Membrane Remodeling by Arc/Arg3.1
Arc/Arg3.1 膜重塑
基本信息
- 批准号:9889184
- 负责人:
- 金额:$ 18.71万
- 依托单位:
- 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:
- 关键词:AMPA ReceptorsAdaptor Signaling ProteinAlzheimer&aposs DiseaseAngelman SyndromeBindingBiological AssayC-terminalCapsidCell membraneCellsClathrin AdaptorsCognition DisordersCrystallizationCytoskeletonDataDendritic SpinesDockingDrug AddictionDynaminElementsEndocytosisExtracellular SpaceFluorescenceFragile X SyndromeGoalsGuanosine Triphosphate PhosphohydrolasesHIVImmediate-Early GenesImpairmentLaboratoriesLearningLinkLipidsLong-Term DepressionLong-Term PotentiationMediatingMembraneMemoryMental RetardationMessenger RNAModificationMonitorMorphologyMusN-terminalNeuronsPhasePhosphorylationPlayPost-Translational Protein ProcessingProcessProteinsRegulationReportingRoleSchemeSchizophreniaSpectrum AnalysisStructureSubstance abuse problemSurfaceSynapsesSynaptic plasticityTaste PerceptionTestingTherapeutic InterventionTranslatingVesicleViralVirus AssemblyVirus-like particlealpha helixbaseclinically significantcofactorexperienceexperimental studyextracellular vesiclesfear memoryfluiditygene productintercellular communicationinterestlong term memorynew therapeutic targetoverexpressionpalmitoylationparticleself assemblyunilamellar vesiclevesicular 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。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Fluorescence Lifetime Phasor Analysis of the Decamer-Dimer Equilibrium of Human Peroxiredoxin 1.
- DOI:10.3390/ijms23095260
- 发表时间:2022-05-09
- 期刊:
- 影响因子:5.6
- 作者:
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JOSEPH P ALBANESI其他文献
JOSEPH P ALBANESI的其他文献
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{{ truncateString('JOSEPH P ALBANESI', 18)}}的其他基金
Guanylyl cyclase receptors: Targets for medical intervention
鸟苷酸环化酶受体:医疗干预的目标
- 批准号:
7989868 - 财政年份:2009
- 资助金额:
$ 18.71万 - 项目类别:
Guanylyl cyclase receptors: Targets for medical intervention
鸟苷酸环化酶受体:医疗干预的目标
- 批准号:
7333226 - 财政年份:2006
- 资助金额:
$ 18.71万 - 项目类别: