Making Sense of Voltage Sensors

理解电压传感器

• 批准号: 7569070
• 负责人: STEPHEN H. WHITE
• 金额: $ 141.18万
• 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/7569070
• 关键词: Making; Sense; Voltage; Sensors

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：电压门控通道是膜蛋白，包含三个关键的结构元件：离子传导孔结构域（PD），可以区分 K+ 与 Na+ 和 Ca2+ 离子； PD 内的门可最大限度地减少关闭状态下的离子流；电压传感域（VSD）检测膜电压的变化并触发门的打开和关闭。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。该计划项目（主任Stephen White）旨在通过协同使用特定氘化、中子衍射、中子反射率和分子动力学模拟来获取有关流体脂质双层中VSD的关键结构信息。该计划由六个紧密相连的项目和一个重要的合作组成：核心 A. 管理核心。斯蒂芬·怀特，PI。该核心为整个程序提供管理支持。核心 B. 中子散射核心。斯蒂芬·怀特，PI。中子核心为将在 NIST 中子研究中心进行的中子衍射/反射率测量提供技术和培训支持。 Core C. 有机合成核心，Richard Chamberlin，PI。有机合成核心将提供新型特定氘化化合物，例如脂质和氨基酸，并将进行 VSD 和通道的半合成。它将位于加州大学欧文分校。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，PI。该项目位于加州大学欧文分校，致力于 MD 模拟，该模拟是项目 2 和 3 中大部分实验工作的基础和启发。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，PI。这些实验旨在对双层中 KvAP VSD 的相互作用、多层双层中 KvAP S4 螺旋与脂质的相互作用以及双层中 VSD 阻断毒素 VSTxl 毒素的处置进行结构理解。项目 3。电压门控钾通道的结构研究作为跨膜电化学势的函数。 J. Kent Blasie，PI。该项目位于宾夕法尼亚大学，旨在将 VSD 和整个钾通道整合到单个束缚脂质双层中，并通过时间分辨 X 射线反射率和中子反射率来观察跨膜电化学势引起的传感器和通道的结构变化。合作。钾通道生物物理学。肯顿·斯沃茨，PI。 Swartz 博士在 NINDS 的实验室有一个颇具影响力的研究项目，致力于电压门控离子通道的机制。他的工作直接关注电压传感器域的分子基础及其与 VSD 阻断毒素的相互作用。