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 是一种微管 (MT) 相关蛋白 (MAP)，被发现在阿尔茨海默病 (AD) 和其他神经退行性疾病的神经原纤维缠结沉积物中聚集成直 (SF) 或成对螺旋 (PHF) 丝。编码 tau 蛋白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）相关，表明 tau 蛋白在这种疾病以及 AD 等其他疾病的发病机制中发挥着致病作用。许多 FTDP-17 连锁突变属于 tau 的 MT 结合域 (MBD)，该区域根据同种型，包含 31 至 32 个残基 MT 相互作用的三个或四个假重复序列（3R 与 4R）主题。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体外 tau PHF 的形成。不同类别的 FTDP-17 相关突变会影响 tau mRNA 剪接并改变体内 4R 与 3R tau 异构体的比例，这既可以调节 tau 的正常功能，又可以通过改变游离和 MT 结合的相对群体来增强 tau 聚集同工型。因此，tau 突变可能通过干扰 tau 功能、增强 tau 聚集或同时通过这两种方式发挥致病作用。 Tau 在游离于溶液中时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发生结构转变。游离 tau 蛋白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。我们建议使用核磁共振波谱以高分辨率表征自由态 tau 的结构和动态特性。我们还将详细阐明洗涤剂胶束相关 tau 蛋白的结构以及脂质囊泡和 MT 结合 tau 蛋白的拓扑结构。我们将探讨 FTDP-17 连锁突变对游离、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。我们的研究将集中于 tau MBD 的 3R 和 4R 形式。结果将阐明正常 tau 功能和 tau 诱导的神经变性的分子机制，并可能为开发新疗法提供策略建议。这项工作还可能对理解和治疗其他蛋白质聚集疾病具有更广泛的影响。