Struture snd Dynamic Determinants of Ion Channel Assembly by Adapter Proteins

描述(由申请人提供)：囊性纤维化是一种毁灭性的、慢性的、进行性的、经常是致命的遗传病，在肺部尤为明显。主要原因是囊性纤维化跨膜电导调节器(CFTR)跨细胞膜的离子转运异常。CFTR是几种上皮组织中主要的氯离子转运体。两种适配蛋白--Na+/H+交换调节因子(NHERF)和Ezrin--调节CFTR的细胞表面浓度，组织CFTR与一系列信号蛋白网络的大分子相互作用以进行有效的转导，最终控制氯离子转运的强度。本研究的目的是确定接头蛋白协调工作的分子机制，以调节CFTR的大分子组装。需要检验的中心假设是，NHERF是一种信号转导分子，其特定的分子内相互作用受Ezrin调控，控制NHERF组装CFTR的能力。通过研究多价适配子蛋白组装的CFTR大分子复合体的结构、能量学和形成动力学，本研究将对适配蛋白相互作用组装CFTR通道的分子机制进行定量分析。了解大分子与CFTR的相互作用是制定囊性纤维化治疗策略的重要因素。

DESCRIPTION (provided by applicant): Cystic fibrosis is a devastating, chronic, progressive, and frequently fatal genetic disease that is particularly manifest in the lungs. The major cause is an abnormality in ion transport across cell membranes by the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR is the dominant chloride ion transporter in several epithelial tissues. Two adapter proteins-Na+/H+ exchanger regulator factor (NHERF) and ezrin-regulate the cell surface concentrations of CFTR, organize the macromolecular interactions of CFTR with a network of signaling proteins for efficient transduction, and ultimately control the strength of chloride ion transport. The goal of this research is to determine the molecular mechanisms by which adapter proteins work in coordination to regulate the macromolecular assembly of CFTR. The central hypothesis to be tested is that NHERF is a signal transducer whose specific intra-molecular interactions, which are modulated by ezrin, control the ability of NHERF to assemble CFTR. By studying the architecture, energetics, and dynamics of the formation of CFTR macromolecular complexes assembled by multivalent adapter proteins, this research will provide a quantitative analysis of the molecular mechanisms by which adapter proteins interact to assembly CFTR channels. A molecular understanding of the macromolecular interactions with CFTR is an essential element for developing a therapeutic strategy for the cure of cystic fibrosis.