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于听觉、神经和心脏系统的功能至关重要，并且是治疗剂的潜在靶点。一些K通道被组装为孔形成（α）和辅助或调节（β）亚基的异多聚体复合物。在β亚基中有KCNE 1（minK），它属于KCNE家族的单跨膜蛋白，调节包括KCNQ 1在内的几种K+通道的活性。在心脏中，KCNQ 1与KCNE 1共组装形成通道复合物，该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，这种相同的通道复合体能够将K+分泌到内淋巴中，并且对听力至关重要。KCNE 1的突变可导致耳聋和先天性长QT综合征（LOTS），这强调了KCNE 1与正常通道功能的相关性。在这里，提出了一个长期项目的第一阶段，以解开耳聋和先天性LOTS的各种表型的分子基础。具体目标集中在KCNE 1，相关家族成员及其疾病相关突变形式。KCNE 1和相关突变体/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NMR光谱进行表征。结构信息将阐明β亚基在生理和病理生理条件下如何调节钾通道功能。同时，我们还将通过KCNE家族成员和相关疾病突变形式对KCNQVs进行电生理和生物化学研究，以测试这些蛋白质如何相互作用的结构性假设和模型。

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.