Structural studies of ion channel assembly and signalin*

离子通道组装和信号传导的结构研究*

• 批准号: 7078576
• 负责人: DANIEL L MINOR
• 金额: $ 36.98万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7078576
• 关键词: X ray crystallography; Xenopus oocyte; affinity chromatography; binding sites; biological signal transduction; calmodulin; cytoskeletal proteins; electrophysiology; gene mutation; molecular assembly /self assembly; molecular site; phosphoprotein phosphatase; potassium channel; protein engineering; protein kinase; protein protein interaction; protein structure function; voltage gated channel

DESCRIPTION (provided by applicant): The long-term goals of this project are to develop a high-resolution understanding of ion channel function and regulation. We are investigating the KCNQ family of voltage-gated potassium channels. These channels play central roles in auditory, cardiac, and brain function. Because channel function depends on subunit composition and interactions with proteins of cellular signaling networks, we are investigating the molecular bases for both of these phenomena. Due to difficulties in studying mammalian membrane protein structure, our present efforts are focused on understanding the function cytoplasmic domains that are important for channel assembly and for the recruitment of cellular signaling factors. We are pursuing a multidisciplinary approach that includes biochemical, biophysical, X-ray crystallographic, and electrophysiological measurements to dissect KCNQ channel function. Because of their important roles in human physiology, mutations of KCNQ channels lead to a variety of hereditary diseases including congenital deafness, cardiac arrhythmias, and epilepsy. We are particularly interested in understanding how disease mutations change channel properties and interactions with other proteins. KCNQ channels are the targets for drugs directed at cardiac arrhythmias, seizures, and memory disorders. Thus, understanding their structures and mechanisms of action may lead to the development of new, valuable therapeutic agents.

描述（由申请人提供）：该项目的长期目标是对离子渠道功能和调节的高分辨率理解。我们正在研究电压门控钾通道的KCNQ家族。这些通道在听觉，心脏和大脑功能中起着核心作用。由于通道功能取决于亚基组成以及与细胞信号网络的蛋白质相互作用，因此我们正在研究这两种现象的分子碱基。由于难以研究哺乳动物膜蛋白结构，我们目前的工作集中在理解对通道组装和募集细胞信号传导因子重要的功能细胞质结构域。我们正在采用一种多学科方法，其中包括生化，生物物理，X射线晶体学和电生理测量，以剖析KCNQ通道功能。由于它们在人类生理学中的重要作用，KCNQ通道的突变导致了各种遗传性疾病，包括先天性耳聋，心律不齐和癫痫。我们特别有兴趣了解疾病突变如何改变通道特性以及与其他蛋白质的相互作用。 KCNQ通道是针对心律失常，癫痫发作和记忆障碍的药物的靶标。因此，了解其作用的结构和机制可能会导致新的，有价值的治疗剂的发展。