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Glutamate transporters have a chloride channel with two hydrophobic gates
Nature ( IF 64.8 ) Pub Date : 2021-02-17 , DOI: 10.1038/s41586-021-03240-9
Ichia Chen 1 , Shashank Pant 2, 3, 4 , Qianyi Wu 1 , Rosemary J Cater 1, 5 , Meghna Sobti 6, 7 , Robert J Vandenberg 1 , Alastair G Stewart 6, 7 , Emad Tajkhorshid 2, 3, 4 , Josep Font 1 , Renae M Ryan 1
Affiliation  

Glutamate is the most abundant excitatory neurotransmitter in the central nervous system, and its precise control is vital to maintain normal brain function and to prevent excitotoxicity1. The removal of extracellular glutamate is achieved by plasma-membrane-bound transporters, which couple glutamate transport to sodium, potassium and pH gradients using an elevator mechanism2,3,4,5. Glutamate transporters also conduct chloride ions by means of a channel-like process that is thermodynamically uncoupled from transport6,7,8. However, the molecular mechanisms that enable 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, which reveals an aqueous cavity that is formed during the glutamate transport cycle. The functional properties of this cavity, combined with molecular dynamics simulations, reveal it to be an aqueous-accessible chloride permeation pathway that is 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 information that will assist in mapping the complete transport cycle shared by the solute carrier 1A transporter family.



中文翻译:

谷氨酸转运蛋白有一个带有两个疏水门的氯离子通道

谷氨酸是中枢神经系统中最丰富的兴奋性神经递质,其精确控制对于维持正常的大脑功能和预防兴奋性毒性至关重要1。细胞外谷氨酸的去除是通过质膜结合转运蛋白实现的,它使用电梯机制2,3,4,5将谷氨酸转运与钠、钾和 pH 梯度耦合。谷氨酸转运蛋白还通过通道样过程传导氯离子,该过程在热力学上与转运6,7,8不耦合. 然而,使这些双功能转运蛋白发挥两种看似矛盾的作用的分子机制尚不清楚。在这里,我们报告了处于开放通道状态的谷氨酸转运蛋白同系物的低温电子显微镜结构,它揭示了在谷氨酸转运循环中形成的水​​腔。该空腔的功能特性与分子动力学模拟相结合,表明它是一种水可及的氯化物渗透途径,由两个疏水区域门控,并且在哺乳动物和古细菌谷氨酸转运蛋白中是保守的。我们的研究结果深入了解了谷氨酸转运蛋白支持其双重功能的机制,并增加了有助于绘制溶质载体 1A 转运蛋白家族共享的完整转运周期的信息。

更新日期:2021-02-17
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