Functional Adaptation of Microtubules by Acetylation
乙酰化对微管的功能适应
基本信息
- 批准号:8257521
- 负责人:
- 金额:$ 28.67万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-05-01 至 2014-04-30
- 项目状态:已结题
- 来源:
- 关键词:AcetylationAcetyltransferaseAffectAmino AcidsAnimal ModelAxonBindingBiochemicalBiological AssayCaenorhabditis elegansCell ShapeCell physiologyCellsCollaborationsDeacetylaseDefectDendritesDiseaseEmployee StrikesEnzymesEukaryotic CellFiberGlutamineHDAC6 geneIn VitroIntracellular TransportKinesinLocationLysineMediatingMicrotubulesModelingMotorMotor NeuronsNervous system structureNeurodegenerative DisordersNeuronal DifferentiationNeuronsOrganellesOrthologous GenePathologyPatternPhenocopyPhenotypePlayPost-Translational Protein ProcessingProteinsReportingStructureSurfaceTestingTetrahymenaTouch sensationTubulinZebrafishbasecell motilitydimerhuman diseasein vivoloss of functionneuronal cell bodyprotein complexpublic health relevancereceptortrafficking
项目摘要
DESCRIPTION (provided by applicant): Microtubules are ubiquitous eukaryotic structures, built of dimers of 1- and 2-tubulin. Microtubules play key roles in cell motility, intracellular trafficking and cell polarization. It is not well understood how diverse microtubules function in multiple contexts inside the cell. Commonly, motor proteins move specific cellular cargoes along subsets of microtubules, and this selective transport is critical for cell polarization. One striking example is the neuron, where specific cargoes are moved from the cell body either into the dendrite or axon projections. The principles and mechanisms that govern the selective transport on the surface of microtubules are not well understood. We explore a hypothesis that microtubules are functionally adapted for selective transport and other localized functions, by spatially restricted post-translational modifications (PTMs) of tubulin subunits. Acetylation of K40 on 1- tubulin is a highly conserved PTM, that marks microtubules which turnover relatively slowly. In neurons, K40 acetylation of 1-tubulin is highly enriched on microtubules of the axon as compared to microtubules in dendrites. Recent studies indicate that K40 acetylation of axonal microtubules stimulates binding and motility of specific motor proteins, including kinesin-1 inside the axon. We report here an identification of a conserved protein that is required for K40 1-tubulin acetylation in the model protist Tetrahymena and zebrafish. This protein is an ortholog of MEC-17, a previously studied protein which is required for the function of touch receptor neurons in C. elegans. We show that MEC-17 mediates acetylation of K40 on 1- tubulin in vitro. We will test the hypothesis that MEC17 is the long-sought 1-tubulin K40 acetyltransferase, and that MEC-17, by acetylating K40 on 1-tubulin, contributes to neuronal differentiation and function. We will use model organisms, the worm Caenorhabditis elegans and zebrafish Danio rerio, to evaluate the function of MEC-17 and K40 acetylation on 1- tubulin, specifically in two types of neurons: in touch receptor neurons (C. elegans) and in primary motor neurons (zebrafish). As acetylation of 1-tubulin is highly enriched in the nervous system, this proposal is relevant to a broad range of diseases and in particular to the neurodegenerative disorders.
PUBLIC HEALTH RELEVANCE: Eukaryotic cells are filled with fibers known as microtubules, that serve as tracks for intracellular transport and regulate the shape of cells. This project will test a hypothesis that patterns of biochemical marks on the surface of microtubules adapt specific microtubule fibers for specific functions, including a selective transport of certain cellular components. This project will have an impact on understanding of pathology of human diseases that are associated with defects in microtubules, including some neurodegenerative disorders.
描述(申请人提供):微管是真核生物中普遍存在的结构,由1-微管蛋白和2-微管蛋白二聚体组成。微管在细胞运动、细胞内运输和细胞极化中起着关键作用。不同的微管如何在细胞内的多种环境中发挥作用还不是很清楚。通常情况下,马达蛋白沿着微管的亚群移动特定的细胞货物,这种选择性运输对细胞极化至关重要。一个引人注目的例子是神经元,在那里特定的货物从细胞体移动到树突或轴突投射中。微管表面选择性传输的原理和机制还不是很清楚。我们探索了一个假设,即微管通过微管蛋白亚基的空间受限翻译后修饰(PTM)在功能上适用于选择性运输和其他局部功能。K40在1-微管蛋白上的乙酰化是一种高度保守的PTM,标志着微管的更新相对缓慢。在神经元中,1-微管蛋白的K40乙酰化在轴突的微管上比在树突中的微管上高度丰富。最近的研究表明,轴突微管的K40乙酰化刺激特定运动蛋白的结合和运动,包括轴突内的Kinesin-1。我们在这里报告了在模式原生动物四膜虫和斑马鱼中鉴定了K401-微管蛋白乙酰化所需的保守蛋白。该蛋白是MEC-17的同源蛋白,MEC-17是一种先前研究过的蛋白质,是线虫触觉感受器神经元功能所必需的。我们发现MEC-17在体外介导了K40在1-微管蛋白上的乙酰化。我们将检验这一假设,即MEC17是长期寻找的1-微管蛋白K40乙酰转移酶,并且MEC-17通过乙酰化1-微管蛋白上的K40,促进神经元的分化和功能。我们将使用模式生物,线虫线虫和斑马鱼Danio rerio,评估MEC-17和K40乙酰化对1-微管蛋白的功能,特别是在两种类型的神经元:触摸感受器神经元(线虫)和初级运动神经元(斑马鱼)。由于1-微管蛋白的乙酰化在神经系统中高度丰富,这一建议与广泛的疾病有关,特别是与神经退行性疾病有关。
与公共健康相关:真核细胞充满了被称为微管的纤维,这些纤维充当细胞内运输的轨迹,并调节细胞的形状。这个项目将测试一个假设,即微管表面的生化标记模式使特定的微管纤维适应特定的功能,包括选择性地运输某些细胞成分。该项目将对理解与微管缺陷相关的人类疾病的病理学产生影响,包括一些神经退行性疾病。
项目成果
期刊论文数量(0)
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JACEK GAERTIG其他文献
JACEK GAERTIG的其他文献
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{{ truncateString('JACEK GAERTIG', 18)}}的其他基金
Functional Adaptation of Microtubules by Acetylation
乙酰化对微管的功能适应
- 批准号:
8066989 - 财政年份:2010
- 资助金额:
$ 28.67万 - 项目类别:
Functional Adaptation of Microtubules by Acetylation
乙酰化对微管的功能适应
- 批准号:
7768986 - 财政年份:2010
- 资助金额:
$ 28.67万 - 项目类别:
Functional Adaptation of Microtubules by Acetylation
乙酰化对微管的功能适应
- 批准号:
8463562 - 财政年份:2010
- 资助金额:
$ 28.67万 - 项目类别:
MECHANISMS OF FUNCTIONAL SPECIALIZATION OF MICROTUBULES
微管功能特化的机制
- 批准号:
2193413 - 财政年份:1996
- 资助金额:
$ 28.67万 - 项目类别:
MECHANISMS OF FUNCTIONAL SPECIALIZATION OF MICROTUBULES
微管功能特化的机制
- 批准号:
2701724 - 财政年份:1996
- 资助金额:
$ 28.67万 - 项目类别:
MECHANISMS OF FUNCTIONAL SPECIALIZATION OF MICROTUBULES
微管功能特化的机制
- 批准号:
2415351 - 财政年份:1996
- 资助金额:
$ 28.67万 - 项目类别:
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