The Ca(2+)-binding helix-loop-helix structural motif called "EF-hand" is a common building block of a large family of proteins that function as intracellular Ca(2+)-receptors. These proteins respond specifically to micromolar concentrations of Ca(2+) in the presence of ~1000-fold excess of the chemically similar divalent cation Mg(2+). The intracellular free Mg(2+) concentration is tightly controlled in a narrow range of 0.5-1.0mM, which at the resting Ca(2+) levels is sufficient to fully or partially saturate the Ca(2+)-binding sites of many EF-hand proteins. Thus, to convey Ca(2+) signals, EF-hand proteins must respond differently to Ca(2+) than to Mg(2+). In this review the structural aspects of Mg(2+) binding to EF-hand proteins are considered and interpreted in light of the recently proposed two-step Ca(2+)-binding mechanism (Grabarek, Z., J. Mol. Biol., 2005, 346, 1351). It is proposed that, due to stereochemical constraints imposed by the two-EF-hand domain structure, the smaller Mg(2+) ion cannot engage the ligands of an EF-hand in the same way as Ca(2+) and defaults to stabilizing the apo-like conformation of the EF-hand. It is proposed that Mg(2+) plays an active role in the Ca(2+)-dependent regulation of cellular processes by stabilizing the "off state" of some EF-hand proteins, thereby facilitating switching off their respective target enzymes at the resting Ca(2+) levels. Therefore, some pathological conditions attributed to Mg(2+) deficiency might be related to excessive activation of underlying Ca(2+)-regulated cellular processes. This article is part of a Special Issue entitled: 11th European Symposium on Calcium.
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