![]() ![]() In many C2 domains, binding of two or three Ca 2+ ions in the three variable loops creates a substantial electrostatic potential that accelerates a protein's association with anionic membrane leaflets, such as the cytoplasmic surface of eukaryotic plasma membranes and the outer leaflet of outer mitochondrial membranes ( Figure 1D). The local nature of Ca 2+ signaling is intimately tied to this large range of affinities. Hundreds of cellular proteins have been adapted to bind Ca 2+ over a million-fold range of affinities (nM to mM), in some cases simply to buffer or lower Ca 2+ levels, and in others to trigger cellular processes. Thus, to exert control over Ca 2+, cells must chelate, compartmentalize, or extrude it. Unlike complex molecules, Ca 2+ cannot be chemically altered. ![]() Hence, cells have evolved ways to sequester this dangerous divalent, perhaps at first to simply reduce its cytosolic levels but later to use its binding energy for signal transduction. Why is Ca 2+ so avidly excluded from the cytosol? One reason is that Ca 2+ binds water much less tightly than Mg 2+ and precipitates phosphate. In contrast, the concentration of Ca 2+'s cousin, Mg 2+, barely differs across the plasma membrane. Underlying the speed and effectiveness of Ca 2+ is the 20,000-fold gradient maintained by cells between their intracellular (∼100 nM free) and extracellular (mM) concentrations. Cells invest much of their energy to effect changes in Ca 2+ concentration (). ![]()
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