Voltage Gating Mechanisms

电压门控机制

• 批准号: 9010555
• 负责人: Ehud Isacoff
• 金额: $ 29.49万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9010555
• 关键词: Address; Architecture; Arginine; Aspartate; Biological Process; Catalytic Domain; Complex; Coupling; Dependence; Electrostatics; Enzymes; Epithelial; Family member; Gated Ion Channel; Goals; Homologous Gene; Ion Channel; Ions; Ligands; Malignant Neoplasms; Mediating; Membrane; Membrane Potentials; Membrane Proteins; Methods; Molecular; Molecular Conformation; Molecular Models; Monitor; Motion; Movement; Natural Immunity; Optical Methods; PTEN gene; Pathway interactions; Peripheral; Phosphoric Monoester Hydrolases; Physiological Processes; Play; Probability; Proteins; Protons; Reproduction; Role; Side; Stroke; Tertiary Protein Structure; Vestibule; Water; Work; design; dimer; insight; interest; molecular modeling; monomer; novel; pH gradient; public health relevance; receptor; response; sensor; voltage

 DESCRIPTION (provided by applicant): Voltage-gated ion channels have evolved to open and close in response to changes in the membrane potential and rapidly conduct ions selectively. The members of the family that longest eluded isolation were the voltage-gated proton channel, Hv1, and its relatively close relative, the voltage sensing phosphatase (VSP). Hv1 plays a central role in innate immunity and other physiological processes. The biological function of VSP is not known. This proposal focuses on 3 fundamental aspects to the function of these VSD proteins, which, despite their similarities, differ radically in their effectors: with Hv1 having is channel effector uniquely situated within its VSD, while VSP's effector is the only one so far to have its effector outside of the membrane, in this case on the internal side. Our aims for Hv1 are to elucidate its pore pathway, understand how it is "gated", how the gating apparatus in one subunit influences that of the dimeric partner and elucidate the mechanism by which Hv1 detects the absolute transmembrane gradient of pH and uses it to regulate gating. Our aim for VSP is to understand how conformational sequences in the VSD induce conformational sequences in the enzyme domain to alter the choice of substrate. Our goal is to arrive at mechanistic molecular models of gating, cooperativity and modulation of the VSD by pH and modulation by the VSD of the effector. The proposed studies should provide insight into the function of VSDs across voltage-gated proteins and the new methods should be applicable to a range of other channels and receptors whose protein motions, subunit interactions and modulation by ligands are of interest. The proposed work is designed to elucidate the mechanism of function of the voltage-gated proton channel (which is fundamental to innate immunity, reproduction and epithelial transport, and appears to have a role in stroke and cancer) and its relative, the voltage sensing phosphatase. The approach employs several novel optical methods that should prove to be applicable to the study of a broad set of ion channels and receptors.

 描述（由适用提供）：电压门控离子通道已演变为开放和关闭，以响应膜电位的变化和迅速进行离子。最长隔离的家族成员是电压门控质子通道HV1及其相对亲密的电压传感磷酸酶（VSP）。 HV1在先天免疫和其他物理过程中起着核心作用。 VSP的生物学功能尚不清楚。该提案重点介绍了这些VSD蛋白功能的3个基本方面，它们的相似性在根本上是不同的：HV1具有唯一位于其VSD内的通道效应器，而VSP的效应器是迄今为止唯一一个在膜外部具有效应器的唯一一个。我们对HV1的目的是阐明其孔路途径，了解它的“封闭式”，一个亚基中的门控设备如何影响二聚体伴侣的孔，并阐明HV1检测pH的绝对跨膜梯度的机制，并使用它来调节门控。我们对VSP的目的是了解VSD中的会议序列如何诱导酶结构域中的浓度序列改变底物的选择。我们的目标是达到通过pH和VSD对VSD进行门控，配位和调节的机械分子模型，拟议的研究应提供对电压门控蛋白质VSD的功能的深入了解，新方法应适用于其他渠道和接收器，其属于蛋白质的相互作用，subunit Motions autig and Ligigands s rive Invients s rive Invients和接收器。拟议的工作旨在阐明电压门控质子通道的功能机理（这是先天免疫，繁殖和上皮转运的基础，并且似乎在中风和癌症中起作用）及其相对，电压感应磷酸酶。该方法采用了几种新型的光学方法，这些方法应被证明适用于对一系列离子通道和接收器的研究。