Structural analysis and stochastic modelling suggest a mechanism for calmodulin trapping by CaMKII.

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TitleStructural analysis and stochastic modelling suggest a mechanism for calmodulin trapping by CaMKII.
Publication TypeJournal Article
Year of Publication2012
AuthorsStefan, MI, Marshall, DP, Le Novère, N
JournalPLoS One
Volume7
Issue1
Paginatione29406
Date Published2012
ISSN1932-6203
KeywordsAnimals, Binding Sites, Binding, Competitive, Caenorhabditis elegans Proteins, Calcium, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Calmodulin, Computer Simulation, Models, Molecular, Phosphorylation, Protein Binding, Protein Structure, Tertiary, Stochastic Processes, Threonine
Abstract

<p>Activation of CaMKII by calmodulin and the subsequent maintenance of constitutive activity through autophosphorylation at threonine residue 286 (Thr286) are thought to play a major role in synaptic plasticity. One of the effects of autophosphorylation at Thr286 is to increase the apparent affinity of CaMKII for calmodulin, a phenomenon known as "calmodulin trapping". It has previously been suggested that two binding sites for calmodulin exist on CaMKII, with high and low affinities, respectively. We built structural models of calmodulin bound to both of these sites. Molecular dynamics simulation showed that while binding of calmodulin to the supposed low-affinity binding site on CaMKII is compatible with closing (and hence, inactivation) of the kinase, and could even favour it, binding to the high-affinity site is not. Stochastic simulations of a biochemical model showed that the existence of two such binding sites, one of them accessible only in the active, open conformation, would be sufficient to explain calmodulin trapping by CaMKII. We can explain the effect of CaMKII autophosphorylation at Thr286 on calmodulin trapping: It stabilises the active state and therefore makes the high-affinity binding site accessible. Crucially, a model with only one binding site where calmodulin binding and CaMKII inactivation are strictly mutually exclusive cannot reproduce calmodulin trapping. One of the predictions of our study is that calmodulin binding in itself is not sufficient for CaMKII activation, although high-affinity binding of calmodulin is.</p>

DOI10.1371/journal.pone.0029406
Alternate JournalPLoS ONE
PubMed ID22279535
PubMed Central IDPMC3261145