Structure and Function of Water Channels

描述（由申请人提供）：水通道蛋白（AQP）对于正常细胞功能所需的水平衡的主动调节至关重要; AQP水通道的缺陷与肾源性尿崩症等疾病有关。AQP 1与甘油促进剂GIPF的结构最近已通过X射线晶体学方法确定为2.2A分辨率。这些结构揭示了离子的分子机制，包括质子，排斥和水和甘油通过这些通道的特定运输。与所有其他已知的AQP水通道形成鲜明对比的是，已经发现AQP 6还促进带负电荷的溶质（如硝酸盐）的运输。AQP 6阴离子渗透性增强的存在下，汞2+或酸性pH值。激活后，汞2+结合阴离子电导结构是非常感兴趣的汞2+治疗已被证明在其他水通道废除溶质渗透性，包括水。最近的研究表明，即使接近中性pH，AQP 6对硝酸盐的选择性高于Cl，这表明这种水通道蛋白的主要生物功能可能不是水运输。AQP 6独特的选择性特性的结构基础仍有待确定。为了揭示建立AQP 6独特功能特性的详细机制，我们建议确定AQP 6与硝酸盐，Hg 2+，在中性和酸性pH下的结构，并进行分子动力学模拟。这些努力反过来将使人们更好地了解调节水和离子通过水通道以及其他离子通道运输的一般机制。

DESCRIPTION (provided by applicant): Aquaporins (AQPs) are critical for the active regulation of water balance required for normal cell function; defects in AQP water channels have been related to diseases such as nephrogenic diabetes insipidus. The structures of AQP1 together with that of glycerol facilitator, GIpF, have recently been determined to 2.2A, resolution by X-ray crystallographic methods. These structures have revealed the molecular mechanisms of ion, including proton, exclusion and the specific transport of water and glycerol across these channels. In dramatic contrast to all other known AQP water channels, AQP6 has been found to also facilitate the transport of negatively charged solutes (such as nitrate). AQP6 anion permeability is enhanced by the presence of Hg 2+ or by acidic pH. The activation of anion conductance upon Hg2+ binding is of great interest structurally as Hg2+ treatment has been shown in other aquaporins to abolish solute permeability including that for water. Recent studies have revealed that, even near neutral pH, AQP6 has a high selectivity for nitrate over CI, suggesting that the primary biological function of this aquaporin may not be water transport. The structural basis for the unique selectivity properties of AQP6 remains to be determined. To reveal the detailed mechanisms establishing the unique functional characteristics of AQP6, we propose to determine the structures of AQP6 with nitrate, Hg 2+, and at neutral and acidic pH, and conduct molecular dynamic simulations. These efforts, in turn, will provide a greater understanding of the general mechanisms regulating the transport of water and ions across water channels as well as through other ion channels.