热休克蛋白解聚致病淀粉样纤维的结构与分子机理研究

Over 30 devastating human diseases including Alzheimer's,Parkingson's and Amyotrophic lateral sclerosis, are closely related to abnormal protein fibrillation and deposition. Amyloid-related diseases constitute a great thread to human health. Currently, over 35 million patients are suffering from Azherimer's worldwide. The most widely used strategy for drug development is to prevent the formation of pathogenic amyloid aggregates. This project focuses on an unique amyloid disaggregase -- Hsp104 from yeast. By using micro-focus X-ray crystallography, and other biophysical and biochemical methods, we aim to (1) reveal the structural basis and molecular mechanism of amyloid fibril disaggregation by Hsp104; (2) study how yeast survives from fluctuating environments by Hps104-regulated functional amyloid; (3) perform structural-based design of amyloid disaggregase, which will shed light on development of a novel type of inhibitor against amyloid diseases.

30余种人类重要疾病都与蛋白在体内的淀粉样聚集密切相关，例如：阿尔茨海默病、帕金森症及渐动人症等。淀粉样沉淀相关疾病对人类健康造成巨大威胁，仅阿尔茨海默病，目前全球患者就超过了三千五百万。抑制及清除淀粉样蛋白聚集一直是相应疾病药物研发的核心方向。本项目聚焦于已知自然界唯一具有解聚蛋白淀粉样纤维能力的热休克蛋白Hsp104。以微X射线晶体学技术为核心，整合多种生物物理学及生物化学技术手段，试图揭示Hsp104解聚不同种类纤维的分子机理及原子结构基础；阐释Hsp104在酵母调控功能性淀粉样聚集行使正常生物学功能的机理；基于结构信息，设计开发具有高效、专一解聚致病淀粉样纤维的解聚酶。为淀粉样沉淀相关疾病的抑制剂设计提供全新的思路和发展方向。

人类多种重要疾病(例如包括阿尔茨海默病、帕金森症及渐动人症等)都与相应致病蛋白在体内的淀粉样聚集密切相关。淀粉样沉淀相关疾病对人类健康造成巨大威胁。本项目聚焦于具有广谱解聚不同种类致病蛋白纤维能力的来源于酵母的热休克蛋白Hsp104。以低温冷冻电镜以及微晶的电子衍射为核心，整合多种生物物理学及生物化学技术手段，系统地揭示Hsp104抑制以及解聚不同种类纤维的分子机理及原子结构基础.重要的是,通过本课题的实施,发现了Hsp104以前未被发现的独特的holdase的分子伴侣活性,并揭示其全新活性的结构基础.为全面理解Hsp104的底物识别以及抑制致病蛋白聚集的机理提供了重要的基础.