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Issue 1, 2008
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Multiple calcium binding sites make calmodulin multifunctional

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Proteinprotein or protein–ion interactions with multisite proteins are essential to the regulation of intracellular and extracellular events. There is, however, limited understanding of how ligand–multisite protein interactions selectively regulate the activities of multiple protein targets. In this paper, we focus on the important calcium (Ca2+) binding protein calmodulin (CaM), which has four Ca2+ ion binding sites and regulates the activity of over 30 other proteins. Recent progress in structural studies has led to significant improvements in the understanding of Ca2+–CaM-dependent regulation mechanisms. However, no quantitative model is currently available that can fully explain how the structural diversity of protein interaction surfaces leads to selective activation of protein targets. In this paper, we analyze the multisite protein–ligand binding mechanism using mathematical modelling and experimental data for Ca2+–CaM-dependent protein targets. Our study suggests a potential mechanism for selective and differential activation of Ca2+–CaM targets by the same CaM molecules, which are involved in a variety of intracellular functions. The close agreement between model predictions and experimental dose–response curves for CaM targets available in the literature suggests that such activation is due to the selective activity of CaM conformations in complexes with variable numbers of Ca2+ ions. Although the paper focuses on the Ca2+–CaM pair as a particularly data rich example, the proposed model predictions are quite general and can easily be extended to other multisite proteins. The results of the study may therefore be proposed as a general explanation for multifunctional target regulation by multisite proteins.

Graphical abstract: Multiple calcium binding sites make calmodulin multifunctional

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Supplementary files

Article information

03 Sep 2007
08 Oct 2007
First published
30 Oct 2007

Mol. BioSyst., 2008,4, 66-73
Article type

Multiple calcium binding sites make calmodulin multifunctional

N. V. Valeyev, P. Heslop-Harrison, I. Postlethwaite, N. V. Kotov and D. G. Bates, Mol. BioSyst., 2008, 4, 66
DOI: 10.1039/B713461D

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