Regulatory Domain of Calcium/Calmodulin-dependent Protein Kinase II
Open accessAbstract
Regulatory mechanisms of rat brain Ca2+/calmodulin-dependent protein kinase II (CaM-kinase II) were probed using a synthetic peptide (CaMK-(281-309] corresponding to residues 281-309 (alpha-subunit) which contained the calmodulin (CaM)-binding and inhibitory domains and also the initial autophosphorylation site (Thr286). Kinetic analyses indicated that inhibition of a completely Ca2+/CaM-independent form of CaM-kinase II by CaMK-(281-309) was noncompetitive with respect to peptide substrate (syntide-2) but was competitive with respect to ATP. Interaction of CaMK-(281-309) with the ATP-binding site was independently confirmed since inactivation of proteolyzed CaM-kinase II by phenylglyoxal (t1/2 = 7 min) was blocked by ATP analog plus Mg2+ or by CaMK-(281-309). In the presence of Ca2+/CaM, CaMK-(281-309) no longer protected against phenylglyoxal inactivation, consistent with our previous observations (Colbran, R.J., Fong, Y.-L., Schworer, C.M., and Soderling, T.R. (1988) J. Biol. Chem. 263, 18145-18151) that binding of Ca2+/CaM to CaMK-(281-309) 1) blocks its inhibitory property, and 2) enhances its phosphorylation at Thr 286. The present study also showed that phosphorylation of CaMK-(281-309) decreased its inhibitory potency at least 10-fold without affecting its Ca2+/CaM-binding ability. Thus, CaM-kinase II is inactive in the absence of Ca2+/CaM because an inhibitory domain within residues 281-309 interacts with the catalytic domain and blocks ATP binding. Autophosphorylati…
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CaMKII contains an autoinhibitory regulatory segment that binds across the substrate binding groove.
“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 [71]
T286 autophosphorylation is primarily intersubunit within a holoenzyme, although at very high kinase concentration it can also occur by an interholoenzyme mechanism.
“This autophosphorylation is primarily intersubunit autophosphorylation within a holoenzyme, although at very high kinase concentration it can also occur by an interholoenzyme mechanism (FIGURE 2B4) (71, 79–81).”
From Synaptic memory and CaMKII (2023) · cites this paper as [71]
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Lai, Y., Nairn, A. C., & Greengard, P. (1986) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.83.12.4253 · Cited by 292 · see citing works
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Structure–function of the multifunctional Ca2+/calmodulin-dependent protein kinase II
HUDMON, A., & SCHULMAN, H. (2002) · Biochemical Journal · doi:10.1042/bj20020228 · Cited by 615 · see citing works
Rellos, P., Pike, A. C. W., Niesen, F. H., Salah, E., Lee, W. H., von Delft, F., & Knapp, S. (2010) · PLoS Biology · doi:10.1371/journal.pbio.1000426 · Cited by 279 · see citing works
Nicoll, R. A., & Schulman, H. (2023) · Physiological Reviews · doi:10.1152/physrev.00034.2022 · Cited by 126 · see citing works
“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).”
BackgroundIntersubunit capture of regulatory segments is a component of cooperative CaMKII activation
Chao, L. H., Pellicena, P., Deindl, S., Barclay, L. A., Schulman, H., & Kuriyan, J. (2010) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.1751 · Cited by 119 · see citing works
A Peptide Model for Calmodulin Trapping by Calcium/Calmodulin-dependent Protein Kinase II
Putkey, J. A., & Waxham, M. N. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.47.29619 · Cited by 94 · see citing works
- Authors
- Colbran, R. J., Smith, M. K., Schworer, C. M., Fong, Y. L., & Soderling, T. R.
- Affiliations
- Howard Hughes Medical Institute (US)
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1989-03
- Volume
- 264
- Issue
- 9
- Pages
- 4800-4804
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1580110901
- Cited by
- 177
- References
- 1
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 3 · 2023: 2 · 2022: 4 · 2021: 2 · 2020: 4 · 2019: 4 · 2018: 3 · 2017: 2 · 2016: 5 · 2015: 1 · 2014: 5 · 2013: 2 · 2012: 5
- FWCI
- 4.51
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- 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, regulatory domain, calmodulin-binding domain, inhibitory domain, autophosphorylation, ATP binding, non-competitive inhibition, competitive inhibition, kinase activation, catalytic domain, calmodulin
- MeSH terms
- Adenosine Triphosphate, Animals, Binding Sites, Hydrolysis, Kinetics, Peptide Fragments, Phosphorylation, Protein Kinases, Substrate Specificity, Calcium-Calmodulin-Dependent Protein Kinases, Protein Kinase Inhibitors, Rats
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