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Structure of the CaMKIIδ/Calmodulin Complex Reveals the Molecular Mechanism of CaMKII Kinase Activation
Open accessAbstract
UNLABELLED: Long-term potentiation (LTP), a long-lasting enhancement in communication between neurons, is considered to be the major cellular mechanism underlying learning and memory. LTP triggers high-frequency calcium pulses that result in the activation of Calcium/Calmodulin (CaM)-dependent kinase II (CaMKII). CaMKII acts as a molecular switch because it remains active for a long time after the return to basal calcium levels, which is a unique property required for CaMKII function. Here we describe the crystal structure of the human CaMKIIdelta/Ca2+/CaM complex, structures of all four human CaMKII catalytic domains in their autoinhibited states, as well as structures of human CaMKII oligomerization domains in their tetradecameric and physiological dodecameric states. All four autoinhibited human CaMKIIs were monomeric in the determined crystal structures but associated weakly in solution. In the CaMKIIdelta/Ca2+/CaM complex, the inhibitory region adopted an extended conformation and interacted with an adjacent catalytic domain positioning T287 into the active site of the interacting protomer. Comparisons with autoinhibited CaMKII structures showed that binding of calmodulin leads to the rearrangement of residues in the active site to a conformation suitable for ATP binding and to the closure of the binding groove for the autoinhibitory helix by helix alphaD. The structural data, together with biophysical interaction studies, reveals the mechanism of CaMKII activation by calmodulin and explains many of the unique regulatory properties of these two essential signaling molecules. ENHANCED VERSION: This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3-D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the Web plugin are available in Text S1.
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“As is the case with many kinases, CaMKII contains an autoinhibitory regulatory segment (FIGURE 2, A, B1, AND B2) that binds across the substrate binding groove, whose structure and function have been delineated by peptides, mutations, and crystallography (71–77).”
From Synaptic memory and CaMKII (2023) · cites this paper as [75]
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2 retracted
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A Dynamic Pathway for Calcium-Independent Activation of CaMKII by Methionine Oxidation
Erickson, J. R., Joiner, M.-L. A., Guan, X., Kutschke, W., Yang, J., Oddis, C. V., Bartlett, R. K., Lowe, J. S., O'Donnell, S. E., Aykin-Burns, N., et al. (2008) · Cell · doi:10.1016/j.cell.2008.02.048 · Cited by 1,122
Autophosphorylation at Thr 286 of the α Calcium-Calmodulin Kinase II in LTP and Learning
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Metadata
- Authors
- Rellos, P., Pike, A. C. W., Niesen, F. H., Salah, E., Lee, W. H., von Delft, F., & Knapp, S.
- Affiliations
- University of Oxford (GB)
- Corresponding author
- Knapp, Stefan
- Venue
- PLoS Biology
- Publisher
- Public Library of Science (PLoS)
- Published
- 2010-07-27
- Volume
- 8
- Issue
- 7
- Pages
- e1000426
- ISSN
- 1544-9173 (ISSN-L)
- 1545-7885
- PMC
- PMC2910593
- OpenAlex
- W1989492234
- Cited by
- 279
- References
- 62
- Citations by year
- 2026: 10 · 2025: 23 · 2024: 14 · 2023: 21 · 2022: 14 · 2021: 32 · 2020: 19 · 2019: 14 · 2018: 15 · 2017: 19 · 2016: 11 · 2015: 12 · 2014: 22 · 2013: 20 · 2012: 16
- FWCI
- 6.78
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Biology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DORA PSI (Paul Scherrer Institute) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Oxford University Research Archive (ORA) (University of Oxford) (submittedVersion)
- Funders
- GlaxoSmithKline
- Ontario Innovation Trust
- Genome Canada (1097737)
- Wellcome Trust (1097737)
- Ontario Genomics
- Ontario Genomics Institute
- Stiftelsen för Strategisk Forskning
- Karolinska Institutet
- Knut och Alice Wallenbergs Stiftelse
- Paul Scherrer Institut
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- CaMKII, CaMKIIδ, calmodulin, kinase activation, autoinhibition, long-term potentiation, calcium signaling, protein complex structure, catalytic domain, oligomerization domain, ATP binding, learning and memory
- MeSH terms
- Calcium, Calmodulin, Calorimetry, Enzyme Activation, Humans, Isoenzymes, Models, Molecular, Phosphorylation, Phosphothreonine, Protein Binding, Substrate Specificity, Protein Structure, Secondary, Catalytic Domain, Protein Structure, Quaternary, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Protein Multimerization
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