基于冷冻电镜研究eIF3复合物调控真核生物翻译起始过程的分子机制

翻译过程，即核糖体将mRNA翻译为蛋白质是中心法则的关键环节。其中翻译的起始与研究相对清楚的上游转录起始类似，都受到相关起始因子的严格调控。真核生物翻译起始因子3（eIF3）作为参与mRNA翻译起始过程中最大且最复杂的因子，在翻译起始调控中发挥了许多关键作用，但其分子机制尚不清楚，这也是真核生物翻译调控领域研究进展缓慢的原因之一。同时由13个亚基组成，总分子量高达约800kDa的eIF3全复合物的制备也是世界性难题。因此本项目聚焦eIF3复合物功能，致力于阐明其调控真核生物翻译起始调控过程的分子机制。申请人借鉴此前在真核生物转录起始领域积累的相关经验，目前已经可以通过体外重构的方式大量获得稳定的eIF3核心复合物，为后续开展翻译起始动态调控全过程的研究奠定了坚实的基础。真核生物翻译起始全过程调控机制神秘面纱的揭秘，可以为翻译相关疾病的药物发现与诊断治疗提供全新的解决思路。

The translation of mRNA into protein by the ribosome is the critical step of the central dogma. Translation initiation is similar to transcription initiation, which is tightly regulated by a set of conserved initiation factors. Eukaryotic initiation factor 3 (eIF3), as the largest and the most complicated factor involved in mRNA translation initiation, plays several crucial roles in translation regulation. However, the molecular mechanism of elF3 has not been fully elucidated, which is one of the reasons that affect the research in the eukaryotic translation regulation. Thus, the preparation of the eIF3 holo complex which consists of 13 subunits (~800kDa) is also a worldwide challenge. Therefore, this research focuses on the function of the eIF3 complex and aims to elucidate the molecular regulation mechanism of eukaryotic translation initiation. Based on the previous experience in eukaryotic transcriptional initiation research, the applicant has been able to obtain an amount of eIF3 core complexes by in vitro assembly, which is a solid foundation for the following study of the overall process of dynamic regulation of translation initiation. The unraveling of the mysterious mechanism of eukaryotic translation initiation could drive drug discovery and diagnosis for translation-related diseases.