蛋白酶体（proteasome）是真核细胞中极为重要的依赖于ATP的蛋白质降解机器。细胞中约90％受到损伤或错误折叠的蛋白质都会经由泛素（ubiquitin）－蛋白酶体途径降解。但是至今对蛋白酶体在ATP驱动下识别并降解底物的结构机制的了解仍十分有限。此外，蛋白酶体的19S调控颗粒还可以与mRNA加工复合物CCR4-NOT相互作用调节组蛋白H3K4的甲基化，但其机制仍不清楚。本项目拟主要应用新兴的超低温冷冻电镜（cryo-EM）技术，解析蛋白酶体在ATP驱动下的构象变化，揭示该构象变化在蛋白酶体识别、去折叠、降解底物中的作用机制；阐明19S调控颗粒与CCR4-NOT 复合物相互作用的分子机制，为研究蛋白酶体在组蛋白甲基化中的调控功能提供结构基础。本项目有助于深入理解蛋白酶体调节下蛋白质降解的分子机制、及蛋白酶体对组蛋白甲基化的调节机制，将为探索相关疾病的诊治手段提供重要的结构基础。

The proteasome is the most essential ATP-dependent intracellular protein-degradation nanomachine across the eukaryotic kingdom. About 90% of damaged or mis-folded proteins will be processed through the ubiquitin-proteasome pathway. However, the structural mechanism of substrate recognition and degradation by proteasome with the energy provide by ATP remains poorly understood. In addition, recent biochemistry study demonstrated that the proteasome also regulate histone H3K4 methylation through its crosstalk with CCR4-NOT complex, while the mechanism is unclear. By utilizing the emerging powerful electron cryomicroscopy (cryo-EM) technique, the research objectives include: To reveal the ATP-driven conformational changes of proteasome, and the mechanism of how these conformational changes are related to its substrate recognition, unfolding and degradation; To uncover the interaction mechanism of the 19S regulatory particle with CCR4-NOT complex, and their role in regulating histone methylation. The ultimate goal of this study is to uncover the mechanisms of proteasome-mediated degradation, and proteasome-regulated histone methylation, which could provide essential structure basis for the diagnosis and treatment of related human diseases.