X-ray structure of human aquaporin 2 and its implications for nephrogenic diabetes insipidus and trafficking
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/4488445
- author
- 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
- organization
- publishing date
- 2014
- 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 Academy of Sciences
- external identifiers
-
- wos:000335199000054
- scopus:84899634495
- pmid:24733887
- 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
- 2016-04-01 10:14:27
- date last changed
- 2022-04-27 20:00:27
@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}}, keywords = {{membrane protein; X-ray crystallography; water channel protein}}, language = {{eng}}, number = {{17}}, pages = {{6305--6310}}, publisher = {{National Academy of 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}}, doi = {{10.1073/pnas.1321406111}}, volume = {{111}}, year = {{2014}}, }