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<p>Regulation of intracellular levels of reactive oxygen species (ROS) remains poorly understood. Aquaporin 3 (AQP3) facilitates the membrane transport of hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>), a key ROS signaling molecule. Here we elucidate the molecular mechanism of AQP3 and show that its regulatory properties are both pH dependent and autoregulated by H<sub>2</sub>O<sub>2</sub>. Using single particle cryo-electron microscopy, we present open and closed conformations of human AQP3. At pH 8.0, the channel adopts an open state, while acidic pH or exposure to H<sub>2</sub>O<sub>2</sub> promotes closure via a large conformational rearrangement of extracellular loop E. These findings reveal a mechanism for autoregulation of H<sub>2</sub>O<sub>2</sub> transport and establish AQP3 as a key modulator of redox homeostasis in human pancreatic β-cells.</p>

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Structural insights into AQP3 channel closure upon pH and redox changes reveal an autoregulatory molecular mechanism

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月22日

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  • Peng Huang,
  • Raminta Venskutonytė,
  • Carter J. Wilson,
  • Sara Bsharat,
  • Rashmi B. Prasad,
  • Pontus Gourdon,
  • Isabella Artner,
  • Bert L. de Groot,
  • Karin Lindkvist-Petersson

摘要

Regulation of intracellular levels of reactive oxygen species (ROS) remains poorly understood. Aquaporin 3 (AQP3) facilitates the membrane transport of hydrogen peroxide (H2O2), a key ROS signaling molecule. Here we elucidate the molecular mechanism of AQP3 and show that its regulatory properties are both pH dependent and autoregulated by H2O2. Using single particle cryo-electron microscopy, we present open and closed conformations of human AQP3. At pH 8.0, the channel adopts an open state, while acidic pH or exposure to H2O2 promotes closure via a large conformational rearrangement of extracellular loop E. These findings reveal a mechanism for autoregulation of H2O2 transport and establish AQP3 as a key modulator of redox homeostasis in human pancreatic β-cells.