Structure-function Analysis of KCNE Interactions with Cardiac Channels KCNQ1 & HE

描述（由申请人提供）：KCNE家族的辅助通道亚单位与多种电压门控通道相关，以调节其组装和功能。KCNE的突变与遗传性心律失常的长QT综合征（LQTS）、房颤有关，而多态性可能导致药物诱导的室性心律失常。此外，KCNE越来越多地被发现调节心脏以外系统中许多通道的活动。这些蛋白质的研究进展揭示了许多关于其功能，表达和遗传学。然而，仍有许多未解决的问题。其中包括通道门控调节的精确机制、它们与K通道的组装、促细胞突变的分子基础、对特定通道的相对偏好和化学计量。我们以前的工作已经表明，部分的KCNE独立于那些管理激活可能会影响调节通道失活。我们的初步研究表明，KCNEs和KCNQ 1通道的C-末端的物理和功能相互作用，改变通道的失活率和激活的电压依赖性。在这里，我们建议解决几个未解决的问题，控制通道失活率和几个新的问题，有关更广泛的KCNE家庭，可能会影响心律失常的风险。我们的方法将使用生物化学，功能和结构的方法。我们提出了更先进的结构分析KCNE调节KCNQ 1通道和LQT突变如何改变这一过程。 公共卫生相关性：在美国，心律失常每年导致30万至40万例猝死。虽然长QT综合征并不常见，但对其相关基因的鉴定和突变的探索极大地丰富了我们对人类心脏电活动分子机制的认识。对这些蛋白质的进一步研究可能有助于更常见的获得性心脏病心律失常管理的新诊断和治疗策略。我们认为，研究这些通道和辅助亚基的动态调节和蛋白质-蛋白质相互作用之间的串扰是非常重要的。

DESCRIPTION (provided by applicant): The KCNE family of accessory channel subunits associate with a variety of voltage gated channels to regulate their assembly and function. Mutations in KCNEs have been linked to hereditary arrhythmias of the Long QT syndrome (LQTS), atrial fibrillation, and polymorphisms may contribute to drug-induced ventricular arrhythmias. Moreover, the KCNEs are increasingly found to regulate the activity of numerous channels in systems beyond the heart. Progress in the study of these proteins has revealed much regarding their function, expression and genetics. Nevertheless many unresolved issues remain. Among these are the precise mechanisms of regulation of channel gating, their assembly with K channels, molecular basis for pro-arrhythmic mutations, relative preference for specific channels and stoichiometry. Our previous work has shown that portions of the KCNEs separate from those that govern activation may influence regulation of channel deactivation. Our preliminary studies indicate that C-termini of KCNEs and KCNQ1 channels physically and functionally interact to alter channel deactivation rates and voltage-dependence of activation. Here we propose to address several of the unresolved issues concerning control of channel deactivation rates and several newer questions pertaining to the broader KCNE family that may influence cardiac arrhythmia risks. Our approach will use biochemical, functional and structural methodology. We propose more advanced structural analyses on KCNE regulation of KCNQ1 channels and how LQT mutations alter this process. PUBLIC HEALTH RELEVANCE: Cardiac arrhythmias are responsible for 300,000 to 400,000 cases of sudden death per year in the USA. Although the Long QT syndrome is not common identification of the genes involved and exploration of LQT mutations has greatly enriched our understanding of molecular mechanisms human cardiac electrical activity. Further study of these proteins is likely to contribute to new diagnostic and therapeutic strategies in arrhythmia management in more common acquired heart disease. We believe that it is fundamentally important to investigate the dynamic regulation and crosstalk among protein-protein interactions for these channels and accessory subunits.