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

描述（由申请人提供）：KCNE系列附属通道亚基与各种电压门控通道相关联，以调节其组装和功能。KCNEs突变与遗传性长QT综合征（LQTS）、房颤有关，其多态性可能导致药物性室性心律失常。此外，越来越多的研究发现，KCNEs可以调节心脏以外系统中许多通道的活动。对这些蛋白的研究进展揭示了它们的功能、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，促心律失常突变的分子基础，对特定通道的相对偏好和化学计量学。我们之前的工作已经表明，与控制激活的部分分离的KCNEs可能影响通道失活的调节。我们的初步研究表明，KCNEs和KCNQ1通道的c端在物理和功能上相互作用，改变通道失活率和激活的电压依赖性。在这里，我们建议解决几个关于通道失活率控制的未解决的问题，以及一些与可能影响心律失常风险的更广泛的KCNE家族有关的新问题。我们的方法将使用生化、功能和结构方法。我们建议对kcnne调控KCNQ1通道以及LQT突变如何改变这一过程进行更深入的结构分析。

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.