Structural determinants of oligomerization of the aquaporin-4 channel
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Abstract©2016 by The American Society for Biochemistry and Molecular Biology, Inc. The aquaporin (AQP) family of integral membrane protein channels mediate cellular water and solute flow. Although qualitative and quantitative differences in channel permeability, selectivity, subcellular localization, and trafficking responses have been observed for different members of the AQP family, the signature homotetrameric quaternary structure is conserved. Using a variety of biophysical techniques, we show that mutations to an intracellular loop (loop D) of human AQP4 reduce oligomerization. Non-tetrameric AQP4 mutants are unable to relocalize to the plasma membrane in response to changes in extracellular tonicity, despite equivalent constitutive surface expression levels and water permeability to wild-type AQP4. A network of AQP4 loop D hydrogen bonding interactions, identified using molecular dynamics simulations and based on a comparative mutagenic analysis of AQPs 1, 3, and 4, suggest that loop D interactions may provide a general structural framework for tetrameric assembly within theAQPfamily.
CitationKitchen, P., Conner, M. T., Bill, R. M. and Conner, A. C. (2016) Structural determinants of oligomerization of the aquaporin-4 channel, Journal of Biological Chemistry, 29(13), pp. 6858-6871.
JournalJournal of Biological Chemistry
SponsorsSupported by Biotechnology and Biological Sciences Research Council Grants BB/I019960/1, BB/K013319/1, and BB/L502194/1 and Innovative Medicines Joint Undertaking under Grant Agreement 115583 to the ND4BB ENABLE Consortium.
Except where otherwise noted, this item's license is described as Licence for published version: Creative Commons Attribution 4.0 International
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Plasma membrane abundance of human aquaporin 5 is dynamically regulated by multiple pathwaysKitchen, P; Öberg, F; Sjöhamn, J; Hedfalk, K; Bill, RM; Törnroth-Horsefield, S; Conner, Matthew T.; Conner, Alex C.; Molecular Organization and Assembly in Cells Doctoral Training Centre, University of Warwick, Coventry, United Kingdom. (Public Library of Science (PLoS), 2015-11-16)© 2015 Kitchen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Aquaporin membrane protein channels mediate cellular water flow. Human aquaporin 5 (AQP5) is highly expressed in the respiratory system and secretory glands where it facilitates the osmotically-driven generation of pulmonary secretions, saliva, sweat and tears. Dysfunctional trafficking of AQP5 has been implicated in several human disease states, including Sjögren's syndrome, bronchitis and cystic fibrosis. In order to investigate how the plasma membrane expression levels of AQP5 are regulated, we studied real-time translocation of GFP-tagged AQP5 in HEK293 cells. We show that AQP5 plasma membrane abundance in transfected HEK293 cells is rapidly and reversibly regulated by at least three independent mechanisms involving phosphorylation at Ser156, protein kinase A activity and extracellular tonicity. The crystal structure of a Ser156 phosphomimetic mutant indicates that its involvement in regulating AQP5 membrane abundance is not mediated by a conformational change of the carboxy-terminus. We suggest that together these pathways regulate cellular water flow.
A low-protein, high-carbohydrate diet increases browning in perirenal adipose tissue but not in inguinal adipose tissuePereira, Mayara P.; Ferreira, Laís A.A.; da Silva, Flávia H.S.; Christoffolete, Marcelo A.; Metsios, George S.; Chaves, Valéria E.; de França, Suélem A.; Damazo, Amílcar S.; Flouris, Andreas D.; Kawashita, Nair H. (Elsevier, 2017-05-31)Objective The aim of this study was to evaluate the browning and origin of fatty acids (FAs) in the maintenance of triacylglycerol (TG) storage and/or as fuel for thermogenesis in perirenal adipose tissue (periWAT) and inguinal adipose tissue (ingWAT) of rats fed a low-protein, high-carbohydrate (LPHC) diet. Methods LPHC (6% protein, 74% carbohydrate) or control (C; 17% protein, 63% carbohydrate) diets were administered to rats for 15 d. The tissues were stained with hematoxylin and eosin for histologic analysis. The content of uncoupling protein 1 (UCP1) was determined by immunofluorescence. Levels of T-box transcription factor (TBX1), PR domain containing 16 (PRDM16), adipose triacylglycerol lipase (ATGL), hormone-sensitive lipase, lipoprotein lipase (LPL), glycerokinase, phosphoenolpyruvate carboxykinase (PEPCK), glucose transporter 4, β3-adrenergic receptor (AR), β1-AR, protein kinase A (PKA), adenosine-monophosphate-activated protein kinase (AMPK), and phospho-AMPK were determined by immunoblotting. Serum fibroblast growth factor 21 (FGF21) was measured using a commercial kit (Student's t tests, P < 0.05). Results The LPHC diet increased FGF21 levels by 150-fold. The presence of multilocular adipocytes, combined with the increased contents of UCP1, TBX1, and PRDM16 in periWAT of LPHC-fed rats, suggested the occurrence of browning. The contents of β1-AR and LPL were increased in the periWAT. The ingWAT showed higher ATGL and PEPCK levels, phospho-AMPK/AMPK ratio, and reduced β3-AR and PKA levels. Conclusion These findings suggest that browning occurred only in the periWAT and that higher utilization of FAs from blood lipoproteins acted as fuel for thermogenesis. Increased glycerol 3-phosphate generation by glyceroneogenesis increased FAs reesterification from lipolysis, explaining the increased TG storage in the ingWAT.