Breakage of the oligomeric CaMKII hub by the regulatory segment of the kinase
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Abstract
Ca 2+ /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.
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A basic portion of the CaM binding domain exposed after activation and free of CaM may dock at the intersubunit interface of the hub and act as a wedge that breaks integrity of the hub and facilitates release of dimeric units.
“A basic portion of the CaM binding domain exposed after activation and free of CaM may dock at the intersubunit interface of the hub and act as a wedge that breaks integrity of the hub and facilitates release of dimeric units (407, 408).”
From Synaptic memory and CaMKII (2023) · cites this paper as [408]
Recent biochemical evidence suggests that CaMKII may also satisfy the second requirement, i.e., for subunit exchange.
“Recent biochemical evidence suggests that CaMKII may also satisfy this second requirement, i.e., for subunit exchange (28, 406–408).”
From Synaptic memory and CaMKII (2023) · cites this paper as [408]
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Nicoll, R. A., & Schulman, H. (2023) · Physiological Reviews · doi:10.1152/physrev.00034.2022 · Cited by 126 · see citing works
“Recent biochemical evidence suggests that CaMKII may also satisfy this second requirement, i.e., for subunit exchange (28, 406 – 408).”
BackgroundSynaptic memory survives molecular turnover
Lee, J., Chen, X., & Nicoll, R. A. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2211572119 · Cited by 27 · see citing works
- Authors
- Karandur, D., Bhattacharyya, M., Xia, Z., Lee, Y. K., Muratcioglu, S., McAffee, D., McSpadden, E. D., Qiu, B., Groves, J. T., Williams, E. R., & Kuriyan, J.
- Affiliations
- QB3 (US)
- University of California, Berkeley (US)
- Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
- Corresponding author
- Williams, Evan R
- Kuriyan, John
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2020-09-09
- Volume
- 9
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC7538161
- OpenAlex
- W3086248643
- Cited by
- 35
- References
- 60
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 7 · 2023: 7 · 2022: 8 · 2021: 5 · 2020: 1
- FWCI
- 1.70
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute of General Medical Sciences (K99 GM 126145)
- National Science Foundation (CHE-1609866)
- Howard Hughes Medical Institute
- calsolv
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- CaMKII, calcium/calmodulin-dependent protein kinase II, holoenzyme, oligomerization, subunit exchange, phosphorylation, enzyme activation, protein assembly, single-molecule fluorescence, molecular dynamics simulation
- MeSH terms
- Escherichia coli, Humans, Phosphorylation, Proteins, Signal Transduction, Holoenzymes, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Molecular Dynamics Simulation, HEK293 Cells
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