title: X-ray structure of human aquaporin 2 and its implications for nephrogenic diabetes insipidus and trafficking.
abstract: Human aquaporin 2 (AQP2) is a water channel found in the kidney collecting duct, where it plays a key role in concentrating urine. Water reabsorption is regulated by AQP2 trafficking between intracellular storage vesicles and the apical membrane. This process is tightly controlled by the pituitary hormone arginine vasopressin and defective trafficking results in nephrogenic diabetes insipidus (NDI). Here we present the X-ray structure of human AQP2 at 2.75 Å resolution. The C terminus of AQP2 displays multiple conformations with the C-terminal α-helix of one protomer interacting with the cytoplasmic surface of a symmetry-related AQP2 molecule, suggesting potential protein-protein interactions involved in cellular sorting of AQP2. Two Cd(2+)-ion binding sites are observed within the AQP2 tetramer, inducing a rearrangement of loop D, which facilitates this interaction. The locations of several NDI-causing mutations can be observed in the AQP2 structure, primarily situated within transmembrane domains and the majority of which cause misfolding and ER retention. These observations provide a framework for understanding why mutations in AQP2 cause NDI as well as structural insights into AQP2 interactions that may govern its trafficking.
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, 405 30 Gothenburg, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Frick
authors.forename: Urszula Kosinska
authors.initials: UK
authors.lastname: Eriksson
authors.forename: Fabrizio
authors.initials: F
authors.lastname: de Mattia
authors.forename: Fredrik
authors.initials: F
authors.lastname: Oberg
authors.forename: Kristina
authors.initials: K
authors.lastname: Hedfalk
authors.forename: Richard
authors.initials: R
authors.lastname: Neutze
authors.forename: Willem J
authors.initials: WJ
authors.lastname: de Grip
authors.forename: Peter M T
authors.initials: PM
authors.lastname: Deen
authors.forename: Susanna
authors.initials: S
authors.lastname: Törnroth-Horsefield
mesh_terms: D051399:Aquaporin 2 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D002104:Cadmium / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D018360:Crystallography, X-Ray; D018500:Diabetes Insipidus, Nephrogenic / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D009865:Oocytes / Q000378:metabolism; D017433:Protein Structure, Secondary; D021381:Protein Transport
chemical_list: C496023:AQP2 protein, human; D051399:Aquaporin 2; D056827:Endosomal Sorting Complexes Required for Transport; C499837:VTA1 protein, human; D002104:Cadmium; D002118:Calcium
keywords: X-ray crystallography; membrane protein; water channel protein
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