Grabarek Zenon
Boston Biomedical Research Institute, 64 Grove Street, Watertown, MA 02472-2829, USA.
Biochim Biophys Acta. 2011 May;1813(5):913-21. doi: 10.1016/j.bbamcr.2011.01.017. Epub 2011 Jan 22.
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.
被称为“EF 手”的钙离子结合螺旋-环-螺旋结构基序是一大类作为细胞内钙离子受体发挥作用的蛋白质的常见组成部分。这些蛋白质在化学性质相似的二价阳离子镁离子过量约 1000 倍的情况下，能特异性地响应微摩尔浓度的钙离子。细胞内游离镁离子浓度被严格控制在 0.5 - 1.0 毫摩尔的狭窄范围内，在静息钙离子水平时，这足以使许多 EF 手蛋白的钙离子结合位点完全或部分饱和。因此，为了传递钙离子信号，EF 手蛋白对钙离子的反应必须不同于对镁离子的反应。在这篇综述中，根据最近提出的两步钙离子结合机制（Grabarek, Z., J. Mol. Biol., 2005, 346, 1351），对镁离子与 EF 手蛋白结合的结构方面进行了考量和阐释。有人提出，由于双 EF 手结构域结构所施加的立体化学限制，较小的镁离子不能像钙离子那样与 EF 手的配体结合，而是默认稳定 EF 手的脱辅基样构象。有人提出，镁离子通过稳定一些 EF 手蛋白的“关闭状态”，在钙离子依赖的细胞过程调节中发挥积极作用，从而在静息钙离子水平促进关闭它们各自的靶酶。因此，一些归因于镁离子缺乏的病理状况可能与潜在的钙离子调节细胞过程的过度激活有关。本文是名为：第 11 届欧洲钙研讨会的特刊的一部分。
