Glutamate transporters have a chloride channel with two hydrophobic gates.
Glutamate transporters have a chloride channel with two hydrophobic gates.
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谷氨酸转运蛋白有一个氯离子通道，有两个疏水门。
DOI：
10.1038/s41586-021-03240-9
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发表时间：
2021-03
期刊：
影响因子：
64.8
通讯作者：
Ryan RM
中科院分区：
文献类型：
--
作者：
Chen I;Pant S;Wu Q;Cater RJ;Sobti M;Vandenberg RJ;Stewart AG;Tajkhorshid E;Font J;Ryan RM
谷氨酸是中枢神经系统中含量最丰富的兴奋性神经递质，其精确调控对维持正常脑功能、预防兴奋性毒性具有重要意义。细胞外谷氨酸的去除是通过质膜结合的转运蛋白实现的，该转运蛋白通过升降机制将谷氨酸转运到钠、钾和pH梯度。谷氨酸转运体也通过一个类似通道的过程进行氯离子转运，这个过程在热力学上是与转运无关的。然而，允许这些双功能转运蛋白执行两个看似矛盾的角色的分子机制尚不清楚。在这里，我们报告了谷氨酸转运体同系物在开放通道状态下的冷冻电子显微镜结构，揭示了在运输周期中形成的水腔。通过研究功能性质并结合分子动力学模拟，我们发现这个空腔是一个由两个疏水区域控制的水中可达的氯离子渗透途径，并且在哺乳动物和古生代谷氨酸转运体中是保守的。我们的发现为谷氨酸转运蛋白支持其双重功能的机制提供了洞察力，并增加了一条重要的信息来帮助绘制SLC1A转运蛋白家族共享的完整运输周期的图谱。
Glutamate is the most abundant excitatory neurotransmitter in the central nervous system, therefore its precise control is vital for maintaining normal brain function and preventing excitotoxicity. Removal of extracellular glutamate is achieved by plasma membrane-bound transporters, which couple glutamate transport to sodium, potassium and pH gradients using an elevator mechanism. Glutamate transporters also conduct chloride ions via a channel-like process that is thermodynamically uncoupled from transport. However, the molecular mechanisms that allow these dual-function transporters to carry out two seemingly contradictory roles are unknown. Here we report the cryo-electron microscopy structure of a glutamate transporter homologue in an open-channel state, revealing an aqueous cavity that is formed during the transport cycle. By studying functional properties combined with molecular dynamics simulations, we show that this cavity is an aqueous-accessible chloride permeation pathway gated by two hydrophobic regions and is conserved across mammalian and archaeal glutamate transporters. Our findings provide insight into the mechanism by which glutamate transporters support their dual function and add a crucial piece of information to aid mapping of the complete transport cycle shared by the SLC1A transporter family.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
5.5
作者：
Best, Robert B.;Zhu, Xiao;Shim, Jihyun;Lopes, Pedro E. M.;Mittal, Jeetain;Feig, Michael;MacKerell, Alexander D., Jr.
通讯作者：
MacKerell, Alexander D., Jr.
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
影响因子：
64.8
作者：
Canul-Tec JC;Assal R;Cirri E;Legrand P;Brier S;Chamot-Rooke J;Reyes N
通讯作者：
Reyes N
影响因子：
2.5
作者：
Aragão D;Aishima J;Cherukuvada H;Clarken R;Clift M;Cowieson NP;Ericsson DJ;Gee CL;Macedo S;Mudie N;Panjikar S;Price JR;Riboldi-Tunnicliffe A;Rostan R;Williamson R;Caradoc-Davies TT
通讯作者：
Caradoc-Davies TT