KCNE1 Structure and Interaction with KCNQ1 Channel

描述（由申请人提供）：电压门控钾离子通道对听觉、神经和心脏系统的功能至关重要，是治疗剂的潜在靶点。一些K通道组装成成孔形成（α）和辅助或调节（β）亚基的异质复合物。β亚基中有KCNE1 (minK)，它属于KCNE家族，该家族是单膜跨越蛋白，可调节多种K+通道的活性，包括KCNQ1。在心脏中，KCNQ1与KCNE1共同组装形成通道复合物，产生缓慢激活的心脏钾电流，这是心肌复极的重要决定因素。在耳蜗中，同样的通道复合体使K+分泌到内淋巴，对听力至关重要。KCNE1基因突变可导致耳聋和先天性长QT综合征（LOTS），因此KCNE1基因与正常通道功能的相关性得到了强调。在这里，我们提出了一项长期项目的第一阶段，旨在揭示耳聋和先天性lot各种表型的分子基础。具体目标集中在KCNE1，相关家庭成员，及其疾病相关的突变形式。KCNE1及其相关突变体/家族成员的高分辨率结构和运动动力学将在模型膜中使用溶液核磁共振光谱进行表征。结构信息将阐明β亚基如何在生理和病理生理条件下调节钾通道功能。同时，我们还将进行kcnqv由KCNE家族成员和相关疾病突变形式调节的电生理和生化研究，以测试这些蛋白质如何相互作用的结构启发假设和模型。

DESCRIPTION (provided by applicant): Voltage-gated potassium ion channels are essential for the function of the auditory, nervous, and cardiac systems and are potential targets for therapeutic agents. Some K channels are assembled as heteromultimeric complexes of pore-forming (alpha) and accessory or modulatory (beta) subunits. Among the beta subunits is KCNE1 (minK), which belongs to the KCNE family of single membrane-spanning proteins that modulate the activity of several K+ channels, including KCNQ1. In the heart KCNQ1 co- assembles with KCNE1 to form a channel complex that generates the slowly activating cardiac potassium current, an important determinant of myocardial repolarization. In the cochlea, this same channel complex enables secretion of K+ into endolymph and is critical for hearing. The relevance of KCNE1 for proper channel function is underscored by mutations in KCNE1 that can cause deafness and congenital long QT syndrome (LOTS). Here, the first stage of a long term project is proposed to unravel the molecular basis for various phenotypes of deafness and congenital LOTS. The specific aims focus upon KCNE1, related family members, and its disease-linked mutant forms. The high resolution structures and motional dynamics of KCNE1 and related mutants/family members will be characterized in model membranes using solution NMR spectroscopy. Structural information will shed light upon how the beta subunits modulate potassium channel function under both physiological and pathophysiological conditions. In concert, we will also conduct electrophysiological and biochemical studies of KCNQVs modulation by KCNE family members and related disease mutant forms in order to test structurally-inspired hypotheses and models for how these proteins interact.