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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

DOI 10.1016/j.cell.2005.10.029

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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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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
ORCID: Rosenberg, Oren S.
Deindl, Sebastian
Nairn, Angus C.
Kuriyan, John
Venue: Cell
Publisher: Elsevier BV
Published: 2005-12
Volume: 123
Issue: 5
Pages: 849-860
ISSN: 0092-8674 (ISSN-L)
DOI: 10.1016/j.cell.2005.10.029
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: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 2821 d)
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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Structure of the Autoinhibited Kinase Domain of CaMKII and SAXS Analysis of the Holoenzyme

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