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Abstract：
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 3.7 Å. 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.
摘要：
人甘油通道水通道蛋白7（AQP7）从脂肪细胞中释放甘油并进入胰岛细胞，肌肉,和肾小管，从而调节这些组织中的甘油代谢。与其他人类水甘油相比，AQP7在中心腔中显示出较不保守的“NPA”基序，在Ar/R选择性过滤器上显示出一对芳族残基。要了解甘油电导的结构基础，我们结晶了人类AQP7，并确定了3.7µ的结构。在Ar/R过滤器附近发现了底物结合袋，其中甘油分子被R229结合并稳定。人AQP7以及AQP3和AQP10的甘油摄取测定在生理条件下显示出强的甘油转运活性。人AQP7结构,结合分子动力学模拟，揭示了一个完全封闭的构象，其渗透途径被Ar/R过滤器严格限制在外质侧和细胞质侧的门，甘油在Ar/R过滤器上的结合在通过驱动AQP7中甘油途径最窄部分的残基错位来控制甘油通量中起关键作用。
