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Cited by 95Protein Kinase Regulation and GTPase SignalingSignaling Pathways in DiseaseNeuroscience and Neuropharmacology Research

Structural Insights into the Regulation of Ca2+/Calmodulin-Dependent Protein Kinase II (CaMKII)

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Bhattacharyya, Moitrayee, Karandur, Deepti, Kuriyan, John·2020·Cold Spring Harbor Perspectives in Biology
DOI 10.1101/cshperspect.a035147PMC PMC7263085
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Abstract

Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) is a highly conserved serine/threonine kinase that is ubiquitously expressed throughout the human body.Specialized isoforms of CaMKII play key roles in neuronal and cardiac signaling.The distinctive holoenzyme architecture of CaMKII, with 12-14 kinase domains attached by flexible linkers to a central hub, poses formidable challenges for structural characterization.Nevertheless, progress in determining the structural mechanisms underlying CaMKII functions has come from studying the kinase domain and the hub separately, as well as from a recent electron microscopic investigation of the intact holoenzyme.In this review, we discuss our current understanding of the structure of CaMKII.We also discuss the intriguing finding that the CaMKII holoenzyme can undergo activation-triggered subunit exchange, a process that has implications for the potentiation and perpetuation of CaMKII activity.C a 2+ /calmodulin-dependent protein kinase II (CaMKII) is a multimeric Ser/Thr protein kinase with a unique holoenzyme architecture (Hook and Means 2001;Hudmon and Schulman 2002;Lisman et al. 2002Lisman et al. , 2012;;Stratton et al. 2013).It is one of the most predominant proteins in the brain, where it is critical for the long-term potentiation of synaptic signaling and in processes underlying the development of learning and memory (Silva et al. 1992;Giese et al. 1998;Elgersma et al. 2002;Hudmon and Schulman 2002;Giese and Mizuno 2013;Lisman and Raghavachari 2015).CaMKII is also expressed in the heart, where it plays a pivotal role in the modulation of excitation-contraction coupling (Maier and Bers 2007;Swaminathan et al. 2012;Erickson 2014).Most Ca 2+ /CaM-dependent kinases are monomeric (Swulius and Waxham 2008).By contrast, CaMKII is organized into large oligomers, typically with 12 or 14 subunits for the human α-isoform (Fig. 1A).Central to the organization

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  • CaMKII is unique in having a COOH-terminal hub or association domain that assembles 12 subunits as a double-ringed, yoyolike holoenzyme.

    “it is unique in having a COOH-terminal hub or association domain that assembles 12 subunits as a double-ringed, yoyolike holoenzyme (FIGURE 2, A AND B) (28).”

    From Synaptic memory and CaMKII (2023) · cites this paper as [28]

    The sections on hub geometry and flexible linkers describe a distinctive ring-shaped hub built from vertical dimers, and report 12-subunit CaMKIIα holoenzymes. But the paper also reports 14-subunit forms and says the kinase domains are flexibly arranged around the hub, so it does not support an unqualified, fixed 12-subunit, double-ringed yo-yo shape for the whole holoenzyme. Page numbers were not available in our copy. (LLM, conf=0.86)

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  • 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 [28]

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Authors
Bhattacharyya, M., Karandur, D., & Kuriyan, J.
Affiliations
QB3 (US)
ORCID
Venue
Cold Spring Harbor Perspectives in Biology
Publisher
Cold Spring Harbor Laboratory
Published
2019-10-25
Volume
12
Issue
6
Pages
a035147
ISSN
1943-0264 (ISSN-L)
DOI
10.1101/cshperspect.a035147
PMC
PMC7263085
OpenAlex
W2982161982
Cited by
95
References
11
Citations by year
2026: 9 · 2025: 15 · 2024: 27 · 2023: 14 · 2022: 10 · 2021: 9 · 2020: 9 · 2019: 2
Type
posted content
Language
en
Open access
Locations
  • Cold Spring Harbor Perspectives in Biology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute of General Medical Sciences (K99GM126145, R00GM126145)
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, kinase domain, subunit exchange, long-term potentiation, synaptic plasticity, excitation-contraction coupling, cardiac signaling, protein kinase structure
MeSH terms
Protein Domains, Animals, Calcium, Calmodulin, Gene Expression Regulation, Humans, Microscopy, Electron, Neurons, Phosphorylation, Protein Processing, Post-Translational, Signal Transduction, Caenorhabditis elegans, Cell Lineage, Protein Isoforms, Calcium-Calmodulin-Dependent Protein Kinase Type 2

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