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Light scattering and transmission electron microscopy studies reveal a mechanism for calcium/calmodulin‐dependent protein kinase II self‐association
Abstract
Calmodulin (CaM)-kinase II holoenzymes composed of either alpha or beta subunits were analyzed using light scattering to determine a mechanism for self-association. Under identical reaction conditions, only alphaCaM-kinase II holoenzymes self-associated. Self-association was detected at a remarkably low enzyme concentration (0.14 microM or 7 microg/mL). Light scattering revealed two phases of self-association: a rapid rise that peaked, followed by a slower decrease that stabilized after 2-3 min. Electron microscopy identified that the rapid rise in scattering was due to the formation of loosely packed clusters of holoenzymes that undergo further association into large complexes of several microns in diameter over time. Self-association required activation by Ca(2+)/CaM and was strongly dependent on pH. Self-association was not detected at pH 7.5, however, the extent of this process increased as reaction pH decreased below 7.0. A peptide substrate (autocamtide-2) and inhibitor (AIP) designed from the autoregulatory domain of CaM-kinase II potently prevented self-association, whereas the peptide substrate syntide-2 did not. Thus, CaM-kinase II self-association is isoform specific, regulated by the conditions of activation, and is inhibited by peptides that bind to the catalytic domain likely via their autoregulatory-like sequence. A model for CaM-kinase II self-association is presented whereby catalytic domains in one holoenzyme interact with the regulatory domains in neighbori…
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Self-association is initiated by Ca2+/CaM.
“Self-association is initiated by Ca2+/CaM (133)”
From Synaptic memory and CaMKII (2023) · cites this paper as [133]
Self-association is strongly dependent upon kinase concentration.
“it is strongly dependent upon kinase concentration (133)”
From Synaptic memory and CaMKII (2023) · cites this paper as [133]
Clustering is inhibited by regulatory segment-derived peptides such as AC-3 and AIP that bind at the T site, but is not inhibited by even high levels of syntide-2, which only binds at the catalytic or S site.
“clustering is inhibited by regulatory segment-derived peptides, e.g., AC-3 and AIP that bind at the T site, but is not inhibited by even high levels of syntide-2, which only binds at the catalytic or S site (133).”
From Synaptic memory and CaMKII (2023) · cites this paper as [133]
Self-association occurs with CaMKIIα but not with CaMKIIβ.
“It occurs with CaMKIIα but not with CaMKIIβ (133).”
From Synaptic memory and CaMKII (2023) · cites this paper as [133]
CaMKIIα but not CaMKIIβ supports a structural function of CaMKII in translocation of proteasomes to synaptic sites and clustering of CaMKII holoenzymes in response to low pH.
“Finally, CaMKIIα but not CaMKIIβ supports a structural function of CaMKII in translocation of proteasomes to synaptic sites (160) and clustering of CaMKII holoenzymes in response to low pH (133).”
From Synaptic memory and CaMKII (2023) · cites this paper as [133]
Self-association is favored by low pH.
“Although self-association is favored by low pH”
From Synaptic memory and CaMKII (2023) · cites this paper as [133]
The added requirement may be that holoenzymes bound to GluN2B also need to bind each other and form clusters, as this is a property of CaMKIIα but not of CaMKIIβ.
“The added requirement may be that holoenzymes bound to GluN2B also need to bind each other and form clusters, as this is a property of CaMKIIα but not of CaMKIIβ (133).”
From Synaptic memory and CaMKII (2023) · cites this paper as [133]
CaMKIIα, but not CaMKIIβ, can self-associate at least at reduced pH or high concentration, and this requires displacement of the autoinhibitory domain.
“It is interesting to note that CaMKIIα, but not CaMKIIβ, can self-associate, at least at reduced pH or high concentration and this requires displacement of the autoinhibitory domain (133–135).”
From Synaptic memory and CaMKII (2023) · cites this paper as [133]
Citations
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Functional Implications of the Subunit Composition of Neuronal CaM Kinase II
Brocke, L., Chiang, L. W., Wagner, P. D., & Schulman, H. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.32.22713 · Cited by 161 · cited 3×
“This result suggests that the ratio of a and b subunits within the same holoenzyme, as found in CaM-kinase II preparations from rat brain (Vallano 1989; Brocke et al. 1999), would in ̄uence their propensity for self-association.”
BackgroundInfluentialA Peptide Model for Calmodulin Trapping by Calcium/Calmodulin-dependent Protein Kinase II
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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
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“Although self-association is favored by low pH, it is strongly dependent upon kinase concentration (133), suggesting that in dendritic spines it could occur at normal pH.”
BackgroundInfluentialCaMKIIβ binding to stable F-actin in vivo regulates F-actin filament stability
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Metadata
- Authors
- Hudmon, A., Kim, S. A., Kolb, S. J., Stoops, J. K., & Waxham, M. N.
- Corresponding author
- Waxham, M. Neal
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2001-03
- Volume
- 76
- Issue
- 5
- Pages
- 1364-1375
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W1977538902
- Cited by
- 46
- References
- 3
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 1 · 2023: 2 · 2022: 1 · 2021: 1 · 2020: 1 · 2019: 1 · 2018: 1 · 2017: 3 · 2015: 1 · 2014: 1
- FWCI
- 1.63
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Texas Health Science Center at Houston
- National Institutes of Health (5r01hl042886-11)
- National Heart, Lung, and Blood Institute (HL42886)
- National Institute of Neurological Disorders and Stroke (NS-26086, T32NS007373, NS-07373)
- 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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- CaMKII, calmodulin, self-association, holoenzyme, autoinhibition, pH dependence, calcium activation, protein aggregation, kinase translocation, ischemia
- MeSH terms
- Amino Acid Sequence, Binding Sites, Calcium, Calmodulin, Hydrogen-Ion Concentration, Kinetics, Light, Microscopy, Electron, Models, Molecular, Peptides, Protein Binding, Protein Conformation, Scattering, Radiation, Calcium-Calmodulin-Dependent Protein Kinases, Catalytic Domain, Calcium-Calmodulin-Dependent Protein Kinase Type 2
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