Abstract
Xenopus oocytes expressing human aquaporin-7 (AQP7) exhibit greater osmotic water permeability and 3H-glycerol uptake vs. those expressing the bacterial glycerol facilitator GlpF. AQP7-expressing oocytes exposed to increasing extracellular [glycerol] under isosmolal conditions exhibit increasing swelling rates, whereas GlpF-expressing oocytes do not swell at all. To provide a structural basis for these observed physiological differences, we performed X-ray crystallographic structure determination of AQP7 and molecular-dynamics simulations on AQP7 and GlpF. The structure reveals AQP7 tetramers containing two monomers with 3 glycerols, and two monomers with 2 glycerols in the pore. In contrast to GlpF, no glycerol is bound at the AQP7 selectivity filter (SF), comprising residues F74, G222, Y223, and R229. The AQP7 SF is resolved in its closed state because F74 blocks the passage of small solutes. Molecular dynamics simulations demonstrate that F74 undergoes large and rapid conformational changes, allowing glycerol molecules to permeate without orientational restriction. The more rigid GlpF imposes orientational constraints on glycerol molecules passing through the SF. Moreover, GlpF-W48 (analogous to AQP7-F74) undergoes rare but long-lasting conformational changes that block the pore to H2O and glycerol.
Highlights
In humans, 13 aquaporins (AQPs) promote whole-body water homeostasis, and osmotic balance across membranes in all major organs, blood cells, and even in organelles like mitochondria (Borgnia et al, 1999)
In mouse and rat kidney, AQP7 is co-expressed with aquaporin-1 (AQP1) on the apical membrane of the proximal straight tubules (Ishibashi et al, 2000; Nejsum et al, 2000; Sohara et al, 2005), where AQP7 plays a minor role in H2O transport but a major role in glycerol reabsorption (Sohara et al, 2005)
AQP7 is abundantly expressed in human adipose tissue, where during lipolysis it mediates the efflux of newly generated glycerol (Madeira et al, 2015)
Summary
13 aquaporins (AQPs) promote whole-body water homeostasis, and osmotic balance across membranes in all major organs, blood cells, and even in organelles like mitochondria (Borgnia et al, 1999). The four independent monomeric pores in each AQP tetramer facilitate the osmotic passage of H2O and, in some AQPs, passive translocation of other small, uncharged solutes, including glycerol, urea, arsenite, NH3 and H2O2 (Borgnia et al, 1999; Heymann and Engel, 1999; Liu et al, 2002; Sohara et al, 2006, 2009; Litman et al, 2009; Geyer et al, 2013; Bienert and Chaumont, 2014). The comparable W48 in GlpF undergoes infrequent conformational changes that close the pore for prolonged periods, contributing to low glycerol permeability
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