本项目与本年度重大研究计划重点资助方向第（二）条高度契合。淀粉样蛋白是一类易聚集形成纤维的蛋白，该类蛋白聚集过程中经历一系列凝集状态改变和相变。翻译后修饰调控淀粉样蛋白的性质，这种调控非常精细：不同位点的修饰或同一位点的不同修饰都会对蛋白的凝集和相变等行为产生影响，而获得定点且均一修饰的蛋白质是此方面研究的重要瓶颈。本项目拟以TDP-43，α-synuclein，Tau等淀粉样蛋白为研究对象，以化学和酶法合成的位点明确、组成均一的修饰蛋白（如：磷酸化、糖基化、糖化等修饰）为切入点，探讨这些修饰对蛋白结构、凝集和相变等的影响，并探讨调控的分子本质，为理解翻译后修饰对淀粉样蛋白功能调控及与此类蛋白相关的疾病（如：神经退行性疾病等）的发生、发展机制研究提供帮助。

This project is highly compatible with the key research directions of this annual project guide (Article 2). Amyloid proteins are a group of proteins that share the ability of forming aggregated fibres. Amyloid protein aggregation undergoes coacervate state changes and phase transition. The properties of amyloid are regulated by post-translational modifications (PTMs) which are accurate since one modification at different sites or different modifications at the same site can affect the phase behaviour or the protein aggregation. However, the availability of proteins with specific modification at specific site becomes a bottleneck in this area. In this project, three types of amyloid proteins including TDP-43, α-synuclein and Tau become the major focus. These post-translationally modified proteins will be obtained through chemical and enzymatic synthesis which are uniformly formed and contain site-specific modifications such as phosphorylation, glycosylation, glycation, etc. We pursue to investigate the impact of the modifications on proteins’ structure, aggregation and phase behaviour, especially liquid-liquid phase separation. Additionally, molecular mechanism of the regulation will be investigated which will contribute to understand PTM’s regulation on protein function and provide direct insight into the pathologic mechanism of degenerative diseases.