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arXiv · 2311.04545

Molecular mechanism of anion permeation through aquaporin 6

Eiji Yamamoto·Keehyoung Joo·Jooyoung Lee·Mark S. P. Sansom·Masato Yasui
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Abstract

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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Eiji Yamamoto, Keehyoung Joo, Jooyoung Lee, Mark S. P. Sansom, Masato Yasui. 2023-11-08. Molecular mechanism of anion permeation through aquaporin 6. https://arxiv.org/abs/2311.04545

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