X-ray structure of human aquaporin 2 and its implications for nephrogenic diabetes insipidus and trafficking

Research output: Contribution to journalArticle

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 angstrom resolution. The C terminus of AQP2 displays multiple conformations with the C-terminal alpha-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 Cd2+-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.

Details

Authors
  • Anna Frick
  • Urszula Kosinska Eriksson
  • Fabrizio de Mattia
  • Fredrik Oberg
  • Kristina Hedfalk
  • Richard Neutze
  • Willem J. de Grip
  • Peter M. T. Deen
  • Susanna Horsefield
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Biological Sciences

Keywords

  • membrane protein, X-ray crystallography, water channel protein
Original languageEnglish
Pages (from-to)6305-6310
JournalProceedings of the National Academy of Sciences
Volume111
Issue number17
Publication statusPublished - 2014
Publication categoryResearch
Peer-reviewedYes