Copper Homeostasis in Yeast

描述（由申请人提供）：微量金属铜（Cu）和铁（Fe）是生命必需的营养物质，在多种酶促反应中作为催化辅助因子，涉及血液凝固、能量产生、DMA复制、肽激素成熟、氧运输和各种其他基本过程。铜或铁平衡的缺陷会导致严重的人类疾病，包括门克斯病和威尔逊病、血色素沉着症、贫血等，并与阿尔茨海默病、帕金森病、朊病毒病、癌症和衰老有关。Cu和Fe的重要性以及这两种金属之间的功能相互作用要求生物体拥有微调的稳态机制，以确保获得、分配和利用足够水平的Cu和Fe来驱动生化反应。此外，细胞必须对限制Cu或Fe可用性的变化做出反应，以调动这些金属的储存，或者重新编程细胞代谢以应对金属的限制。本提案描述了研究途径，使用酵母作为模型系统，了解真核细胞调节Cu和Fe可用性的基本机制。本文首先概述了在Cu剥夺条件下酵母Ctr2蛋白动员细胞内Cu储存的生理作用、调控和机制。第二个特定目标概述了实验，以了解Cth2蛋白在Cu或Fe缺乏条件下靶向特定mRNA分子降解的功能，作用机制和作用，作为优先利用Fe的手段。考虑到适当的Cu和Fe稳态控制对人类健康的重要性，以及Ctr2和Cth2在人类中潜在的功能同源物的存在，本提案中描述的研究将提供关于细胞在健康和疾病中维持Cu和Fe稳态的机制的重要信息。

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.