小分子热休克蛋白（sHSP）是细胞内存在的分子量为12-43kDa的一类小分子量蛋白，其功能是在细胞应激时，与由外界胁迫条件（如高温、氧化）导致的部分变性的蛋白结合，阻止部分变性蛋白在细胞内聚集，从而防止细胞受到变性蛋白的伤害。sHSP的这一功能，使得其在生命活动中起着至关重要的作用。sHSP结构和功能异常，常常导致严重疾病，如神经系统疾病、心血管疾病、癌症等。sHSP因此成为治疗这些疾病的关键靶标。sHSP如何与部分变形的蛋白结合并阻止其聚集，目前尚不清楚。我们提出sHSP的工作模式不是单一模式，而是多种模式。虽然sHSP不是以单一模式而是以多种模式工作，但其结构基础和工作机制尚不清楚。本项目拟用以球状寡聚体形式工作的AgsA和以平面超分子组装体形式工作的CeHSP-17为模型系统，应用冷冻电镜解析这两种系统中所涉及的蛋白质复合体的结构，阐明其分子伴侣功能的结构基础和工作机制。

Small heat shock proteins (sHSPs) are a family of cellular proteins with molecular mass of 12-43kDa. sHSPs function as molecular chaperones to bind partially denatured proteins induced by stress (such as high temperature and oxidation), thereby prevent them from irreversible aggregation and protect cell from the harmful attack by these aggregated proteins. sHSPs play indispensable roles in biological processes. The structural and functional abnormality of sHSPs could cause severe diseases, such as neurodegenerative disease, cardiovascular disease and cancer. sHSPs have become the key targets for drug development to treat these diseases. How sHSP bind partially denatured proteins and prevent them from irreversible aggregation is still elusive. We propose that sHSPs act not in single mode but in multiple modes, but their structural and action mechanisms are not known. In this project, we will employ two kinds of sHSPs, AgsA, which acts in spherecal oligomeric form, and CeHSP-17, which acts in planar super-molecular assembly form, as model systems, and study the structures of sHSP and sHSP-client protein complexes by cryo-electron microscopy, to elucidate the structural basis and action mechanism of their molecular chaperone function.