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水通道蛋白 6 介导阴离子渗透的分子机制。

Molecular mechanism of anion permeation through aquaporin 6.

机构信息

Department of System Design Engineering, Keio University, Yokohama, Kanagawa, Japan.

Center for Advanced Computation, Korea Institute for Advanced Study, Seoul, Korea.

出版信息

Biophys J. 2024 Aug 20;123(16):2496-2505. doi: 10.1016/j.bpj.2024.06.013. Epub 2024 Jun 17.

DOI:10.1016/j.bpj.2024.06.013
PMID:38894539
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11365104/
Abstract

Aquaporins (AQPs) are recognized as transmembrane water channels that facilitate selective water permeation through their monomeric pores. Among the AQP family, AQP6 has an intriguing characteristic as an anion channel, which is allosterically controlled by pH conditions and is eliminated by a single amino acid mutation. However, the molecular mechanism of anion permeation through AQP6 remains unclear. Using molecular dynamics simulations in the presence of a transmembrane voltage utilizing an ion concentration gradient, we show that chloride ions permeate through the pore corresponding to the central axis of the AQP6 homotetramer. Under low pH conditions, a subtle opening of the hydrophobic selectivity filter (SF), located near the extracellular part of the central pore, becomes wetted and enables anion permeation. Our simulations also indicate that a single mutation (N63G) in human AQP6, located at the central pore, significantly reduces anion conduction, consistent with experimental data. Moreover, we demonstrate that the pH-sensing mechanism in which the protonation of H184 and H189 under low pH conditions allosterically triggers the gating of the SF region. These results suggest a unique pH-dependent allosteric anion permeation mechanism in AQP6 and could clarify the role of the central pore in some of the AQP tetramers.

摘要

水通道蛋白(AQPs)被认为是跨膜水分子通道,通过其单体孔选择性地促进水渗透。在 AQP 家族中,AQP6 作为阴离子通道具有独特的特性,其受 pH 条件的变构调控,并可通过单个氨基酸突变消除。然而,AQP6 中阴离子渗透的分子机制仍不清楚。本研究采用跨膜电压存在下的分子动力学模拟以及离子浓度梯度,表明氯离子通过对应 AQP6 同源四聚体中央轴的孔道渗透。在低 pH 条件下,位于中央孔道细胞外部分附近的疏水性选择性滤器(SF)的细微开口变得湿润,从而允许阴离子渗透。我们的模拟还表明,位于中央孔道的人类 AQP6 中的单个突变(N63G)显著降低了阴离子传导性,这与实验数据一致。此外,我们证明了 pH 感应机制,即低 pH 条件下 H184 和 H189 的质子化可变构触发 SF 区域的门控。这些结果表明 AQP6 中存在独特的 pH 依赖性变构阴离子渗透机制,并可阐明中央孔道在某些 AQP 四聚体中的作用。

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本文引用的文献

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The structural basis of divalent cation block in a tetrameric prokaryotic sodium channel.四聚体原核钠离子通道中二价阳离子阻断的结构基础。
Nat Commun. 2023 Jul 15;14(1):4236. doi: 10.1038/s41467-023-39987-0.
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Proteoliposomes reconstituted with human aquaporin-1 reveal novel single-ion-channel properties.用人水通道蛋白-1重构的蛋白脂质体展现出新型单离子通道特性。
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Aquaporin ion conductance properties defined by membrane environment, protein structure, and cell physiology.水通道蛋白的离子传导特性由膜环境、蛋白质结构和细胞生理学所决定。
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