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

Abstract

Abstract 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.