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

基于 NMR 的阿尔茨海默病相关蛋白 tau 中磷酸化诱导的构象转变的表征

• 批准号: 185614764
• 负责人: Professor Dr. Markus Zweckstetter
• 金额: --
• 依托单位: Forschungsgruppe Translationale strukturelle Biologie der Demenz
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2012-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/185614764?language=en
• 关键词: NMR; basierte; Charakterisierung; phosphorylierungsinduzierter; konformationeller

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.

Tau蛋白是一种微管相关的内在紊乱蛋白，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过度磷酸化，失去与微管结合的能力，并聚集成细胞内异常蛋白沉积物。多年来，研究磷酸化对Tau蛋白结构的影响作为了解其功能和作用机制的一种手段已经做出了相当大的努力，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研究了结构和功能。最近，我们已经证明了利用核磁共振光谱在单残基分辨率下研究441残基Tau的结构和动力学是可能的。在这里，我们建议开发一个自一致的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，我们将使用这一描述作为基本的构建块来揭示Tau蛋白从表面正常到患病状态的转变。该项目将为与致病性Tau蛋白错误折叠相关的构象变化提供前所未有的见解。