NMR-basierte Charakterisierung phosphorylierungsinduzierter, konformationeller Übergänge in dem Alzheimer-assozierten Protein Tau

Tau蛋白是一种微管相关的内在无序蛋白，在阿尔茨海默病的进展中起着核心作用。在阿尔茨海默病中，Tau变得过度磷酸化，失去其与微管结合的能力，并聚集成细胞内异常蛋白质沉积物。多年来，已经做出了相当大的努力来研究磷酸化对Tau结构的影响，作为理解其功能和作用机制的手段，但这些努力主要使用传统的生物化学方法，因此在相对原始的水平上解决了结构和功能。最近，我们已经表明，它是可能的，以研究的结构和动力学的441-残基的Tau在单个残基分辨率使用NMR光谱。在这里，我们建议开发一个自洽的Tau分子系综描述，结合并反映了多个互补的构象依赖的实验参数。然后，我们将使用这种描述作为一个基本的构建块，以揭示从明显的正常到疾病状态的Tau的过渡。拟议的项目将提供前所未有的深入了解与Tau致病性错误折叠相关的构象变化。

The Tau protein, which is a microtubule-associated intrinsically disordered protein, plays a central role in the progression of Alzheimer disease. In Alzheimer disease, Tau becomes excessively phosphorylated, loses its ability to bind to microtubuli, and aggregates into intracellular abnormal protein deposits. Considerable effort has been made over the years to investigate the impact of phosphorylation on the structure of Tau as a means to understand its function and mechanisms of action, but these efforts have primarily used traditional biochemistry approaches and therefore have addressed structure and function at a relatively primitive level. Recently, we have shown that it is possible to study the structure and dynamics of 441-residue Tau at single residue resolution using NMR spectroscopy. Here we propose to develop a self-consistent molecular ensemble description of Tau that combines and reflects multiple complementary conformationally-dependent experimental parameters. We will then use this description as a basic building block to reveal the transition from apparent normality into the diseased state of Tau. The proposed project will provide unprecedented insight into the conformational changes that are associated with pathogenic misfolding of Tau.