| Many downstream signaling events mediated by Ca2+are modulated by a Ca2+-sensing and binding protein, calmodulin
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| Calmodulin is a 17-kDa protein found in all animal and plant cells (comprising up to 1% of cellular protein). It belongs to a family of proteins characterized by one or more copies of a Ca2+-binding structural motif called an EF hand motif (Fig. 38.7). Calmodulin is comprised of two similar globular domains joined by a long (6.5 nm; 65Å) α-helix, each globular lobe having two EF hand motifs/Ca2+-binding sites, 1.1 nm (11Å) apart. Binding of three to four calcium ions (which occurs when the intracellular calcium ion concentration is increased to about 500 nmol/L) induces a major conformational change that allows calmodulin to bind to and modify target proteins such as cAMP-PDE. Binding of several calcium ions allows cooperativity in the activation of calmodulin, such that small changes in Ca2+ concentration cause large changes in the concentration of an active Ca2+-calmodulin (Ca2+/CAM) complex, providing amplification of the original hormone signal.
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| Calmodulin has a wide range of target effectors, including Ca2+/CAM-dependent protein kinases, which phosphorylate serine-threonine residues on proteins to regulate a variety of processes. For example, the broad-specificity kinase, Ca2+/CAM-kinase II, is involved in the regulation of fuel metabolism, ion permeability, neurotransmitter biology, and myosin light-chain kinase and phosphorylase kinase activity. Interestingly, calmodulin serves as a permanent regulatory subunit of phosphorylase kinase and may also regulate non-kinase effectors such as certain adenylyl cyclase isoforms and also cAMP-PDEs, indicating 'cross-talk' between cAMP- and Ca2+-dependent signaling pathways. Moreover, mice defective in the calmodulin-dependent adenylyl cyclase are deficient in spatial memory, showing that this signal transduction system is important for learning and memory in vertebrates.
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