 (version 3)
Copyright
© 2023, Lučić 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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CaMKII autophosphorylation can occur between holoenzymes without subunit exchange
eLife 12:e86090.
https://doi.org/10.7554/eLife.86090
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