Molecular Basis of Aquaporin-7 Permeability Regulation by pH

Cells

Catarina Prista¹  Graça Soveral²  AnaP. Martins²  AndreiaF. Mósca²  TeresaF. Moura²  Farzana Sabir²  Andreia de Almeida³  Stefano Leoni³  Darren Wragg³  Angela Casini³ 

[1] 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;Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal;School of Chemistry, Cardiff University, Park Place, Cardiff CF10 3AT, UK;

关键词: aquaporin;    aquaglyceroporin;    AQP7;    pH;    yeast;    regulation;    water and glycerol permeability;   

DOI  :  10.3390/cells7110207

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown