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Lobe-specific Functions of Ca2+center dot Calmodulin in alpha Ca2+center dot Calmodulin-dependent Protein Kinase II Activation

Jama, AM; Gabriel, J; Al-Nagar, AJ; Martin, S; Baig, SZ; Soleymani, H; Chowdhury, Z; Beesley, P; Török, K (2011) Lobe-specific Functions of Ca2+center dot Calmodulin in alpha Ca2+center dot Calmodulin-dependent Protein Kinase II Activation. JOURNAL OF BIOLOGICAL CHEMISTRY, 286 (14). ISSN 0021-9258
SGUL Authors: Torok, Katalin

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N-Methyl-d-aspartic acid receptor-dependent long term potentiation (LTP), a model of memory formation, requires Ca2+·calmodulin-dependent protein kinase II (αCaMKII) activity and Thr286 autophosphorylation via both global and local Ca2+ signaling, but the mechanisms of signal transduction are not understood. We tested the hypothesis that the Ca2+-binding activator protein calmodulin (CaM) is the primary decoder of Ca2+ signals, thereby determining the output, e.g. LTP. Thus, we investigated the function of CaM mutants, deficient in Ca2+ binding at sites 1 and 2 of the N-terminal lobe or sites 3 and 4 of the C-terminal CaM lobe, in the activation of αCaMKII. Occupancy of CaM Ca2+ binding sites 1, 3, and 4 is necessary and sufficient for full activation. Moreover, the N- and C-terminal CaM lobes have distinct functions. Ca2+ binding to N lobe Ca2+ binding site 1 increases the turnover rate of the enzyme 5-fold, whereas the C lobe plays a dual role; it is required for full activity, but in addition, via Ca2+ binding site 3, it stabilizes ATP binding to αCaMKII 4-fold. Thr286 autophosphorylation is also dependent on Ca2+ binding sites on both the N and the C lobes of CaM. As the CaM C lobe sites are populated by low amplitude/low frequency (global) Ca2+ signals, but occupancy of N lobe site 1 and thus activation of αCaMKII requires high amplitude/high frequency (local) Ca2+ signals, lobe-specific sensing of Ca2+-signaling patterns by CaM is proposed to explain the requirement for both global and local Ca2+ signaling in the induction of LTP via αCaMKII.

Item Type: Article
Additional Information: © 2011 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version full access. Creative Commons Attribution Non-Commercial License applies to Author Choice Articles
Keywords: Animals, Calcium, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Calmodulin, Cell Line, Humans, Long-Term Potentiation, Phosphorylation, Spodoptera, Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, LONG-TERM POTENTIATION, ALPHA-CAMKII, CALCIUM DISSOCIATION, DENDRITIC SPINES, STOPPED-FLOW, BINDING-SITE, CALMODULIN, MECHANISM, AUTOPHOSPHORYLATION, RECEPTOR
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) > Cell Sciences (INCCCS)
ISSN: 0021-9258
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8 April 2011Published
Web of Science ID: WOS:000289077500045
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