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

描述(由申请人提供)：KCNE系列附属通道亚单位与各种电压门控通道相关联，以调节它们的组装和功能。KCNE基因突变与长QT间期综合征(LQTS)、房颤等遗传性心律失常有关，基因多态性可能与药物所致室性心律失常有关。此外，越来越多的研究发现，KCNE在心脏以外的系统中调节许多通道的活动。这些蛋白质的研究进展揭示了它们的功能、表达和遗传学方面的许多问题。然而，仍然存在许多悬而未决的问题。其中包括通道门控的精确调节机制，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。我们以前的工作表明，与那些管理激活的KCNE分离的部分KCNE可能影响通道失活的调节。我们的初步研究表明，KCNE和KCNQ1通道的C末端在物理和功能上相互作用，从而改变通道失活率和激活的电压依赖性。在这里，我们建议解决与通道失活率控制有关的几个悬而未决的问题，以及与可能影响心律失常风险的更广泛的KCNE家族有关的几个新问题。我们的方法将使用生化、功能和结构方法。我们对KCNE对KCNQ1通道的调控以及LQT突变如何改变这一过程提出了更高级的结构分析。 公共卫生相关性：在美国，每年有300,000至400,000例猝死是由心律失常引起的。尽管长QT综合征并不常见，但对相关基因的识别和对LQT突变的探索极大地丰富了我们对人类心脏电活动的分子机制的理解。对这些蛋白的进一步研究可能有助于在更常见的获得性心脏病中进行心律失常治疗的新的诊断和治疗策略。我们认为，研究这些通道和附属亚基的蛋白质-蛋白质相互作用之间的动态调节和串扰是非常重要的。

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.