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.
活性调节细胞骨架相关蛋白(Arc,又称Arg3.1)是一种即刻早期基因
由活动/经验诱导的产物,需要多种突触可塑性模式。两者都是长期的
增强(LTP)和长期抑制(LTD)在Arc缺失时受损,以及形成
长期的空间、味觉和恐惧记忆。Arc最具特点的功能是增强了
树突棘中AMPA受体(AMPAR)的内化,这一过程与LTD有关。这
Arc在AMPAR内吞作用中的作用得到了一份报告的支持,该报告认为Arc直接与AMPAR内吞作用的两个元件结合
内吞机制、动力素和内亲素,通过我们的发现,Arc刺激动力素自组装和
GTP酶活性。Arc C-末端片段的晶体结构的解决方案显示出与
HIV Gag的衣壳结构域。此外,Arc组装成病毒衣壳状结构,包裹Arc mRNA,
被释放到细胞外空间,并被相邻细胞内化。因此,Arc在
促进质膜在细胞内外的萌发。此项目的目标是定义
Arc介导的膜泡化机制及其调控。荧光涨落光谱学
(FFS)将被用来监测膜萌发的巨大单层囊泡(GUV)。在目标1中,我们将使用
光谱相量分析,以确定脂肪成分和流动性如何影响发芽过程,以及
数字和亮度(N&B)分析,以获得弧形自组装在GUV表面的定量图像。
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介导的膜泡化。圆弧中的变化
表达与许多认知障碍有关,包括智力低下、阿尔茨海默病、
和药物滥用。因此,阐明调节Arc介导的细胞间质的机制
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:














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