Structure and Function of Tau

Tau 的结构和功能

• 批准号: 6984438
• 负责人: David Eliezer
• 金额: $ 31万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6984438
• 关键词: Alzheimer' s disease; conformation; electron spin resonance spectroscopy; gene mutation; intermolecular interaction; micelles; molecular pathology; nuclear magnetic resonance spectroscopy; protein structure function; proteolysis; tau proteins; vesicle /vacuole

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是微管（MT）相关蛋白（MAP），发现其在阿尔茨海默病（AD）和其他神经退行性疾病中的神经元缠结沉积物内聚集成直（SF）或成对螺旋（PHF）丝。编码tau的基因突变与遗传综合征FTDP-17（与17号染色体相关的额颞叶痴呆和帕金森综合征）相关，表明tau在这种疾病和可能的其他疾病（如AD）的发病机制中起着致病作用。许多FTDP-17连锁突变属于tau的MT结合结构域（MBD），根据同种型，该区域含有31至32个残基MT相互作用基序的三个或四个假重复序列（3R与4 R）。这些突变破坏了tau-MT相互作用和tau促进的MT组装，并且一些突变还增强了体外tau PHF的形成。不同类型的FTDP-17相关突变影响tau mRNA剪接并改变体内4 R与3R tau亚型的比例，这既可以调节tau的正常功能，又可以通过改变游离和MT结合亚型的相对群体来增强tau聚集。因此，tau突变可以通过干扰tau功能、通过增强tau聚集或通过这两种方式来发挥致病作用。Tau在溶液中游离时本质上是非结构化的，但在与MT结合后、在细丝形成后以及在与脂质膜缔合后经历结构转变。游离tau蛋白中的残留结构可能在介导这些不同的分子间相互作用中发挥重要作用。我们建议，在高分辨率，结构和动力学性质的tau在其自由状态下使用NMR光谱的特征。我们还将详细阐明洗涤剂胶束相关的tau蛋白和脂质囊泡和MT结合的tau蛋白的拓扑结构。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4 R形式。这些结果将阐明正常tau蛋白功能和tau蛋白诱导的神经变性的分子机制，并可能为开发新的治疗方法提供建议。这项工作也可能对理解和治疗其他蛋白质聚集疾病具有更广泛的意义。