金属蛋白CoaR调控钴离子稳态平衡和钴胺素生物合成的结构与机制研究

体内金属离子的稳态平衡是维持生物体各项功能的正常运转和代谢稳定的必要前提。各类金属调控蛋白质和转运蛋白是负责维持金属离子稳态平衡的首要控制因素，因此理解其结构和机理对破解生命的奥秘有重要意义。钴离子作为生物体必须的微量元素，最重要的作用是作为钴胺素辅基的中心离子参与各种催化和代谢调控过程。CoaR是一种在蓝细菌中进化出的的钴离子转录因子，研究报导CoaR不仅可高特异性的响应Co(II)，还能响应钴胺素合成途径中的四吡咯类（TP）中间产物，从而实现对钴胺素生物合成的反馈调控，但至今CoaR的结构和变构调控机制均不明确。因此，本项目拟从TP-CoaR复合物和结构域间相互作用为切入点，并结合近期发展的蛋白质工程手段、蛋白质晶体学和多种谱学表征手段，旨在详细阐明CoaR调控钴离子稳态平衡和钴胺素合成的分子机理，从而可加深人们对转录因子结构-功能关系的理解和为研究蛋白质功能的融合进化提供新见解。

Metal ion homeostasis is essential for living organisms to maintain cell viability. It is strictly controlled by a variety of metal sensors and transporters. Therefore, understanding their structure and mechanism is of great importance to reveal the mystery of life. Cobalt, an essential trace element for organism, plays a vital role in various catalytic and metabolic processes as the central ion of the coenzyme cobalamin. The metalloregulatory protein CoaR found in cyanobacteria is responsible for maintaining cobalt homeostasis and provides feedback control to cobalamin biosynthesis. It can response both to Co (II) with high specificity and to tetrapyrrole (TP) intermediates in the cobalamin biosynthesis pathway. However, the structure and allosteric regulation mechanism of CoaR are still unclear. This project aims to elucidate the molecular mechanism of CoaR involved in cobalt homeostasis and cobalamin biosynthesis by using protein engineering, protein crystallography and spectroscopic methods. Our studies could deepen the understanding of the structure-function relationship of transcription factors and provide insights for protein evolution.