Regulation of Iron Metabolism Genes in Eukaryotes

真核生物中铁代谢基因的调控

• 批准号: 7670327
• 负责人: WILLIAM EDWARD WALDEN
• 金额: $ 31.85万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-01-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7670327
• 关键词: ATP phosphohydrolase; Animal Model; Animals; Ataxia; Binding; Biochemical; Biochemistry; Biogenesis; Cell Nucleus; Cell physiology; Cells; Chemicals; Complex; Cytoplasm; Cytosol; Defect; Elements; Equilibrium; Eukaryota; Evolution; Friedreich Ataxia; Genes; Goals; Hand; Heme Iron; Human; Hydrolysis; Iron; Iron-Regulatory Proteins; Lead; Life; Light; Link; Malignant Neoplasms; Mediating; Mitochondria; Modeling; Molecular; Molecular Genetics; Monitor; Nuclear; Nuclear Protein; Nuclear Proteins; Nuclear Structure; Organism; Parkinson Disease; Pathway interactions; Phenotype; Play; Process; Proteins; Proteomics; Regulation; Role; Saccharomyces cerevisiae; Sideroblastic Anemia; Signal Transduction; Sulfur; System; Terminology; Work; Yeasts; cell growth regulation; human disease; iron metabolism; mutant; nervous system disorder; novel; numb protein; overexpression; protein complex; protein protein interaction; transcription factor

DESCRIPTION (provided by applicant): Iron is an essential element for nearly all organisms in the biosphere, being required for the activity of a number of proteins in cells. Defects in iron acquisition, utilization, or storage lead to human illness, constituting some of the most common forms of human disease, including hemochromotosis, sideroblastic anemia with ataxia, Freidreich's Ataxia, and cancer. Aberrant iron metabolism has also been linked to neurologic disorders, such as Parkinson's Disease. Organisms utilize iron in a variety of chemical forms, including as elemental iron, heme, and combined with sulfur in iron-sulfur (FeS) clusters. FeS clusters are assembled into proteins through a protein mediated processes that is conserved through evolution. FeS cluster biogenesis itself is an essential process in living organisms, and in eukaryotes this process also plays a central role in cellular iron regulation. At least two systems for FeS cluster biogenesis exist in eukaryotic organisms; one is primarily mitochondrial and the other is primarily cytosolic. A link between these pathways exsits, but is not yet completely understood. The newly emerging cytosolic FeS cluster assembly (CIA) machinery currently consist of four proteins factors, called Cfd1p, Nbp35p, Nar1p, and Cia1p (using the yeast terminology). Each of the cytosolic CIA factors is essential for FeS cluster assembly in cytoplasmic and nuclear proteins, and for yeast viability. The broader goals of the studies outlined in this proposal are to define the functional roles of the CIA factors in FeS protein biogenesis and to determine their role in cellular iron regulation. To achieve these goals, we will pursue the following specific aims: 1) Determine the molecular mechanism through which CIA factors assist extra-mitochondrial FeS cluster assembly; 2) Determine the relationship of cytosolic and nuclear FeS cluster assembly to cellular iron regulation; and 3) Decipher the protein-interaction network mediating cytosolic and nuclear FeS cluster assembly and cellular iron regulation. These aims will be achieved using a combination of molecular genetic, biochemical and proteomic approaches in the model organism Saccharomyces cerevisiae. Completion of the proposed studies will lead to a significant advance in our understanding of the essential process of FeS cluster assembly in eukaryotic organisms, and will illustrate how this process is integrated into overall cellular iron metabolism.

描述（由申请人提供）：铁是生物圈中几乎所有生物的必不可少的元素，是细胞中许多蛋白质活性所必需的。铁获取，利用或储存的缺陷导致了人类疾病，构成了一些最常见的人类疾病形式，包括血液流传症，共济失调，弗雷德里希共济失调和癌症的副细胞性贫血。异常铁代谢也与神经系统疾病有关，例如帕金森氏病。生物体利用各种化学形式的铁，包括元素铁，血红素，并与铁硫（FES）簇中的硫一起使用。 FES簇通过通过进化保守的蛋白质介导的过程组装成蛋白质。 FES簇生物发生本身是生物体中的重要过程，在真核生物中，此过程在细胞铁调节中也起着核心作用。真核生物中至少存在两个用于FES簇生物发生的系统。一个主要是线粒体，另一个主要是胞质。这些途径之间的联系，但尚未完全理解。新出现的胞质FES簇组装（CIA）机械当前由四个蛋白质因子组成，称为CFD1P，NBP35P，NAR1P和CIA1P（使用酵母术语）。每个胞质CIA因子对于细胞质和核蛋白中的FES簇组装以及酵母活性至关重要。该提案中概述的研究的更广泛的目标是定义CIA因子在FES蛋白生物发生中的功能作用，并确定其在细胞铁调节中的作用。为了实现这些目标，我们将追求以下特定目的：1）确定CIA因子有助于Minochrial FES簇组装的分子机制； 2）确定胞质和核FES簇组装与细胞铁调节的关系； 3）破译蛋白质相互作用网络介导胞质和核FES簇组装和细胞铁调节。这些目标将通过模型有机体酿酒酵母中的分子遗传，生化和蛋白质组学方法的结合来实现。拟议研究的完成将导致我们对真核生物中FES簇组装的基本过程的理解，并将说明如何将该过程整合到整体细胞铁代谢中。