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Membrane Remodeling by Arc/Arg3.1

Arc/Arg3.1 膜重塑

基本信息

批准号：
9889184
负责人：
JOSEPH P ALBANESI
金额：
$ 18.71万
依托单位：
UNIVERSITY OF HAWAII AT MANOA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-15 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9889184
关键词：
AMPA Receptors Adaptor Signaling Protein Alzheimer&apos s Disease Angelman Syndrome Binding Biological Assay C-terminal Capsid Cell membrane Cells Clathrin Adaptors Cognition Disorders Crystallization Cytoskeleton Data Dendritic Spines Docking Drug Addiction Dynamin Elements Endocytosis Extracellular Space Fluorescence Fragile X Syndrome Goals Guanosine Triphosphate Phosphohydrolases HIV Immediate-Early Genes Impairment Laboratories Learning Link Lipids Long-Term Depression Long-Term Potentiation Mediating Membrane Memory Mental Retardation Messenger RNA Modification Monitor Morphology Mus N-terminal Neurons Phase Phosphorylation Play Post-Translational Protein Processing Process Proteins Regulation Reporting Role Scheme Schizophrenia Spectrum Analysis Structure Substance abuse problem Surface Synapses Synaptic plasticity Taste Perception Testing Therapeutic Intervention Translating Vesicle Viral Virus Assembly Virus-like particle alpha helix base clinically significant cofactor experience experimental study extracellular vesicles fear memory fluidity gene product intercellular communication interest long term memory new therapeutic target overexpression palmitoylation particle self assembly unilamellar vesicle vesicular release

项目摘要

The activity-regulated cytoskeletal-associated protein (Arc, also known as Arg3.1) is an immediate early gene product induced by activity/experience and required multiple modes of synaptic plasticity. Both long-term potentiation (LTP) and long-term depression (LTD) are impaired upon Arc deletion, as well as the ability to form long-term spatial, taste and fear memories. The best-characterized function of Arc is enhancement of the endocytic internalization of AMPA receptors (AMPARs) in dendritic spines, a process associated with LTD. This role for Arc in AMPAR endocytosis was supported by a report that Arc binds directly to two elements of the endocytic machinery, dynamin and endophilin, and by our finding that Arc stimulates dynamin self-assembly and GTPase activity. Solution of the crystal structure of a C-terminal segment of Arc revealed a striking similarity to the capsid domain of HIV Gag. Moreover, Arc assembles into viral capsid-like structures that enclose Arc mRNA, are released into the extracellular space, and are internalized by neighboring cells. Thus, Arc is unique in promoting plasma membrane budding both into and out of the cell. The goal of this project is to define the mechanism and regulation of Arc-mediated membrane vesiculation. Fluorescence fluctuation spectroscopy (FFS) will be utilized to monitor membrane budding giant unilamellar vesicles (GUVs). In Aim 1 we will use spectral phasor analysis to determine how lipid composition and fluidity influence the budding process, and Number and Brightness (N&B) analysis to obtain a quantitative picture of Arc self-assembly on the GUV surface. In Aim 2 we will determine how post-translational modifications of Arc, recently identified in our laboratories, control the binding of Arc to lipids and mRNA and Arc-mediated membrane vesiculation. Changes in Arc expression have been linked to numerous cognitive disorders, including mental retardation, Alzheimer's Disease, and substance abuse. Therefore, elucidation of mechanisms that regulate Arc-mediated intercellular communication has potential clinical significance.

活性调节的细胞凋亡相关蛋白（Arc，也称为Arg3.1）是一种立即早期基因，由活动/经验诱导的产物，需要多种突触可塑性模式。长期的增强（LTP）和长时程抑制（LTD）在Arc缺失后受损，长期的空间、味觉和恐惧记忆。Arc的最佳特征功能是增强树突棘中AMPA受体（AMPAR）的内吞内化，这是一个与LTD相关的过程。 Arc在AMPAR内吞作用中的作用得到了Arc直接结合AMPAR的两个元件的报道的支持。内吞机制，发动蛋白和内啡肽，并通过我们的发现，弧刺激发动蛋白自组装， GT活性。Arc的C-末端片段的晶体结构的解揭示了与 HIV Gag的衣壳结构域。此外，Arc组装成包围Arc mRNA的病毒衣壳样结构，被释放到细胞外空间，并被邻近细胞内化。因此，Arc是独一无二的，促进质膜出芽进出细胞。本项目的目标是定义 ARC介导的膜囊泡形成的机制和调控。荧光涨落光谱学 (FFS)将用于监测膜出芽巨单层囊泡（GUV）。在目标1中，我们将使用光谱相量分析，以确定脂质成分和流动性如何影响出芽过程，以及数字和亮度（N&B）分析，以获得电弧自组装在GUV表面上的定量图片。在目标2中，我们将确定最近在我们的实验室中发现的Arc的翻译后修饰，控制Arc与脂质和mRNA的结合以及Arc介导的膜囊泡形成。Arc的变化表达与许多认知障碍有关，包括精神发育迟滞，阿尔茨海默病，和药物滥用因此，阐明调节ARC介导的细胞间沟通具有潜在的临床意义。