2. Academic Validation
  3. Molecular Basis of Aquaporin-7 Permeability Regulation by pH

Molecular Basis of Aquaporin-7 Permeability Regulation by pH

  • Cells. 2018 Nov 10;7(11):207. doi: 10.3390/cells7110207.
Andreia F Mósca 1 2,  Andreia de Almeida 3 4,  Darren Wragg 5,  Ana P Martins 6 7,  Farzana Sabir 8 9,  Stefano Leoni 10,  Teresa F Moura 11 12,  Catarina Prista 13,  Angela Casini 14,  Graça Soveral 15 16
Affiliations

Affiliations

  • 1 Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal. [email protected].
  • 2 Dept. Bioquímica e Biologia Humana, Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal. [email protected].
  • 3 School of Chemistry, Cardiff University, Park Place, Cardiff CF10 3AT, UK. [email protected].
  • 4 Tumour MicroEnvironment Group, Division of Cancer and Genetics, School of Medicine, Cardiff University, Tenovus Building, Cardiff CF14 4XN, UK. [email protected].
  • 5 School of Chemistry, Cardiff University, Park Place, Cardiff CF10 3AT, UK. [email protected].
  • 6 Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal. [email protected].
  • 7 Dept. Bioquímica e Biologia Humana, Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal. [email protected].
  • 8 Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal. [email protected].
  • 9 LEAF, Linking Landscape, Environment, Agriculture and Food, and DRAT, Dept. de Recursos Biológicos, Ambiente e Território, Instituto Superior de Agronomia, Universidade de Lisboa, Tapada da Ajuda, 1349017 Lisboa, Portugal. [email protected].
  • 10 School of Chemistry, Cardiff University, Park Place, Cardiff CF10 3AT, UK. [email protected].
  • 11 Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal. [email protected].
  • 12 Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal. [email protected].
  • 13 LEAF, Linking Landscape, Environment, Agriculture and Food, and DRAT, Dept. de Recursos Biológicos, Ambiente e Território, Instituto Superior de Agronomia, Universidade de Lisboa, Tapada da Ajuda, 1349017 Lisboa, Portugal. [email protected].
  • 14 School of Chemistry, Cardiff University, Park Place, Cardiff CF10 3AT, UK. [email protected].
  • 15 Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal. [email protected].
  • 16 Dept. Bioquímica e Biologia Humana, Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal. [email protected].
PMID: 30423801 DOI: 10.3390/cells7110207
Abstract

The aquaglyceroporin AQP7, a family member of Aquaporin membrane channels, facilitates the permeation of water and glycerol through cell membranes and is crucial for body lipid and energy homeostasis. Regulation of glycerol permeability via AQP7 is considered a promising therapeutic strategy towards fat-related metabolic complications. Here, we used a yeast aqy-null strain for heterologous expression and functional analysis of human AQP7 and investigated its regulation by pH. Using a combination of in vitro and in silico approaches, we found that AQP7 changes from fully permeable to virtually closed at acidic pH, and that Tyr135 and His165 facing the extracellular environment are crucial residues for channel permeability. Moreover, instead of reducing the pore size, the protonation of key residues changes AQP7's protein surface electrostatic charges, which, in turn, may decrease glycerol's binding affinity to the pore, resulting in decreased permeability. In addition, since some pH-sensitive residues are located at the monomer-monomer interface, decreased permeability may result from cooperativity between AQP7's monomers. Considering the importance of glycerol permeation via AQP7 in multiple pathophysiological conditions, this mechanism of hAQP7 pH-regulation may help the design of selective modulators targeting aquaglyceroporin-related disorders.

Keywords

AQP7; aquaglyceroporin; aquaporin; pH; regulation; water and glycerol permeability; yeast.

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