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Detailed state model of CaMKII activation and autophosphorylation

Lučić, Vladan and Greif, Gabriela J. and Kennedy, Mary B. (2008) Detailed state model of CaMKII activation and autophosphorylation. European Biophysics Journal, 38 (1). pp. 83-98. ISSN 0175-7571. PMCID PMC2801814. doi:10.1007/s00249-008-0362-4.

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By combining biochemical experiments with computer modelling of biochemical reactions we elucidated some of the currently unresolved aspects of calcium-calmodulin-dependent protein kinase II (CaMKII) activation and autophosphorylation that might be relevant for its physiological function and provided a model that incorporates in detail the mechanism of CaMKII activation and autophosphorylation at T286 that is based on experimentally determined binding constants and phosphorylation rates. To this end, we developed a detailed state model of CaMKII activation and autophosphorylation based on the currently available literature, and constrained it with data from CaMKII autophosphorylation essays. Our model takes exact phosphorylation patterns of CaMKII holoenzymes into account, and is valid at physiologically relevant conditions where the concentrations of calcium and calmodulin are not saturating. Our results strongly suggest that even when bound to less than fully calcium-bound calmodulin, CaMKII is in the active state, and indicate that the autophosphorylation of T286 by an active non-phosphorylated CaMKII subunit is significantly faster than by an autophosphorylated CaMKII subunit. These results imply that CaMKII can be efficiently activated at significantly lower calcium concentrations than previously thought, which may explain how CaMKII gets activated at calcium concentrations existing at synapses in vivo. We also investigated the significance of CaMKII holoenzyme structure on CaMKII autophosphorylation and obtained estimates of previously unknown binding constants.

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URLURL TypeDescription CentralArticle
Kennedy, Mary B.0000-0003-1369-0525
Additional Information:© The Author(s) 2008. This article is published with open access at Received: 14 December 2007 / Revised: 2 July 2008 / Accepted: 3 July 2008 / Published online: 4 September 2008. The work was supported by a fellowship to V. L. from the Caltech computational Biology Initiative funded by a Burroughs Wellcome Fund Interfaces Award and by grant no. NS44306 to M.B.K. from the US Public Health Service National Institutes of Health. We wish to thank Alan J. Rosenstein for technical assistance. V. L. would like to acknowledge the generous support of W. Baumeister. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
Funding AgencyGrant Number
Caltech Computational Biology InitiativeUNSPECIFIED
Burroughs Wellcome FundUNSPECIFIED
Subject Keywords:CaMKII; calcium-calmodulin-dependent protein kinase; computer simulation; calcium signalling; modelling; synapse
Issue or Number:1
PubMed Central ID:PMC2801814
Record Number:CaltechAUTHORS:LUCebj08
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:13516
Deposited By: Tony Diaz
Deposited On:03 Apr 2009 21:57
Last Modified:01 Jun 2023 22:27

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