Molecular Mechanism of Cation Channel Selectivity

阳离子通道选择性的分子机制

基本信息

批准号：
8624699
负责人：
YOUXING JIANG
金额：
$ 28.94万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8624699
关键词：
Affinity Architecture Arrhythmia Ataxia Bacillus cereus Binding Binding Sites Biochemical Biological Biological Models Biological Process Cations Cell membrane Chemicals Chimera organism Crystallography Cyclic Nucleotides Defect Disease Drosophila genus Electrophysiology (science)Engineering Environment Exhibits Experimental Models Family Foundations Functional disorder Genetic Goals Heating Hormones Human Human Pathology Human body Imagery Ion Channel Ions Lead Membrane Methanobacterium Modeling Molecular Muscle Contraction Mutation Nerve Physiological Processes Play Potassium Channel Prevalence Property Proteins Research Resolution Role Seizures Signal Transduction Site Specificity Structure Testing Theoretical model Tissues Variant Work base cyclic-nucleotide gated ion channels deafness design insight member mutant novel peptide chemical synthesis tool

项目摘要

DESCRIPTION (provided by applicant): Transfer of ions across biological membranes is central to physiological processes like nerve excitation, muscle cell contraction, signal transduction and hormone secretion. Ion channels play a vital role by providing a passageway, the ion conduction pore, within membranes to allow specific ions to traverse down their electrochemical gradient. In humans, ion channels are found in nearly all tissues serving a variety of physiologically essential functions. Because of their prevalence and importance in the human body, dysfunction of a channel is often to blame for a wide range of human pathologies. The ability to select for specific ionic species is known as ion selectivity and is a fundamental property defining ion channel function. In tetrameric cation channels, which comprise the single largest family of ion channels including the K+, Ca2+, Na+, and cyclic nucleotide-gated (CNG) channels, selectivity is usually a direct consequence of the unique structural and chemical environment within part of the ion channel pore, the selectivity filter, which is distinct among different channels. Our understanding of the molecular details governing ion selectivity in this group of channels has come a long way with the advancement of genetic, biochemical, and electrophysiological analysis of ion channels and, more recently, the structural characterization of several members beginning with the ground breaking work of the KcsA K+ channel structure and subsequent work on other K+ selective channels. Although these structural studies offer a direct visualization of the selectivity filter of K+ channels, the determinant factors contributingto K+ selectivity are still under heated debate. Moreover, there is little structural information available for other tetrameric cation channels and the molecular basis for their ion selectivity remains unclear. The overall goal of our research is to understand the structural basis of ion selectivity in tetrameric cation channels. Taking advantage of the extremely high resolution crystal structures of several model proteins representing the ion conduction pores of both selective and non-selective channels, we aim to elucidate basic principles of ion selectivity in two groups of physiologically essential cation channels. One is the non-selective, Ca2+ permeable cyclic nucleotide-gated (CNG) channels, using NaK from Bacillus cereus and its CNG- mimicking chimeras as model systems; the other is K+ selective channels, using a K+ selective NaK mutant (NaK2K) and the MthK K+ channel from Methanobacterium thermoautotrophicum as model systems. A combined approach of protein crystallography, electrophysiology and protein chemical synthesis will be employed in the proposed studies

描述（由申请人提供）：离子跨生物膜的转移是神经激发，肌肉细胞收缩，信号转导和激素分泌等生理过程的核心。离子通道通过在膜内提供通道，即离子传导孔，从而使特定离子穿越其电化学梯度，从而发挥至关重要的作用。在人类中，几乎所有具有生理上重要功能的组织中都发现了离子通道。由于它们在人体中的普遍性和重要性，频道的功能障碍通常应归咎于广泛的人类病理。选择特定离子物种的能力称为离子选择性，是定义离子通道函数的基本特性。在四聚阳离子通道中，该通道包括一个最大的离子通道家族，包括K+，Ca2+，Na+和环状核苷酸门控通道（CNG）通道，选择性通常是离子一部分内独特结构和化学环境的直接结果通道孔，选择性过滤器，在不同的通道之间是不同的。随着离子通道的遗传，生化和电生理分析的发展，我们对这组通道中控制离子选择性的分子细节的理解已经走了很长一段路。 KCSA K+通道结构以及其他K+选择性通道的后续工作。尽管这些结构研究提供了K+通道的选择性滤波器的直接可视化，但导致K+选择性的决定性因素仍在加热的争论中。此外，其他四聚阳离子通道几乎没有结构信息，其离子选择性的分子基础尚不清楚。我们研究的总体目标是了解四聚阳离子通道中离子选择性的结构基础。利用代表选择性和非选择性通道的离子传导孔的几种模型蛋白的极高分辨率晶体结构，我们旨在阐明两组生理上必不可少的阳离子通道中离子选择性的基本原理。一种是使用蜡状芽孢杆菌及其CNG-Mimicking Chimeras作为模型系统的NAK，是非选择性的Ca2+可渗透循环核苷酸门控通道；另一个是K+选择性通道，使用K+选择性NAK突变体（NAK2K）和来自甲烷杆菌的MTHK K+通道作为模型系统。蛋白质晶体学，电生理学和蛋白质化学合成的组合方法将在拟议的研究中采用