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（由申请人提供）：电压门控离子通道已经进化为响应膜电位的变化而打开和关闭，并选择性地快速传导离子。最长的逃避隔离的家庭成员是电压门控质子通道，Hv1，和它的相对较近的亲戚，电压敏感磷酸酶（VSP）。Hv1在先天免疫和其他生理过程中起着核心作用。VSP的生物学功能尚不清楚。该建议集中于这些VSD蛋白的功能的3个基本方面，尽管它们相似，但它们的效应器根本不同：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具有其效应器的效应器，在这种情况下在内侧。我们的目标是Hv1的孔通路，了解它是如何“门控”，如何在一个亚基的门控装置的影响，二聚体的合作伙伴，并阐明Hv1检测的绝对跨膜梯度的pH值和使用它来调节门控的机制。我们的目标是VSP是了解如何在VSD构象序列诱导构象序列的酶结构域改变底物的选择。我们的目标是达到门控，协同性和调制的VSD pH值和调制的效应器的VSD的机制的分子模型。拟议的研究应提供深入了解跨电压门控蛋白质的VSD的功能，新方法应适用于一系列其他通道和受体，其蛋白质运动，亚基相互作用和配体的调制感兴趣。拟议的工作旨在阐明电压门控质子通道的功能机制（这是先天免疫，生殖和上皮运输的基础，似乎在中风和癌症中发挥作用）及其相关的电压敏感磷酸酶。该方法采用了几种新的光学方法，应证明是适用于一个广泛的离子通道和受体的研究。