PDF(Pubmed)
Abstract：
EF-hand Ca2+-binding proteins (CBPs), such as S100 proteins (S100s) and calmodulin (CaM), are signaling proteins that undergo conformational changes upon increasing intracellular Ca2+. Upon binding Ca2+, S100 proteins and CaM interact with protein targets and induce important biological responses. The Ca2+-binding affinity of CaM and most S100s in the absence of target is weak (CaKD > 1 μM). However, upon effector protein binding, the Ca2+ affinity of these proteins increases via heterotropic allostery (CaKD < 1 μM). Because of the high number and micromolar concentrations of EF-hand CBPs in a cell, at any given time, allostery is required physiologically, allowing for (i) proper Ca2+ homeostasis and (ii) strict maintenance of Ca2+-signaling within a narrow dynamic range of free Ca2+ ion concentrations, [Ca2+]free. In this review, mechanisms of allostery are coalesced into an empirical \"binding and functional folding (BFF)\" physiological framework. At the molecular level, folding (F), binding and folding (BF), and BFF events include all atoms in the biomolecular complex under study. The BFF framework is introduced with two straightforward BFF types for proteins (type 1, concerted; type 2, stepwise) and considers how homologous and nonhomologous amino acid residues of CBPs and their effector protein(s) evolved to provide allosteric tightening of Ca2+ and simultaneously determine how specific and relatively promiscuous CBP-target complexes form as both are needed for proper cellular function.
摘要：
EF-手Ca2+结合蛋白（CBPs），如S100蛋白（S100s）和钙调蛋白（CaM），是在增加细胞内Ca2+时发生构象变化的信号蛋白。在结合Ca2+时，S100蛋白和CaM与蛋白靶标相互作用并诱导重要的生物学反应。在不存在靶标的情况下,CaM和大多数S100s的Ca2+结合亲和力弱(CaKD>1μM)。然而,在效应蛋白结合时，这些蛋白质的Ca2+亲和力通过异向变构(CaKD<1μM)增加。由于细胞中EF手CBPs的数量和微摩尔浓度很高，在任何给定的时间，生理上需要变形金刚，允许（i）适当的Ca2稳态和（ii）严格维持Ca2-信号在狭窄的游离Ca2离子浓度动态范围内，[Ca2+]自由。在这次审查中,变构机制被合并成一个经验的“结合和功能折叠(BFF)”生理框架。在分子水平上,折叠(F),装订和折叠（BF），BFF事件包括所研究的生物分子复合物中的所有原子。BFF框架引入了两种直接的BFF类型的蛋白质（1型，一致；2型，逐步），并考虑了CBP及其效应蛋白的同源和非同源氨基酸残基如何进化以提供Ca2的变构紧缩，并同时确定如何形成特异性和相对混杂的CBP-靶复合物，因为两者都是适当的细胞功能所必需的。
