Structure, interactions, and dynamic self-assembly of tubulin with different tau isoforms

Tubulin nucleation and microtubule (MT) assembly are frequent events in cells. The mechanisms directing these processes are poorly understood, owing to the size of tubulin and its highly dynamic character. The MT-associated tau proteins, including six isoforms, are major determinants of axon cytoskeleton stability and dynamics. Malfunctions of tubulin and tau are involved in various pathologies including cancer and neurodegenerative diseases. We propose to use time-resolved solution small-angle-X-ray scattering (TR-SAXS) methods, and our advanced analysis tools to follow the coassembly dynamics of different tubulin with different tau isoforms. Our aim is to determine the structures and intermolecular interactions dictating how tubulin dimers and different tau isoforms dynamically nucleate, assemble, and interact with one another to form tau-stabilized MT.

微管蛋白（Tubulin）成核与微管（microtubule, MT）组装是细胞内频发的生物学过程。由于微管蛋白分子量庞大且具有高度动态的特性，调控此类过程的分子机制至今尚未被充分阐明。微管相关tau蛋白（tau proteins）包含6种亚型（isoforms），是维持轴突细胞骨架稳定性与动态性的核心调控因子。微管蛋白与tau蛋白的功能异常与包括癌症、神经退行性疾病在内的多种病理状态密切相关。本研究拟采用时间分辨溶液小角X射线散射（time-resolved solution small-angle-X-ray scattering, TR-SAXS）技术，并结合本团队开发的先进分析工具，追踪不同微管蛋白与不同tau蛋白亚型的共组装动态过程。本研究旨在解析决定微管蛋白二聚体与不同tau蛋白亚型如何动态成核、组装并相互作用，进而形成tau蛋白稳定化微管的分子结构与分子间相互作用机制。