Divalent calcium ion (Ca²⁺) plays an indispensable role as a second messenger in a myriad of signal transduction processes. Of utmost importance for the faultless functioning of calcium-modulated signaling proteins is their binding selectivity of the native metal cation over rival biogenic/abiogenic metal ion contenders in the intra/extracellular fluids. In this Perspective, we summarize recent findings on the competition between the cognate Ca²⁺ and other biogenic or abiogenic divalent cations for binding to Ca²⁺-signaling proteins or organic cofactors. We describe the competition between the two most abundant intracellular biogenic metal ions (Mg²⁺ and Ca²⁺) for Ca²⁺-binding sites in signaling proteins, followed by the rivalry between native Ca²⁺ and “therapeutic” Li⁺ as well as “toxic” Pb²⁺. We delineate the key factors governing the rivalry between the native and non-native cations in proteins and highlight key implications for the biological performance of the respective proteins/organic cofactors.

中文翻译：

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信号中的钙：其对生物和非生物金属离子的特异性和脆弱性

二价钙离子 (Ca ²⁺ ) 在无数信号转导过程中作为第二信使发挥着不可或缺的作用。对于钙调节信号蛋白的完美功能而言，最重要的是它们对天然金属阳离子的结合选择性，而不是细胞内/外液中的生物/非生物金属离子竞争者。在这个视角中，我们总结了最近关于同源 Ca ²⁺与其他生物或非生物二价阳离子之间竞争与 Ca ²⁺信号蛋白或有机辅因子结合的发现。我们描述了两种最丰富的细胞内生物金属离子（Mg ²⁺和 Ca ²⁺）之间对 Ca ²⁺的竞争- 信号蛋白中的结合位点，随后是天然 Ca ²⁺和“治疗性” Li ⁺以及“有毒” Pb ²⁺之间的竞争。我们描述了控制蛋白质中天然和非天然阳离子之间竞争的关键因素，并强调了对相应蛋白质/有机辅因子的生物学性能的关键影响。