Making Sense of Voltage Sensors

理解电压传感器

• 批准号: 8025961
• 负责人: STEPHEN H. WHITE
• 金额: $ 131.89万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-06 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8025961
• 关键词: Making; Sense; Voltage; Sensors

Voltage-gated channels are membrane proteins that contain three crucial structural elements: an ion conduction pore domain (PD) that can distinguish K+ from Na+ and Ca2+ ions; a gate within the PD that minimizes the flow of ions in the closed state; and voltage-sensing domains (VSD) that detect changes in membrane voltage and trigger opening and closing of the gate. A fundamental experimental problem is the difficulty of capturing critical atomic details of VSDs in membranes by crystallography. This program project (Stephen White, Director) is designed to obtain critical structural information about VSDs in fluid lipid bilayers through the concerted use of specific deuteration, neutron diffraction, neutron reflectivity, and molecular dynamics simulations. The Program consists of six closely interlocked Projects and an important collaboration: Core A. Administrative Core. Stephen White, PI. This core provides administrative support for the entire Program. Core B. Neutron Scattering Core. Stephen White, PI. The neutron Core provides technical and training support for neutron diffraction/reflectivity measurements that will be carried out at the NIST Center for Neutron Research. Core C. Organic Synthesis Core, Richard Chamberlin, PI. The Organic Synthesis Core will provide novel specifically deuterated compounds, such as lipids and amino acids, and will carry out semi-syntheses of VSDs and channels. It will be located at UC Irvine. Project 1. Molecular Dynamics Simulations of Channels and Voltage Sensor Domains. Douglas Tobias, PI. Located at UC Irvine, this project is devoted to MD simulations that underlie-and inspire-most of the experimental work in projects 2 and 3. Project 2. Neutron Diffraction Studies of Voltage Sensor Molecules in Lipid Bilayers. Stephen White, PI. The experiments are directed toward a structural understanding of the interactions of the KvAP VSD in bilayers, the interaction of the KvAP S4 helix with lipids in multilamellar bilayers, and the disposition of the VSD-blocking toxin VSTxl toxin in bilayers. Project 3. Structural Studies of Voltage-Gated Potassium Channels as a Function of Transmembrane Electrochemical Potential. J. Kent Blasie, PI. Located at the University of Pennsylvania, this project is directed toward incorporating VSDs and whole potassium channels into single, tethered lipid bilayers and to observe by time-resolved x-ray reflectivity and neutron reflectivity structural changes in the sensors and channels induced by transmembrane electrochemical potentials. Collaboration. Potassium Channel Biophysics. Kenton Swartz, PI. Dr. Swartz's laboratory at the NINDS has an influential research program devoted to the mechanism of voltage gated ion channels. His work focuses directly on the molecular basis of voltage sensor domains and their interactions with VSD-blocking toxins.

电压门控通道是包含三个关键结构元件的膜蛋白：一个可以将K+与Na+和Ca2+离子区分开的离子传导孔域（PD）； PD内的一个门可以最大程度地减少封闭状态下离子的流动；和电压感应域（VSD），可检测膜电压的变化以及触发门的开口和闭合。一个基本的实验问题是，难以通过晶体学捕获膜中VSD的关键原子细节。这个程序项目 （主任斯蒂芬·怀特（Stephen White），旨在通过一致使用特定的神，中子衍射，中子反射率和分子动力学模拟来获取流体脂质双层中VSD的关键结构信息。该计划由六个紧密联锁的项目和一个重要的合作组成：核心A.行政核心。斯蒂芬·怀特（Stephen White），pi。该核心为整个程序提供了管理支持。核心B.中子散射核心。斯蒂芬·怀特（Stephen White），pi。中子核为中子衍射/反射率测量值提供了技术和培训支持，该测量将在NIST中子研究中心进行。核心C.有机合成核心，理查德·张伯林（Richard Chamberlin），PI。有机合成核心将提供新颖的一个特异性氘化化合物，例如脂质和氨基酸，并将进行VSD和通道的半合成。它将位于UC Irvine。项目1。通道和电压传感器域的分子动力学模拟。道格拉斯·托比亚斯（Douglas Tobias），pi。位于UC Irvine， 该项目专门用于MD模拟，这些模拟是项目2和3的实验工作的基础。项目2。脂质双层中电压传感器分子的中子衍射研究。斯蒂芬·怀特（Stephen White），pi。实验是针对对双层中KVAP VSD相互作用的结构理解，KVAP S4螺旋与多层双层中的脂质与脂质的相互作用，以及在倍层中的VSD-Blocking blocking toxd-blocking毒素VSTXL毒素。项目3。电源门控钾通道的结构研究是跨膜电化学潜力的函数。 J. Kent Blasie，PI。该项目位于宾夕法尼亚大学，致力于将VSD和全钾通道纳入单个束缚的脂质双层，并通过时间分辨的X射线反射率和中子反射率的结构变化来观察，由跨膜电位电位引起的传感器和通道。 合作。钾通道生物物理学。肯顿·斯瓦茨（Kenton Swartz），pi。 Swartz博士在NINDS的实验室有一个有影响力的研究计划，专门介绍了电压封闭离子通道的机制。他的工作直接集中在电压传感器域的分子基础上，以及它们与VSD阻滞毒素的相互作用。