Intersubunit capture of regulatory segments is a component of cooperative CaMKII activation
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The dodecameric holoenzyme of calcium-calmodulin-dependent protein kinase II (CaMKII) responds to high-frequency Ca(2+) pulses to become Ca(2+) independent. A simple coincidence-detector model for Ca(2+)-frequency dependency assumes noncooperative activation of kinase domains. We show that activation of CaMKII by Ca(2+)-calmodulin is cooperative, with a Hill coefficient of approximately 3.0, implying sequential kinase-domain activation beyond dimeric units. We present data for a model in which cooperative activation includes the intersubunit 'capture' of regulatory segments. Such a capture interaction is seen in a crystal structure that shows extensive contacts between the regulatory segment of one kinase and the catalytic domain of another. These interactions are mimicked by a natural inhibitor of CaMKII. Our results show that a simple coincidence-detection model cannot be operative and point to the importance of kinetic dissection of the frequency-response mechanism in future experiments.
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A CaMKIIN peptide binds across the CaMKII surface groove at docking sites designated A, B, and C.
“The structure of a CaMKIIN peptide to CaMKII shows it to bind across the surface groove, with docking sites designated as A, B, and C (3 oval indentations in FIGURE 2) (62).”
From Synaptic memory and CaMKII (2023) · cites this paper as [62]
The requirements for clustering are consistent with the subunit capture conformation seen in a crystal structure of CaMKII truncated after a portion of the regulatory segment and lacking the CaM binding domain and the remaining COOH-terminal end of the protein.
“The requirements for clustering are consistent with the subunit capture conformation seen in a crystal structure of CaMKII truncated after a portion of the regulatory segment and lacking the CaM binding domain and the remaining COOH-terminal end of the protein (62).”
From Synaptic memory and CaMKII (2023) · cites this paper as [62]
In the crystal structure, monomeric units form a repeating chain in which the regulatory segment of one monomer is bound to the kinase groove of a second monomer and the regulatory segment of that second monomer is bound across the kinase groove of a third monomer, and so on.
“The monomeric units form a repeating chain of regulatory segment of one bound to the kinase groove of a second monomer and regulatory segment of that second monomer bound across the kinase groove of a third monomer, and so on.”
From Synaptic memory and CaMKII (2023) · cites this paper as [62]
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“The structure of a CaMKIIN peptide to CaMKII shows it to bind across the surface groove, with docking sites designated as A, B, and C (3 oval indentations in FIGURE 2 ) (62).”
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- Self-citation
- Authors
- Chao, L. H., Pellicena, P., Deindl, S., Barclay, L. A., Schulman, H., & Kuriyan, J.
- Affiliations
- University of California, Berkeley (US)
- QB3 (US)
- Corresponding author
- Kuriyan, John
- Venue
- Nature Structural & Molecular Biology
- Published
- 2010-02-07
- Volume
- 17
- Issue
- 3
- Pages
- 264-272
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- PMC
- PMC2855215
- OpenAlex
- W1993504559
- Cited by
- 119
- References
- 49
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 10 · 2023: 5 · 2022: 5 · 2021: 6 · 2020: 7 · 2019: 10 · 2018: 15 · 2017: 6 · 2016: 4 · 2015: 6 · 2014: 8 · 2013: 11 · 2012: 9
- FWCI
- 4.56
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Structural & Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- 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 › Signaling Pathways in Disease
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- CaMKII, calcium/calmodulin-dependent protein kinase II, intersubunit interactions, Hill coefficient, coincidence detection, CaMKII inhibitor, crystal structure, kinase domain, frequency response
- MeSH terms
- Animals, Binding Sites, Calcium, Calmodulin, Humans, Models, Biological, Phosphorylation, Protein Binding, Caenorhabditis elegans, Protein Structure, Secondary, Crystallography, X-Ray, Caenorhabditis elegans Proteins, Calcium-Calmodulin-Dependent Protein Kinase Type 2
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