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

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.