Structure and Function of Water Channels

描述（由申请人提供）：水通道蛋白（AQPs）对正常细胞功能所需的水平衡的主动调节至关重要；AQP水渠缺陷与肾源性尿崩症等疾病有关。AQP1和甘油促进剂GIpF的结构最近通过x射线晶体学方法被确定为2.2A，分辨率。这些结构揭示了离子的分子机制，包括质子、排斥以及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，AQP6也被发现促进带负电荷的溶质（如硝酸盐）的运输。Hg - 2+或酸性ph的存在会增强AQP6阴离子的渗透性。Hg2+结合时阴离子电导率的激活在结构上是非常有趣的，因为Hg2+处理已经在其他水通道蛋白中被证明可以消除溶质渗透性，包括水通道蛋白。最近的研究表明，即使在接近中性的pH值下，AQP6对硝酸盐的选择性也高于CI，这表明该水通道蛋白的主要生物学功能可能不是输水。AQP6独特选择性的结构基础尚不清楚。为了揭示AQP6独特功能特征建立的详细机制，我们建议在硝酸盐、Hg +、中性和酸性pH下确定AQP6的结构，并进行分子动力学模拟。这些努力，反过来，将提供一个更大的了解一般机制调节水和离子的运输跨水通道，以及通过其他离子通道。

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.