Verkman A S, Mitra A K
Departments of Medicine and Physiology, Cardiovascular Research Institute, University of California, San Francisco 94143-0521, USA.
Am J Physiol Renal Physiol. 2000 Jan;278(1):F13-28. doi: 10.1152/ajprenal.2000.278.1.F13.
The aquaporins (AQPs) are a family of small membrane-spanning proteins (monomer size approximately 30 kDa) that are expressed at plasma membranes in many cells types involved in fluid transport. This review is focused on the molecular structure and function of mammalian aquaporins. Basic features of aquaporin structure have been defined using mutagenesis, epitope tagging, and spectroscopic and freeze-fracture electron microscopy methods. Aquaporins appear to assemble in membranes as homotetramers in which each monomer, consisting of six membrane-spanning alpha-helical domains with cytoplasmically oriented amino and carboxy termini, contains a distinct water pore. Medium-resolution structural analysis by electron cryocrystallography indicated that the six tilted helical segments form a barrel surrounding a central pore-like region that contains additional protein density. Several of the mammalian aquaporins (e.g., AQP1, AQP2, AQP4, and AQP5) appear to be highly selective for the passage of water, whereas others (recently termed aquaglyceroporins) also transport glycerol (e.g., AQP3 and AQP8) and even larger solutes (AQP9). Evidence for possible movement of ions and carbon dioxide through the aquaporins is reviewed here, as well as evidence for direct regulation of aquaporin function by posttranslational modification such as phosphorylation. Important unresolved issues include definition of the molecular pathway through which water and solutes move, the nature of monomer-monomer interactions, and the physiological significance of aquaporin-mediated solute movement. Recent results from knockout mice implicating multiple physiological roles of aquaporins suggest that the aquaporins may be suitable targets for drug discovery by structure-based and/or high-throughput screening strategies.
水通道蛋白（AQP）是一类小的跨膜蛋白家族（单体大小约为30 kDa），在参与液体运输的多种细胞类型的质膜上表达。本综述聚焦于哺乳动物水通道蛋白的分子结构和功能。水通道蛋白结构的基本特征已通过诱变、表位标记、光谱学和冷冻断裂电子显微镜方法得以确定。水通道蛋白似乎以同四聚体的形式组装在膜中，其中每个单体由六个跨膜的α-螺旋结构域组成，其氨基和羧基末端朝向细胞质，包含一个独特的水通道。电子冷冻晶体学的中分辨率结构分析表明，六个倾斜的螺旋片段形成一个围绕中央孔状区域的桶状结构，该区域含有额外的蛋白质密度。几种哺乳动物水通道蛋白（如AQP1、AQP2、AQP4和AQP5）似乎对水的通过具有高度选择性，而其他一些（最近被称为水甘油通道蛋白）还运输甘油（如AQP3和AQP8）甚至更大的溶质（AQP9）。本文综述了离子和二氧化碳可能通过水通道蛋白移动的证据，以及翻译后修饰（如磷酸化）对水通道蛋白功能直接调控的证据。重要的未解决问题包括水和溶质移动的分子途径的定义、单体-单体相互作用的性质以及水通道蛋白介导的溶质移动的生理意义。基因敲除小鼠的最新结果表明水通道蛋白具有多种生理作用，这表明水通道蛋白可能是基于结构和/或高通量筛选策略进行药物发现的合适靶点。
