Crystallographic studies of CLIC family proteins

CLIC 家族蛋白的晶体学研究

• 批准号: nhmrc : 350844
• 负责人: Prof Paul Curmi
• 金额: $ 33.71万
• 依托单位: The University of New South Wales
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2005
• 资助国家: 澳大利亚
• 起止时间: 2005-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/crystallographic-studies-clic-family-proteins/97171
• 关键词: Crystallographic; studies; CLIC; family; proteins

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.

细胞必须调节离子和水穿过其膜的流动，以便正常生存和功能。离子和水的平衡是由离子通道-蛋白质控制的细胞膜的渗透性。在离子通道中，氯离子通道在细胞中最丰富。它们是正常细胞功能的核心，在许多疾病状态中发挥关键作用。我们的研究小组是第一个发现并鉴定出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。这些通道是不寻常的，因为它们可以在两种状态之间移动：可溶状态和驻留在细胞膜上的状态。我们已经确定了这类通道的第一个结构，在可溶性状态和被认为是膜对接状态。这给了我们第一个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：蛋白质如何完成到膜状态的转变;这类通道蛋白的其他关键成员的结构;通道蛋白和其他细胞蛋白之间的复合物;以及膜状态下蛋白质的结构。我们还将确定几种药物如何控制该通道的活性。我们的工作结果将对我们的通道产生具体的影响，并将作为这类新的氯离子通道的其他成员的范例。了解该通道的功能以及当前药物如何控制它将导致一类新治疗剂的开发，这些治疗剂将通过阻止从可溶态转变为膜态来控制这些通道。