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

Frick, Anna; Eriksson, Urszula Kosinska; de Mattia, Fabrizio; Oberg, Fredrik; Hedfalk, Kristina; Neutze, Richard; de Grip, Willem J.; Deen, Peter M. T. and Horsefield, Susanna LU (2014) In Proceedings of the National Academy of Sciences 111(17). p.6305-6310
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
membrane protein, X-ray crystallography, water channel protein
in
Proceedings of the National Academy of Sciences
volume
111
issue
17
pages
6305 - 6310
publisher
National Acad Sciences
external identifiers
  • wos:000335199000054
  • scopus:84899634495
ISSN
1091-6490
DOI
10.1073/pnas.1321406111
language
English
LU publication?
yes
id
b2697c72-0c25-4d63-9cc9-389cd00b5a74 (old id 4488445)
date added to LUP
2014-06-23 14:02:29
date last changed
2017-11-19 03:07:58
@article{b2697c72-0c25-4d63-9cc9-389cd00b5a74,
  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.},
  author       = {Frick, Anna and Eriksson, Urszula Kosinska and de Mattia, Fabrizio and Oberg, Fredrik and Hedfalk, Kristina and Neutze, Richard and de Grip, Willem J. and Deen, Peter M. T. and Horsefield, Susanna},
  issn         = {1091-6490},
  keyword      = {membrane protein,X-ray crystallography,water channel protein},
  language     = {eng},
  number       = {17},
  pages        = {6305--6310},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences},
  title        = {X-ray structure of human aquaporin 2 and its implications for nephrogenic diabetes insipidus and trafficking},
  url          = {http://dx.doi.org/10.1073/pnas.1321406111},
  volume       = {111},
  year         = {2014},
}