Crystallographic studies of CLIC family proteins

细胞必须调节穿过膜的离子和水的流动，才能生存和正常运作。离子和水的平衡由离子通道控制，离子通道是控制细胞膜通透性的蛋白质。在离子通道中，氯离子通道是细胞中含量最丰富的。它们是正常细胞功能的核心，在许多疾病状态中发挥着关键作用。我们小组首次发现并鉴定了一类新的氯离子通道，它在免疫系统的调节中起着关键作用。这些通道的不同寻常之处在于它们可以在两种状态之间移动：可溶状态和驻留在细胞膜中的状态。我们已经确定了这类通道在溶解状态和被认为是膜对接状态下的第一结构。这给了我们第一张关于这种通道蛋白如何改变其结构以实现其功能的原子图像。在这个项目中，我们将确定：蛋白质如何完成向膜状态的转变；这类通道蛋白的其他关键成员的结构；通道蛋白与其他细胞蛋白之间的复合体；以及膜状态下的蛋白质结构。我们还将确定几种药物如何控制这一通道的活动。我们的工作结果将对我们的通道有具体的影响，并将作为这类新的氯离子通道的其他成员的范例。了解这一通道是如何发挥作用的，以及目前的药物是如何控制它的，这将导致一类新的治疗剂的开发，这种药物将通过防止从可溶状态到膜状态的转变来控制这些通道。

Cells must regulate the flow of ions and water across their membranes in order to survive and function normally. The balance of ions and water is controlled by ion channels - proteins that control the permeability of the cell membrane. Of the ion channels, chloride channels are the most abundant in cells. They are central to the functioning of normal cells as well as playing a key role in many disease states. Our group was the first to identify and characterise a new class of chloride channel which plays a key roles in the regulation of the immune system. These channels are unusual in that they can move between two states: a soluble state and a state that resides in the cell membrane. We have determined the first structures of this class of channel in both the soluble state and what is believed to be the membrane docking state. This has given us the first atomic picture of how this channel protein can alter its structure so as to carry out its function. In this project, we will determine: how the protein completes the transition into the membrane state; the structures of other key members of this class of channel protein; complexes between channel proteins and other cellular proteins; and the structure of the protein in the membrane state. We will also determine how several drugs control the activity of this channel. The results of our work will have specific implications for our channel and will serve as a paradigm other members of this new class of chloride channel. Understanding how this channel functions and how the current drugs control it will lead to the development of a new class of therapeutic agents that will control these channels by preventing the transition from the soluble to the membrane state.