Structure and Function of Tau

描述(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纤维缠绕沉积中被发现聚集成直(SF)或成对螺旋(PHF)细丝。编码tau的基因突变与遗传综合征FTDP-17(与17号染色体连锁的额颞性痴呆和帕金森病)有关，这表明tau在这种疾病以及其他疾病(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)，根据异构体的不同，该区域包含31到32个残基MT相互作用基序的三个或四个伪重复(3R对4R)。这些突变破坏了tau-MT的相互作用和tau促进的MT组装，几个突变还在体外促进了tau PHF的形成。另一类与FTDP-17相关的突变影响tau基因的剪接，改变体内4R/3R tau亚型的比例，既可以调节tau的正常功能，又可以通过改变游离亚型和MT结合亚型的相对群体来增强tau的聚集。因此，tau突变可能通过干扰tau功能、增强tau聚集或两者兼而有之而发挥致病效应。当在溶液中游离时，tau本质上是无结构的，但在与MTS结合时、在细丝形成时以及在与脂膜结合时经历结构转变。游离tau中的残基结构可能在这些分子间相互作用中起着重要的作用。我们建议用核磁共振波谱在高分辨率下表征自由状态的tau的结构和动力学性质。我们还将详细阐述与tau相关的洗涤剂胶束的结构以及脂泡和MT结合的tau的拓扑结构。我们将探索FTDP-17连锁突变对自由、脂质相关和MT结合的tau结构性质的影响，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3R和4R形式的tau MBD。这一结果将阐明tau功能正常和tau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性疾病具有更广泛的意义。

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.