Functional Adaptation of Microtubules by Acetylation

乙酰化对微管的功能适应

• 批准号: 7768986
• 负责人: JACEK GAERTIG
• 金额: $ 28.39万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/7768986
• 关键词: Acetylation; Acetyltransferase; Affect; Amino Acids; Animal Model; Axon; Binding; Biochemical; Biological Assay; Caenorhabditis elegans; Cell Shape; Cell physiology; Cells; Collaborations; Deacetylase; Defect; Dendrites; Disease; Employee Strikes; Enzymes; Eukaryotic Cell; Fiber; Glutamine; HDAC6 gene; In Vitro; Intracellular Transport; Kinesin; Location; Lysine; Mediating; Microtubules; Modeling; Motor; Motor Neurons; Nervous system structure; Neurodegenerative Disorders; Neuronal Differentiation; Neurons; Organelles; Orthologous Gene; Pathology; Pattern; Phenocopy; Phenotype; Play; Post-Translational Protein Processing; Proteins; Reporting; Role; Structure; Surface; Testing; Tetrahymena; Touch sensation; Tubulin; Zebrafish; base; cell motility; dimer; human disease; in vivo; loss of function; neuronal cell body; protein complex; public health relevance; receptor; trafficking

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（由申请人提供）：微管是普遍存在的真核结构，由1-和2-微管蛋白的二聚体构成。微管在细胞运动、细胞内运输和细胞极化中起关键作用。目前还不清楚不同的微管如何在细胞内的多种环境中发挥作用。通常，马达蛋白沿着沿着微管的子集移动特定的细胞货物，并且这种选择性运输对于细胞极化至关重要。一个引人注目的例子是神经元，其中特定的物质从细胞体转移到树突或轴突突起中。微管表面选择性转运的原理和机制还不清楚。我们探讨了一个假设，即微管的功能适应选择性运输和其他本地化的功能，空间限制翻译后修饰（PTM）的微管蛋白亚基。K40在1-微管蛋白上的乙酰化是高度保守的PTM，其标记相对缓慢更新的微管。在神经元中，与树突中的微管相比，1-微管蛋白的K40乙酰化在轴突的微管上高度富集。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，包括轴突内的驱动蛋白-1。我们在这里报告的一个保守的蛋白质，是需要K40 1-微管蛋白乙酰化的模型原生动物四膜虫和斑马鱼的鉴定。这种蛋白质是MEC-17的直系同源物，MEC-17是一种先前研究的蛋白质，是C.优雅的我们发现MEC-17在体外介导K40在1-微管蛋白上的乙酰化。我们将测试的假设，MEC-17是长期寻找的1-微管蛋白K40乙酰转移酶，MEC-17，通过乙酰化K40的1-微管蛋白，有助于神经元的分化和功能。我们将使用模式生物，蠕虫秀丽隐杆线虫和斑马鱼，以评估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中：触觉受体神经元（C。elegans）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富集，因此该提议与广泛的疾病相关，特别是与神经退行性疾病相关。 公共卫生关系：真核细胞充满了被称为微管的纤维，微管作为细胞内运输的轨道并调节细胞的形状。该项目将测试一种假设，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。