The Dynamic Regulation in Copper Ion Homeostasis

[807786 .]铜离子对所有生物都是必需的，但也是有毒的。由于这种双重性质，细胞必须具有动态的体内平衡来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？这仍然是一个需要解决的基本问题。因此，了解铜离子的稳态机制是至关重要的。本课题旨在以酵母为模型系统，研究铜离子稳态的动态调控。酵母细胞进行的生化反应与人类相似，铜离子稳态机制在酵母、人类和其他不同物种中基本上是保守的。在酵母中，生理条件下铜离子的摄取和运输是由一种假定的铜离子感应蛋白Mac 1p调节的。最近的研究表明，Mac lp也通过一种未知的调节蛋白质降解机制对铜离子的毒性水平做出反应。Mac - lp降解是铜离子稳态的一种新机制。mclp在生理和毒性铜离子条件下的不同功能反映了铜离子的动态生物学性质。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。这些方法将用于实现两个特定目标：(1)进一步表征Mac lp对生理和毒性铜离子水平的反应差异；(2)阐明Mac 1p感知和区分生理和毒性铜离子水平的生化机制。本研究结果将为进一步了解铜离子动态稳态的分子机制做出基础性贡献。该结果还将为金属离子在生物学和调节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.