阴离子通过水通道蛋白6渗透的分子机制
Molecular mechanism of anion permeation through aquaporin 6
AI总结：
本研究通过跨膜电压与离子浓度梯度下的分子动力学模拟，揭示AQP6中央孔道在低pH时经选择性过滤器润湿而传导氯离子，并阐明H184/H189质子化的变构门控机制。
摘要：
水通道蛋白（AQPs）被公认为跨膜水通道，可通过其单体孔道促进选择性水渗透。在AQP家族中，AQP6具有作为阴离子通道的独特特征，该通道受pH条件变构控制，并可因单个氨基酸突变而消失。然而，阴离子通过AQP6渗透的分子机制仍不清楚。利用在跨膜电压存在下并采用离子浓度梯度进行的分子动力学模拟，我们表明氯离子通过对应于AQP6同源四聚体中心轴的孔道渗透。在低pH条件下，位于中央孔道胞外部分附近的疏水选择性过滤器（SF）发生轻微开放并被润湿，从而使阴离子能够渗透。我们的模拟还表明，位于中央孔道的人AQP6中的单个突变（N63G）显著降低了阴离子传导，这与实验数据一致。此外，我们证明了pH感知机制：在低pH条件下，H184和H189的质子化变构触发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。
英文摘要：
Aquaporins (AQPs) are recognized as transmembrane water channels that facilitate selective water permeation through their monomeric pores. Among the AQP family, AQP6 has a unique 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 selective 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 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.
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