An Iris-Like Mechanism of Pore Dilation in the CorA Magnesium Transport System
An Iris-Like Mechanism of Pore Dilation in the CorA Magnesium Transport System
复制标题
DOI：
10.1016/j.bpj.2009.11.009
复制
发表时间：
2010-03-03
影响因子：
3.4
通讯作者：
Pomes, Regis
中科院分区：
文献类型：
--
作者：
Chakrabarti, Nilmadhab;Neale, Chris;Pomes, Regis
镁跨细胞膜转运是许多生理过程所必需的。最近报道的Cora镁运输系统的三个晶体结构揭示了一个令人惊讶的结构，一束巨大的a-螺旋形成了一个60埃长的孔，这个孔延伸到膜之外，然后扩展成漏斗状的胞液结构域。二价阳离子存在于可能的细胞内调控部位，表明这些结构对应于CORA的闭合构象。为了检验传导途径的性质，我们对有和没有调节离子的脂质双层中的两个结构进行了110 ns的分子动力学模拟。结果表明，横跨膜-胞质界面的15埃长的疏水收缩构成了空间瓶颈，其位置与反对阳离子转移的静电势垒重合。在其中一个模拟中，去除调节离子后的结构松弛导致孔螺旋的倾斜度发生协调变化，导致虹膜样扩张和疏水颈部的自发水化。这一简单而稳健的机制与细胞内镁浓度对孔道开放的调节是一致的，并解释了CORA不寻常的结构。
Magnesium translocation across cell membranes is essential for numerous physiological processes. Three recently reported crystal structures of the CorA magnesium transport system revealed a surprising architecture, with a bundle of giant a-helices forming a 60-angstrom-long pore that extends beyond the membrane before widening into a funnel-shaped cytosolic domain. The presence of divalent cations in putative intracellular regulation sites suggests that these structures correspond to the closed conformation of CorA. To examine the nature of the conduction pathway, we performed 110-ns molecular-dynamics simulations of two of these structures in a lipid bilayer with and without regulatory ions. The results show that a 15-angstrom-long hydrophobic constriction straddling the membrane-cytosol interface constitutes a steric bottleneck whose location coincides with an electrostatic barrier opposing cation translocation. In one of the simulations, structural relaxation after the removal of regulatory ions led to concerted changes in the tilt of the pore helices, resulting in iris-like dilation and spontaneous hydration of the hydrophobic neck. This simple and robust mechanism is consistent with the regulation of pore opening by intracellular magnesium concentration, and explains the unusual architecture of CorA.