Structural modeling of calcium binding in the selectivity filter of the L-type calcium channel
Structural modeling of calcium binding in the selectivity filter of the L-type calcium channel
复制标题
DOI：
10.1007/s00249-009-0574-2
复制
发表时间：
2010-04-01
影响因子：
2
通讯作者：
Zhorov, Boris S.
中科院分区：
文献类型：
--
作者：
Cheng, Ricky C. K.;Tikhonov, Denis B.;Zhorov, Boris S.
钙通道在生理上起着至关重要的作用。由于缺乏高分辨率的通道结构，离子渗透的机制是未知的。在这里，我们使用了一篇随附论文中提出的方法（Cheng和Zhorov在Eur Biophys J， 2009）来预测l型钙通道结构模型中钙离子可能的螯合模式。我们比较了三种模型，其中两个或三个钙离子与四个选择性过滤谷氨酸和一个保守的天冬氨酸相邻的谷氨酸在重复II相互作用。蒙特卡罗能量最小化产生了许多与钙离子结合至少两种选择性过滤羧酸盐的配合物。在这些配合物中，钙-羧酸盐的吸引力被钙-钙和羧酸-羧酸的斥力所抵消。这些配合物的叠加表明钙离子和谷氨酸的羧酸基团具有高度的流动性。我们利用预测的配合物提出了一种涉及钙离子单纵队运动的渗透机制。这种机制的关键特征是桥接谷氨酸的存在，它协调两个钙离子，使它们能够在不同的螯合模式之间转换，包括来自通道蛋白的4到6个氧原子。保守的天冬氨酸被认为是协调钙离子从细胞外侧进入选择性过滤器。重复序列III和IV中的谷氨酸，距离重复序列II天冬氨酸最远，被认为是协调钙离子，使选择性过滤器进入内孔。根据我们的模型，讨论了已发表的实验数据和早期提出的渗透模型。
Calcium channels play crucial physiological roles. In the absence of high-resolution structures of the channels, the mechanism of ion permeation is unknown. Here we used a method proposed in an accompanying paper (Cheng and Zhorov in Eur Biophys J, 2009) to predict possible chelation patterns of calcium ions in a structural model of the L-type calcium channel. We compared three models in which two or three calcium ions interact with the four selectivity filter glutamates and a conserved aspartate adjacent to the glutamate in repeat II. Monte Carlo energy minimizations yielded many complexes with calcium ions bound to at least two selectivity filter carboxylates. In these complexes calcium-carboxylate attractions are counterbalanced by calcium-calcium and carboxylate-carboxylate repulsions. Superposition of the complexes suggests a high degree of mobility of calcium ions and carboxylate groups of the glutamates. We used the predicted complexes to propose a permeation mechanism that involves single-file movement of calcium ions. The key feature of this mechanism is the presence of bridging glutamates that coordinate two calcium ions and enable their transitions between different chelating patterns involving four to six oxygen atoms from the channel protein. The conserved aspartate is proposed to coordinate a calcium ion incoming to the selectivity filter from the extracellular side. Glutamates in repeats III and IV, which are most distant from the repeat II aspartate, are proposed to coordinate the calcium ion that leaves the selectivity filter to the inner pore. Published experimental data and earlier proposed permeation models are discussed in view of our model.