Human glycerol channel aquaporin 7(AQP7)conducts glycerol release from adipocyte and enters the cells in pancreatic islets,muscles,and kidney tubules,and thus regulates glycerol metabolism in those tissues.Compared wi...Human glycerol channel aquaporin 7(AQP7)conducts glycerol release from adipocyte and enters the cells in pancreatic islets,muscles,and kidney tubules,and thus regulates glycerol metabolism in those tissues.Compared with other human aquaglyceroporins,AQP7 shows a less conserved‘‘NPA”motif in the center cavity and a pair of aromatic residues at Ar/R selectivity filter.To understand the structural basis for the glycerol conductance,we crystallized the human AQP7 and determined the structure at 3.7Å.A substrate binding pocket was found near the Ar/R filter where a glycerol molecule is bound and stabilized by R229.Glycerol uptake assay on human AQP7 as well as AQP3 and AQP10 demonstrated strong glycerol transportation activities at the physiological condition.The human AQP7 structure,in combination with the molecular dynamics simulation thereon,reveals a fully closed conformation with its permeation pathway strictly confined by the Ar/R filter at the exoplasmic side and the gate at the cytoplasmic side,and the binding of glycerol at the Ar/R filter plays a critical role in controlling the glycerol flux by driving the dislocation of the residues at narrowest parts of glycerol pathway in AQP7.展开更多
基金the National Key Research and Development Program of China(2018YFC1004704 and 2017YFC1001303)the National Natural Science Foundation of China(U1632132,31670849,and 91853206)+3 种基金the Shanghai Science and Technology Committee(20S11902000)the SHIPM-pi fund(JY201804)the SHIPM-sigma fund(2018JC002)from Shanghai Institute of Precision Medicine,Ninth People’s Hospital Shanghai Jiao Tong University School of Medicinethe Innovative Research Team of Highlevel Local Universities in Shanghai(SSMU-ZLCX20180600)。
文摘Human glycerol channel aquaporin 7(AQP7)conducts glycerol release from adipocyte and enters the cells in pancreatic islets,muscles,and kidney tubules,and thus regulates glycerol metabolism in those tissues.Compared with other human aquaglyceroporins,AQP7 shows a less conserved‘‘NPA”motif in the center cavity and a pair of aromatic residues at Ar/R selectivity filter.To understand the structural basis for the glycerol conductance,we crystallized the human AQP7 and determined the structure at 3.7Å.A substrate binding pocket was found near the Ar/R filter where a glycerol molecule is bound and stabilized by R229.Glycerol uptake assay on human AQP7 as well as AQP3 and AQP10 demonstrated strong glycerol transportation activities at the physiological condition.The human AQP7 structure,in combination with the molecular dynamics simulation thereon,reveals a fully closed conformation with its permeation pathway strictly confined by the Ar/R filter at the exoplasmic side and the gate at the cytoplasmic side,and the binding of glycerol at the Ar/R filter plays a critical role in controlling the glycerol flux by driving the dislocation of the residues at narrowest parts of glycerol pathway in AQP7.
