Binding and selectivity in L-type calcium channels: A mean spherical approximation
Binding and selectivity in L-type calcium channels: A mean spherical approximation
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DOI：
10.1016/s0006-3495(00)76446-0
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发表时间：
2000-10-01
影响因子：
3.4
通讯作者：
Eisenberg, B
中科院分区：
文献类型：
--
作者：
Nonner, W;Catacuzzeno, L;Eisenberg, B
L型钙通道是一类具有重要生物学意义的钙离子结合蛋白。它们通过允许Ca 2+离子穿过脂质膜进入细胞，从而选择细胞外丰度低的离子来产生活细胞的基本细胞内信号。它们的选择机制涉及四个羧酸基团，含有八个氧离子，属于通道蛋白的“EEEE”位点的侧链，与许多Ca 2+螯合分子中发现的设置类似。本研究探讨的假设，在这个位点的选择性是由相互静电屏蔽和体积排斥离子和羧酸氧的有限直径之间。在该模型中，蛋白质的拴系羧酸基团的八个半带电氧被限制在孔的子体积（“过滤器”）中，但与它们的移动的抗衡离子自发地相互作用，因为离子在浓缩的本体溶液中相互作用。平均球近似（MSA）是用来预测离子特定的过剩化学势在过滤器和浴。该理论是校准使用一个单一的实验观察，关于在生理浓度的NaCl的存在下的Ca 2+的表观解离常数。当离子被指定为它们独立已知的晶体直径并且羧酸根氧受到限制时，例如，在有效介电系数为63.5的环境中，假设的选择性过滤器产生了实验中观察到的钙结合曲线的形状，并预测了Ba ~（2+）/Ca ~（2+）和Na ~+/Li ~+的竞争以及Cl ~-的排斥。Na+，Ca ~（2+），Ba ~（2+），其他碱金属离子和Cl ~-的选择性可以通过体积排阻和静电屏蔽单独预测。离子和羧酸盐的自发配位可以产生宽范围的Ca 2+选择性，这取决于羧酸盐基团的体积密度和所在地的介电常数。一个特定的三维结构的原子在结合位点是不需要解释钙离子的选择性。
L-type calcium channels are Ca2+ binding proteins of great biological importance. They generate an essential intracellular signal of living cells by allowing Ca2+ ions to move across the lipid membrane into the cell, thereby selecting an ion that is in low extracellular abundance. Their mechanism of selection involves four carboxylate groups, containing eight oxygen ions, that belong to the side chains of the "EEEE" locus of the channel protein, a setting similar to that found in many Ca2+-chelating molecules. This study examines the hypothesis that selectivity in this locus is determined by mutual electrostatic screening and volume exclusion between ions and carboxylate oxygens of finite diameters. In this model, the eight half-charged oxygens of the tethered carboxylate groups of the protein are confined to a subvolume of the pore (the "filter"), but interact spontaneously with their mobile counterions as ions interact in concentrated bulk solutions. The mean spherical approximation (MSA) is used to predict ion-specific excess chemical potentials in the filter and baths. The theory is calibrated using a single experimental observation, concerning the apparent dissociation constant of Ca2+ in the presence of a physiological concentration of NaCl. When ions are assigned their independently known crystal diameters and the carboxylate oxygens are constrained, e.g., to a volume of 0.375 nm(3) in an environment with an effective dielectric coefficient of 63.5, the hypothesized selectivity filter produces the shape of the calcium binding curves observed in experiment, and it predicts Ba2+/Ca2+ and Na+/Li+ competition, and Cl- exclusion as observed. The selectivities for Na+, Ca2+, Ba2+, other alkali metal ions, and Cl- thus can be predicted by volume exclusion and electrostatic screening alone. Spontaneous coordination of ions and carboxylates can produce a wide range of Ca2+ selectivities, depending on the volume density of carboxylate groups and the permittivity in the locus. A specific three-dimensional structure of atoms at the binding site is not needed to explain Ca2+ selectivity.