Cited by 333Protein Kinase Regulation and GTPase SignalingProtein Structure and DynamicsSignaling Pathways in Disease

Structure of the Autoinhibited Kinase Domain of CaMKII and SAXS Analysis of the Holoenzyme

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Rosenberg, Oren S., Deindl, Sebastian, Sung, Rou-Jia, Nairn, Angus C., Kuriyan, John·2005·Cell

Abstract

Ca2+/calmodulin-dependent protein kinase-II (CaMKII) is unique among protein kinases for its dodecameric assembly and its complex response to Ca2+. The crystal structure of the autoinhibited kinase domain of CaMKII, determined at 1.8 A resolution, reveals an unexpected dimeric organization in which the calmodulin-responsive regulatory segments form a coiled-coil strut that blocks peptide and ATP binding to the otherwise intrinsically active kinase domains. A threonine residue in the regulatory segment, which when phosphorylated renders CaMKII calmodulin independent, is held apart from the catalytic sites by the organization of the dimer. This ensures a strict Ca2+ dependence for initial activation. The structure of the kinase dimer, when combined with small-angle X-ray scattering data for the holoenzyme, suggests that inactive CaMKII forms tightly packed autoinhibited assemblies that convert upon activation into clusters of loosely tethered and independent kinase domains.

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Crossref · 10.1016/j.cell.2005.10.029

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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 [76]

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Authors
Rosenberg, O. S., Deindl, S., Sung, R.-J., Nairn, A. C., & Kuriyan, J.
Affiliations
  • Howard Hughes Medical Institute (US)
  • Yale University (US)
Corresponding author
Kuriyan, John
Venue
Cell
Publisher
Elsevier BV
Published
2005-12
Volume
123
Issue
5
Pages
849-860
ISSN
0092-8674 (ISSN-L)
OpenAlex
W2023129668
Cited by
333
References
53
Citations by year
2026: 7 · 2025: 10 · 2024: 14 · 2023: 21 · 2022: 16 · 2021: 14 · 2020: 20 · 2019: 14 · 2018: 11 · 2017: 9 · 2016: 7 · 2015: 13 · 2014: 13 · 2013: 13 · 2012: 22
FWCI
8.44
Type
journal article
Language
en
Open access
Locations
  • Cell (publishedVersion)
  • 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 › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
Keywords
CaMKII, calcium/calmodulin-dependent protein kinase II, autoinhibition, kinase domain, threonine phosphorylation, calcium dependence, holoenzyme structure, protein kinase activation
MeSH terms
Amino Acid Sequence, Animals, Binding Sites, Calcium, Calmodulin, Models, Molecular, Molecular Sequence Data, Sequence Alignment, Caenorhabditis elegans, Protein Structure, Secondary, Protein Structure, Tertiary, Calcium-Calmodulin-Dependent Protein Kinases, Crystallography, X-Ray, Dimerization, Holoenzymes, Protein Structure, Quaternary, Caenorhabditis elegans Proteins, Calcium-Calmodulin-Dependent Protein Kinase Type 2

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