The Dynamic Regulation in Copper Ion Homeostasis

9807786朱铜离子对所有生物体都是必需的，但也是有毒的。由于这种双重性质，细胞必须保持动态稳态以维持适当的细胞铜离子水平：不能太低而导致缺乏，也不能太高而导致毒性。动态铜离子稳态的分子机制是什么？这仍然是一个有待解决的根本问题。因此，了解铜离子稳态机制是绝对关键的。本课题的目的是以酵母为模型系统，研究铜离子稳态的动态调节。酵母细胞进行与人类所需的生化反应相似的生化反应，并且铜离子稳态机制在酵母、人类和其他不同物种中很大程度上是保守的。在酵母中，铜离子的吸收和运输在生理条件下是由一个假定的铜离子传感蛋白，Mac 1p。最近的研究表明，Mac lp也通过一种未表征的调节蛋白质降解机制对铜离子的毒性水平作出反应。Mac lp降解是铜离子稳态的一种新机制。Mac lp在生理和毒性铜离子条件下的差异功能反映了铜离子的动态生物学本质。因此，了解Mac lp功能将有助于确定动态铜离子稳态的分子机制。本项目将采用分子生物学、化学和生物化学相结合的方法，确定Mac lp功能的精确分子机制。这些方法将被应用于实现两个特定的目标：（1）进一步表征Mac lp如何差异响应生理和毒性水平的铜离子，（2）阐明Mac 1p传感和区分生理和毒性水平的铜离子的生化机制。本研究的结果将为理解动态铜离子稳态的分子机制做出基础性贡献。研究结果还将为生物学中的金属离子和受调控的蛋白质降解领域提供重要见解。

9807786ZhuCopper ion is essential yet toxic for all living organisms. Because of this dual nature, cells must posses a dynamic homeostasis to maintain a proper cellular level of copper ion: not too low to cause deficiency and not too high to cause toxicity. What is the molecular mechanism of dynamic copper ion homeostasis? This is still a fundamental question to be addressed. Therefore, it is absolutely critical to understand copper ion homeostatic mechanisms. The goal of this project is, using yeast as a model system, to study the dynamic regulation of copper ion homeostasis. Yeast cells carry out similar biochemical reactions to those required in humans, and copper ion homeostatic mechanisms are largely conserved among yeast, human and other divergent species. In yeast, copper ion uptake and transport under physiological conditions is regulated by a putative copper ion-sensing protein, Mac 1p. Recent studies have shown that Mac lp also responds to toxic levels of copper ions through an uncharacterized mechanism of regulated protein degradation. Mac lp degradation is a new mechanism in copper ion homeostasis. The differential functions of Mac lp under physiological and toxic copper ion conditions reflect the dynamic biological nature of copper ions. Therefore, understanding Mac lp functions will be instrumental in determining molecular mechanism of dynamic copper ion homeostasis. This project, using a combination of molecular biological, chemical and biochemical methods, will to determine the precise molecular mechanisms of Mac lp functions. These approaches will be applied to achieve two specific aims: (1) to further characterize how Mac lp responds differentially to physiological and toxic levels of copper ions, (2) to elucidate the biochemical mechanisms of Mac 1p sensing and differentiating physiological and toxic levels of copper ions. The outcomes of this research will make fundamental contributions to understanding of the molecular mechanism of dynamic copper ion homeostasis. The results will also provide critical insights into the fields of metal ions in biology and regulated protein degradation.