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Structure and Function of Tau

Tau 的结构和功能

基本信息

批准号：
7480921
负责人：
David Eliezer
金额：
$ 28.8万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-08-01 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7480921
关键词：
Affect Alzheimer&apos s Disease Amides Amino Acid Sequence Arts Binding Biochemical Chemicals Chromosomes, Human, Pair 17 Circular Dichroism Class Classification Coupling Data Dementia Deposition Detergents Disease Electron Spin Resonance Spectroscopy FTD with parkinsonism Filament Frontotemporal Dementia Genes Genetic Goals In Vitro Inherited Intervention Label Link Lipid Binding Lipids Measurement Mediating Membrane Membrane Lipids Methods Micelles Microtubule-Associated Proteins Microtubules Molecular Molecular Conformation Mutagenesis Mutation NMR Spectroscopy Nature Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Parkinson Disease Parkinsonian Disorders Pathogenesis Phospholipids Play Population Prions Process Property Protein Isoforms Proteins Proteolysis Protons Rate Recombinants Refractory Relative (related person)Relaxation Research Personnel Residual state Resolution Role Site Solutions Structure Surface Syndrome Tauopathies Vesicle Work base conformational conversion design falls improved in vivo insight intermolecular interaction novel therapeutics prevent programs protein aggregate protein aggregation research study tau Proteins tau aggregation tau function tau interaction tau mRNA splicing tau microtubule binding domain tau mutation tau promoted microtubule assembly tau-microtubule interaction

项目摘要

DESCRIPTION (provided by applicant): Tau is a microtubule (MT) associated protein (MAP) that is found aggregated into straight (SF) or paired helical (PHF) filaments within neurofibrillary tangle deposits in Alzheimer's disease (AD) and other neurodegenerative disorders. Mutations in the gene encoding tau are associated with the hereditary syndrome FTDP-17 (frontotemporal dementia and Parkinsonism linked to chromosome 17) indicating that tau plays a causative role in the pathogenesis of this and possibly other diseases such as AD. Many of the FTDP-17 linked mutations fall within the MT binding domain (MBD) of tau, a region that contains, depending on the isoform, three or four pseudo-repeats (3R vs. 4R) of a 31 to 32 residue MT interaction motif. These mutations disrupt tau-MT interactions and tau-promoted MT assembly, and several also enhance tau PHF formation in vitro. A different class of FTDP-17 associated mutations influence tau mRNA splicing and alter the ratio of 4R to 3R tau isoforms in vivo, which can both modulate the normal functions of tau and enhance tau aggregation by altering the relative populations of free and MT-bound isoforms. Thus, tau mutations may exert pathogenic effects by interfering with tau function, by enhancing tau aggregation, or by both means. Tau is intrinsically unstructured when free in solution but undergoes structural transitions upon binding to MTs, upon filament formation, and upon associating with lipid membranes. Residual structure in free tau may play an important role in mediating these various intermolecular interactions. We propose to characterize, at high resolution, the structural and dynamic properties of tau in its free state using NMR spectroscopy. We will also elucidate in detail the structure of detergent micelle associated tau and the topology of lipid vesicle and MT-bound tau. We will probe the effects of FTDP-17 linked mutations on the structural properties of free, lipid-associated and MT-bound tau and will use newly designed mutations to elucidate the structural basis for these intermolecular interactions. Our studies will focus on 3R and 4R forms of the tau MBD. The results will clarify the molecular mechanisms underlying both normal tau function and tau induced neurodegeneration and may suggest strategies for developing new therapeutics. This work may also have broader implications for understanding and treating other protein aggregation diseases.

描述（由申请人提供）：Tau是一种微管（MT）相关蛋白（MAP），在阿尔茨海默病（AD）和其他神经退行性疾病的神经原纤维缠结沉积物中被发现聚集成直（SF）或成对螺旋（PHF）细丝。编码tau的基因突变与遗传性综合征FTDP-17（与17号染色体相关的额颞叶痴呆和帕金森病）有关，表明tau在该发病机制以及可能的其他疾病（如AD）中起着致病作用。许多与FTDP-17相关的突变位于tau的MT结合域（MBD）内，该区域根据同工异构体的不同，包含31至32个残基MT相互作用基序的3或4个假重复序列（3R与4R）。这些突变破坏了tau-MT相互作用和tau促进的MT组装，其中一些突变还增强了tau PHF的体外形成。不同类型的FTDP-17相关突变影响tau mRNA剪接并改变体内4R和3R tau亚型的比例，这既可以调节tau的正常功能，又可以通过改变自由和mt结合亚型的相对种群来增强tau聚集。因此，tau突变可能通过干扰tau功能、增强tau聚集或两种方式发挥致病作用。在溶液中游离时，Tau本质上是非结构化的，但在与mt结合、形成细丝以及与脂质膜结合时，会经历结构转变。游离tau蛋白的残馀结构可能在介导这些不同的分子间相互作用中起重要作用。我们提出了表征，在高分辨率，在其自由状态的tau的结构和动力学性质使用核磁共振波谱。我们还将详细阐明洗涤剂胶束相关tau的结构以及脂质囊泡和mt结合tau的拓扑结构。我们将探讨FTDP-17相关突变对游离、脂质相关和mt结合tau蛋白结构特性的影响，并将使用新设计的突变来阐明这些分子间相互作用的结构基础。我们的研究将集中在tau MBD的3R和4R形式。结果将阐明正常tau功能和tau诱导的神经退行性变的分子机制，并可能为开发新的治疗方法提供策略。这项工作也可能对理解和治疗其他蛋白质聚集性疾病有更广泛的意义。