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Cited by 58Protein Kinase Regulation and GTPase SignalingNeuroscience and Neuropharmacology ResearchProtein Structure and Dynamics

Flexible linkers in CaMKII control the balance between activating and inhibitory autophosphorylation

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Bhattacharyya, Moitrayee, Lee, Young Kwang, Muratcioglu, Serena, Qiu, Baiyu, Nyayapati, Priya, Schulman, Howard, Groves, Jay T, Kuriyan, John·2020·eLife
DOI 10.7554/elife.53670PMC PMC7141811

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Abstract

The many variants of human Ca2+/calmodulin-dependent protein kinase II (CaMKII) differ in the lengths and sequences of disordered linkers connecting the kinase domains to the oligomeric hubs of the holoenzyme. CaMKII activity depends on the balance between activating and inhibitory autophosphorylation (on Thr 286 and Thr 305/306, respectively, in the human α isoform). Variation in the linkers could alter transphosphorylation rates within a holoenzyme and the balance of autophosphorylation outcomes. We show, using mammalian cell expression and a single-molecule assay, that the balance of autophosphorylation is flipped between CaMKII variants with longer and shorter linkers. For the principal isoforms in the brain, CaMKII-α, with a ~30 residue linker, readily acquires activating autophosphorylation, while CaMKII-β, with a ~200 residue linker, is biased towards inhibitory autophosphorylation. Our results show how the responsiveness of CaMKII holoenzymes to calcium signals can be tuned by varying the relative levels of isoforms with long and short linkers.

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  • The linker length affects CaM affinity and Ca2+ spike frequency sensitivity as well as rates of autophosphorylation.

    “The linker length affects CaM affinity and Ca2+ spike frequency sensitivity (69, 158) as well as rates of autophosphorylation (159).”

    From Synaptic memory and CaMKII (2023) · cites this paper as [159]

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Cited by

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Authors
Bhattacharyya, M., Lee, Y. K., Muratcioglu, S., Qiu, B., Nyayapati, P., Schulman, H., Groves, J. T., & Kuriyan, J.
Affiliations
  • QB3 (US)
  • Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
  • Panorama Institute of Molecular Medicine, Sunnyvale, United States
Corresponding author
  • Groves, Jay T
  • Kuriyan, John
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2020-03-09
Volume
9
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.53670
PMC
PMC7141811
OpenAlex
W3012189330
Cited by
58
References
10
Citations by year
2026: 3 · 2025: 11 · 2024: 5 · 2023: 14 · 2022: 12 · 2021: 8 · 2020: 5
FWCI
3.16
Type
journal article
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institute of General Medical Sciences (K99 GM 126145)
  • Howard Hughes Medical Institute
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, calcium/calmodulin-dependent protein kinase II, disordered linker, autophosphorylation, CaMKII isoforms, CaMKIIα, holoenzyme, transphosphorylation, calcium signaling
MeSH terms
Single Molecule Imaging, Calcium, Calmodulin, Enzyme Activation, Humans, Phosphorylation, Protein Isoforms, Catalytic Domain, Calcium-Calmodulin-Dependent Protein Kinase Type 2

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