Structural insights into AQP3 channel closure upon pH and redox changes reveal an autoregulatory molecular mechanism
- Peng Huang
- Raminta Venskutonytė
- Carter J. Wilson
- Sara Bsharat
- Rashmi B. Prasad
- Pontus Gourdon
- Isabella Artner
- Bert L. de Groot
- Karin Lindkvist-Petersson
2025-12-22
Regulation of intracellular levels of reactive oxygen species (ROS) remains poorly understood. Aquaporin 3 (AQP3) facilitates the membrane transport of hydrogen peroxide (H 2 O 2 ), 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 2 O 2 . 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 2 O 2 promotes closure via a large conformational rearrangement of extracellular loop E. These findings reveal a mechanism for autoregulation of H 2 O 2 transport and establish AQP3 as a key modulator of redox homeostasis in human pancreatic β-cells.