An allosteric model of calmodulin explains differential activation of PP2B and CaMKII.

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TitleAn allosteric model of calmodulin explains differential activation of PP2B and CaMKII.
Publication TypeJournal Article
Year of Publication2008
AuthorsStefan, MI, Edelstein, SJ, Le Novère, N
JournalProc Natl Acad Sci U S A
Volume105
Issue31
Pagination10768-73
Date Published2008 Aug 5
ISSN1091-6490
KeywordsAllosteric Regulation, Calcineurin, Calcium, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Calmodulin, Computer Simulation, Enzyme Activation, Kinetics, Models, Molecular, Protein Binding, Synapses
Abstract

<p>Calmodulin plays a vital role in mediating bidirectional synaptic plasticity by activating either calcium/calmodulin-dependent protein kinase II (CaMKII) or protein phosphatase 2B (PP2B) at different calcium concentrations. We propose an allosteric model for calmodulin activation, in which binding to calcium facilitates the transition between a low-affinity [tense (T)] and a high-affinity [relaxed (R)] state. The four calcium-binding sites are assumed to be nonidentical. The model is consistent with previously reported experimental data for calcium binding to calmodulin. It also accounts for known properties of calmodulin that have been difficult to model so far, including the activity of nonsaturated forms of calmodulin (we predict the existence of open conformations in the absence of calcium), an increase in calcium affinity once calmodulin is bound to a target, and the differential activation of CaMKII and PP2B depending on calcium concentration.</p>

DOI10.1073/pnas.0804672105
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID18669651
PubMed Central IDPMC2504824