Molecular Basis of Aquaporin-7 Permeability Regulation by pH
AbstractThe 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. View Full-Text
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Mósca, A.F.; de Almeida, A.; Wragg, D.; Martins, A.P.; Sabir, F.; Leoni, S.; Moura, T.F.; Prista, C.; Casini, A.; Soveral, G. Molecular Basis of Aquaporin-7 Permeability Regulation by pH. Cells 2018, 7, 207.
Mósca AF, de Almeida A, Wragg D, Martins AP, Sabir F, Leoni S, Moura TF, Prista C, Casini A, Soveral G. Molecular Basis of Aquaporin-7 Permeability Regulation by pH. Cells. 2018; 7(11):207.Chicago/Turabian Style
Mósca, Andreia F.; de Almeida, Andreia; Wragg, Darren; Martins, Ana P.; Sabir, Farzana; Leoni, Stefano; Moura, Teresa F.; Prista, Catarina; Casini, Angela; Soveral, Graça. 2018. "Molecular Basis of Aquaporin-7 Permeability Regulation by pH." Cells 7, no. 11: 207.
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