• Structural determinants of oligomerization of the aquaporin-4 channel

      Kitchen, P; Conner, MT; Bill, RM; Conner, AC; From the Molecular Assembly and Organisation in Cells Doctoral Training Centre, University of Warwick, Coventry CV4 7AL, the School of Life & Health Sciences and Aston Research Centre for Healthy Ageing, Aston University, Aston Triangle, Birmingham, B4 7ET, and the Institute of Clinical Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom. (American Society for Biochemistry & Molecular Biology (ASBMB), 2016-01-19)
      ©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.