Regulation of KCNH ion channels

描述（由申请人提供）：离子通道是大脑和心脏中所有电兴奋性的基础，离子通道的缺陷是许多人类疾病的原因。KCNH通道家族，ERG、ELK和EAG，是电压依赖性钾通道，专门用于塑造神经元和心肌细胞的电活动。KCNH通道的缺陷已被证明与认知缺陷，精神分裂症，心律失常和癌症的风险增加有关。最近已经清楚的是，KCNH通道的专门门控来自其独特的细胞内结构域，N-末端eag结构域和C-末端C-接头/CNBHD。在这个建议中，我们将测试的假设，即C-连接/CNBHD的KCNH通道是一个关键的调节域，介导的EAG结构域和其他细胞内调节剂的行动。我们将建立在三个令人兴奋的新的X射线晶体结构，我们已经解决了三个不同的KCNH通道的细胞内结构域：1）ELK的C-接头/CNBHD，2）ERG的C-接头/CNBHD，和3）CNBHD和EAG的eag结构域的复合物。这些新结构揭示了意想不到的功能，如eag结构域和CNBHD之间的直接相互作用，以及调节门控的CNBHD结合位点中的内在配体。它们提供了一个框架，以更好地了解KCNH通道的门控和调节机制。为了实现这一目标，我们将利用X射线晶体学，电生理学和荧光的力量来研究在KCNH通道门控过程中eag结构域和C-接头/CNBHD的结构和重排。

DESCRIPTION (provided by applicant): Ion channels underlie all electrical excitability in the brain and heart, and defects in ion channels are the cause of many human disorders. The KCNH family of channels, ERG, ELK, and EAG, are voltage-dependent potassium channels that are specialized for their role in shaping the electrical activity of neurons and cardiomyocytes. Defects in KCNH channels have been shown to be linked to cognitive defects, increased risk of schizophrenia, cardiac arrhythmias, and cancer. Recently it has become clear that the specialized gating of KCNH channels arises from their unique intracellular domains, the N-terminal eag domain, and the C-terminal C-linker/CNBHD. In this proposal, we will test the hypothesis that the C-linker/CNBHD of KCNH channels is a key regulatory domain that mediates the action of the eag domain and other intracellular regulators. We will build on three exciting new X-ray crystal structures we have solved of the intracellular domains of three different KCNH channels: 1) the C-linker/CNBHD of ELK, 2) the C-linker/CNBHD of ERG, and 3) a complex of the CNBHD and eag domain of EAG. These new structures reveal unexpected features like a direct interaction between the eag domain and the CNBHD, and an intrinsic ligand in the binding site of the CNBHD that regulates gating. They provide a framework to better understand the mechanisms of the gating and regulation of KCNH channels. Toward this goal, we will leverage the power of X-ray crystallography, electrophysiology, and fluorescence to study the structure and rearrangements of the eag domain and C-linker/CNBHD during gating of KCNH channels.