Human aquaporin 5 (HsAQP5) facilitates the transport of water across plasma membranes and has been identified within cells of the stomach, duodenum, pancreas, airways, lungs, salivary glands, sweat glands, eyes, lacrimal glands, and the inner ear. AQP5, like AQP2, is subject to posttranslational regulation by phosphorylation, at which point it is trafficked between intracellular storage compartments and the plasma membrane. Details concerning the molecular mechanism of membrane trafficking are unknown. Here we report the x-ray structure of HsAQP5 to 2.0-Å resolution and highlight structural similarities and differences relative to other eukaryotic aquaporins. A lipid occludes the putative central pore, preventing the passage of gas or ions through the center of the tetramer. Multiple consensus phosphorylation sites are observed in the structure and their potential regulatory role is discussed. We postulate that a change in the conformation of the C terminus may arise from the phosphorylation of AQP5 and thereby signal trafficking.

Significance: Human aquaporin 2 (AQP2) is found in the kidney collecting duct, where it translocates water across the apical membrane and is crucial for urine concentration. AQP2 is regulated by trafficking between intracellular storage vesicles and the apical membrane, a process that is tightly controlled by the pituitary hormone arginine vasopressin. Defective AQP2 trafficking leads to nephrogenic diabetes insipidus (NDI), a water balance disorder characterized by large urine volumes, leading to dehydration. We have solved the X-ray structure of human AQP2 at 2.75 Å resolution. This structure deepens our molecular understanding of AQP2 trafficking, as well as serves as a structural scaffold for understanding why AQP2 mutations cause NDI.