STRUCTURE AND GENESIS OF TAU FILAMENTS

TAU 丝的结构和起源

• 批准号: 2683182
• 负责人: Jeff Kuret
• 金额: $ 2.87万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-15 至 1998-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2683182
• 关键词: chemical binding; chemical kinetics; circular dichroism; glycation; molecular site; phosphorylation; polymerization; posttranslational modifications; protein biosynthesis; protein structure function; tau proteins

DESCRIPTION The applicants have discovered an entirely new and powerful method of polymerizing tau protein into filaments resembling the straight filaments found in the neurofibrillary pathology of Alzheimer's disease. The inducing agents are membrane phospholipids and fatty acids that are known to function as signal transduction molecules in vivo. The resultant filaments are regular, and available in large quantities. By analyzing the structure and genesis of these filaments, they will address important questions regarding tau filament formation and neurodegenerative disease. Which membrane-associated components are capable of stimulating tau self-association and polymerization? Does the resultant structure-activity-relationship point toward the involvement of known signal transduction mechanisms in filament biogenesis? What is the role of phosphorylation on tau self-assembly and intracellular stability? Four Aims are proposed to address these questions. 1) The process of tau filament formation will be quantified. Using a novel assembly assay, they will quantify the rate, extent, and ligand dependence of tau filament formation in vitro. 2) The structural features on tau required for filament formation will be determined. These studies will clarify the structural requirements of tau polymerization and the location of a ligand-binding site potentially useful for development of high-affinity agents for therapeutic and diagnostic applications. 3) The influence of post-translational modification on tau polymerization kinetics will be assessed. These studies will clarify the impact of phosphorylation and glycation on tau filament formation. 4) The effects of polymerization on tau structure will be determined. Using a combination of circular dichroism spectropolarimetry and hydrodynamic measurements, it will be determined whether tau adopts a defined structure upon filament formation. The results will have important implications for the feasibility of developing therapeutic agents capable of preventing, and premortem diagnostic agents capable of detecting, the formation of fibrillar pathology.

描述申请人发现了一个全新的强大 将tau蛋白聚合成类似于笔直的丝的方法 在阿尔茨海默氏病的神经纤维病理学中发现的细丝。 诱导剂是膜磷脂和脂肪酸 在体内被称为信号转导分子。 结果 细丝是常规的，大量可用。 通过分析 这些细丝的结构和起源，它们将解决重要的 有关Tau细丝形成和神经退行性疾病的问题。 哪些膜相关的成分能够刺激tau 自我关联和聚合？ 结果吗？ 结构激活关系指向已知信号的参与 细丝生物发生中的转导机制？ 角色是什么 tau自组装和细胞内稳定性的磷酸化？ 四个目标 建议解决这些问题。 1）tau细丝的过程 形成将被量化。 使用新颖的组装测定法，他们将 量化tau丝形成的速率，程度和配体依赖性 体外。 2）丝形成所需的tau的结构特征 将确定。 这些研究将阐明结构要求 Tau聚合和配体结合位点的位置可能有可能 用于开发用于治疗和治疗的高亲和力药物 诊断应用。 3）翻译后的影响 将评估对TAU聚合动力学的修饰。 这些研究 将阐明磷酸化和糖基化对tau丝的影响 形成。 4）聚合对tau结构的影响将是 决定。 结合圆形二色性光谱法的组合 和流体动力测量，将确定tau是否采用 灯丝形成时定义的结构。 结果将很重要 对开发能够的治疗剂的可行性的影响 预防和预先型诊断剂能够检测到 纤维病理的形成。