Dual role of calmodulin in autophosphorylation of multifunctional cam kinase may underlie decoding of calcium signals
Abstract
Autophosphorylation of multifunctional Ca2+/calmodulin-dependent protein kinase makes it Ca2+ independent by trapping bound calmodulin and by enabling the kinase to remain partially active even after calmodulin dissociates. We show that autophosphorylation is an intersubunit reaction between neighbors in the multimeric kinase which requires two molecules of calmodulin. Ca2+/calmodulin acts not only to activate the "kinase" subunit but also to present effectively the "substrate" subunit for autophosphorylation. Conversion of the kinase to the potentiated or trapped state is a cooperative process that is inefficient at low occupancy of calmodulin. Simulations show that repetitive Ca2+ pulses at limiting calmodulin lead to the recruitment of calmodulin to the holoenzyme, which further stimulates autophosphorylation and trapping. This cooperative, positive feedback loop will potentiate the response of the kinase to sequential Ca2+ transients and establish a threshold frequency at which the enzyme becomes highly active.
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Phosphorylation of T286 requires that the subunit being phosphorylated have Ca2+/CaM bound.
“The phosphorylation of T286 requires that the subunit being phosphorylated have Ca2+/CaM bound (82, 83), resulting in autophosphorylation.”
From Synaptic memory and CaMKII (2023) · cites this paper as [82]
The subunit being phosphorylated apparently needs to have Ca2+/CaM bound; phosphorylation does not significantly occur on inactive subunits.
“A further complication for either of these possibilities is that it appears that the subunit being phosphorylated apparently would need to have Ca2+/CaM bound, i.e., it does not significantly occur on inactive subunits (13, 15, 82, 83, 406).”
From Synaptic memory and CaMKII (2023) · cites this paper as [82]
Autophosphorylation occurs by transphosphorylation between subunits within a holoenzyme, but the substrate subunit needs to be bound to Ca2+/CaM because that is what exposes T286.
“Although autophosphorylation does occur by transphosphorylation between subunits within a holoenzyme, the substrate subunit needs to be bound to Ca2+/CaM because that is what exposes T286 (82, 83), thus challenging the model of perpetuating CaMKII activity.”
From Synaptic memory and CaMKII (2023) · cites this paper as [82]
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References 58 · Cited by 500
- Authors
- Hanson, P. I., Meyer, T., Stryer, L., & Schulman, H.
- Affiliations
- Stanford Medicine (US)
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 1994-05
- Volume
- 12
- Issue
- 5
- Pages
- 943-956
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W2045194954
- Cited by
- 500
- References
- 58
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 14 · 2023: 9 · 2022: 16 · 2021: 10 · 2020: 7 · 2019: 14 · 2018: 10 · 2017: 11 · 2016: 2 · 2015: 10 · 2014: 15 · 2013: 19 · 2012: 19
- FWCI
- 10.39
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01mh045324-04)
- National Institute of Mental Health (MH-45324)
- National Institute of General Medical Sciences (GM-24032, GM 30179)
- 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 › Ion channel regulation and function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- calmodulin, autophosphorylation, calcium signaling, calcium transients, signal decoding, kinase activation, threshold frequency
- MeSH terms
- Amino Acid Sequence, Animals, Base Sequence, Brain, Calcium, Calmodulin, Cell Line, Chlorocebus aethiops, Kinetics, Mathematics, Models, Theoretical, Molecular Sequence Data, Oligodeoxyribonucleotides, Phosphorylation, Recombinant Proteins, Substrate Specificity, Swine, Transfection, Signal Transduction, Mutagenesis, Site-Directed, Calcium-Calmodulin-Dependent Protein Kinases, Macromolecular Substances
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