Copper Homeostasis in Yeast

描述(申请人提供)：微量金属铜(铜)和铁(铁)是生命所必需的营养物质，在多种酶反应中充当催化辅因子，涉及凝血、能量生成、DMA复制、多肽激素成熟、氧气运输和各种其他基本过程。铜或铁平衡缺陷会导致严重的人类疾病，包括门克斯和威尔逊病、血色素沉着症、贫血和其他疾病，并与阿尔茨海默氏症、帕金森氏症和普里恩病以及癌症和衰老有关。铜和铁的重要性以及这两种金属的功能相互作用要求生物体具有微调的宿主机制，以确保获得、分配和利用足够水平的铜和铁来驱动生化反应。此外，细胞必须对限制铜或铁供应的变化做出反应，以动员这些金属的储存，或重新编程细胞代谢以应对金属限制。这项建议描述了以酵母为模型系统的研究途径，以了解真核细胞调节铜和铁有效性的基本机制。在第一个特定目的的实验中，概述了酵母Ctr2蛋白在缺铜条件下动员细胞内铜储存的生理作用、调节和机制。第二个特定目的概述了实验，以了解Cth2蛋白在铜或铁缺乏条件下靶向降解特定mRNA分子的功能、作用机制和作用，作为优先利用铁的一种手段。鉴于适当的铜和铁的动态平衡控制在人类健康中的重要性，以及Ctr2和Cth2在人类中潜在的功能同源基因的存在，这项建议中描述的研究将为细胞在健康和疾病中维持铜和铁的动态平衡的机制提供重要的基础信息。

DESCRIPTION (provided by applicant): The trace metals copper (Cu) and iron (Fe) are nutrients that are essential to life, serving as catalytic cofactors in a wide variety of enzymatic reactions involved in blood clotting, energy generation, DMA replication, peptide hormone maturation, oxygen transport and a variety of other essential processes. Defects in Cu or Fe balance cause severe human diseases that include Menkes and Wilson diseases, hemochromatosis, anemia and others, and are implicated in Alzheimer's, Parkinson's and prion diseases and in cancer and aging. The essentiality of both Cu and Fe, and the functional interactions of these two metals require that organisms possess fine-tuned homestatic mechanisms to ensure that sufficient levels of Cu and Fe are acquired, distributed and utilized to drive biochemical reactions. Furthermore, cells must respond to changes that limit Cu or Fe availability to mobilize stores of these metals, or to reprogram cellular metabolism to cope with metal limitation. This proposal describes avenues of investigation, using yeast as a model system, to understand fundamental mechanisms whereby eukaryotic cells regulate Cu and Fe availability. In the first specific aim experiments are outlined to understand the physiological role, regulation and mechanism by which the yeast Ctr2 protein mobilizes intracellular Cu stores under conditions of Cu deprivation. The second specific aim outlines experiments to understand the function, mechanism of action and role of the Cth2 protein in targeting specific mRNA molecules for degradation under conditions of Cu or Fe deficiency, as a means of prioritizing Fe utilization. Given the importance of proper homeostatic control of Cu and Fe in human health, and the presence of potential functional orthologues of both Ctr2 and Cth2 in humans, the studies described in this proposal will provide fundamentally important information on the mechanisms whereby cells maintain Cu and Fe homeostasis in health and disease.