Insights into modulation of calcium signaling by magnesium in calmodulin, troponin C and related EF-hand proteins

The Ca2+-binding helix-loop-helix structural motif called EF-hand is a common building block of a large family of proteins that function as intracellular Ca2+-receptors. These proteins respond specifically to micromolar concentrations of Ca2+ in the presence of similar to 1000-fold excess of the chemically similar divalent cation Mg2+. The intracellular free Mg2+ concentration is tightly controlled in a narrow range of 0.5-1.0 mM, which at the resting Ca2+ levels is sufficient to fully or partially saturate the Ca2+-binding sites of many EF-hand proteins. Thus, to convey Ca2+ signals, EF-hand proteins must respond differently to Ca2+ than to Mg2+. In this review the structural aspects of Mg2+ binding to EF-hand proteins are considered and interpreted in light of the recently proposed two-step Ca2+-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 Mg2+ ion cannot engage the ligands of an EF-hand in the same way as Ca2+ and defaults to stabilizing the apo-like conformation of the EF-hand. It is proposed that Mg2+ plays an active role in the Ca2+-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 Ca2+ levels. Therefore, some pathological conditions attributed to Mg2+ deficiency might be related to excessive activation of underlying Ca2+-regulated cellular processes. This article is part of a Special Issue entitled: 11th European Symposium on Calcium. (C) 2011 Elsevier B.V. All rights reserved.