2023/11/08 by Eiji Yamamoto, Yamamoto, Eiji, Keehyoung Joo +7
Biochemistry, Genetics and Molecular Biology · Engineering · #Biological Physics (physics.bio-ph) #Biomolecules (q-bio.BM) #FOS: Biological sciences #FOS: Physical sciences #Ion Transport and Channel Regulation #Membrane-based Ion Separation Techniques
paper · pdf · doi:10.48550/arxiv.2311.04545
openalex publication_date 2023/11/08 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/28
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.