Identification of human genes of iron homeostasis

人类铁稳态基因的鉴定

• 批准号: 10006702
• 负责人: Caroline Philpott
• 金额: $ 208.15万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10006702
• 关键词: Apoproteins; Binding Proteins; Biochemical; Biological; Cells; Complex; Cysteine; Cytosol; Destinations; Ensure; Family; Friedreich Ataxia; Genes; Genetic; Genetic Diseases; Glutamates; Glutathione; Heme Iron; Hereditary hemochromatosis; Homeostasis; Human; In Vitro; Ions; Iron; Iron Overload; Iron-Binding Proteins; Ligands; Link; Mammalian Cell; Metalloproteins; Metals; Molecular; Molecular Chaperones; Nutrient; Organism; Oxidation-Reduction; Play; Process; Protein Family; Proteins; Proteomics; Regulation; Role; Sulfur; System; Toxin; Zinc; cofactor; human disease; iron metabolism; trafficking; uptake; virtual

1)Hundreds of cellular proteins require iron cofactors for activity, and cells express systems for their assembly and distribution. Molecular details of the cytosolic iron pool used for iron cofactors are lacking, but iron chaperones of the poly(rC)-binding protein (PCBP) family play a key role in ferrous ion distribution. Here we show that, in cells and in vitro, PCBP1 coordinates iron via conserved cysteine and glutamate residues and a molecule of noncovalently bound glutathione (GSH). Proteomics analysis of PCBP1-interacting proteins identified BolA2, which functions, in complex with Glrx3, as a cytosolic 2Fe-2S cluster chaperone. The Fe-GSH-bound form of PCBP1 complexes with cytosolic BolA2 via a bridging Fe ligand. Biochemical analysis of PCBP1 and BolA2, in cells and in vitro, indicates that PCBP1-Fe-GSH-BolA2 serves as an intermediate complex required for the assembly of 2Fe-2S clusters on BolA2-Glrx3, thereby linking the ferrous iron and Fe-S distribution systems in cells. 2) Mammalian cells contain thousands of metalloproteins and have evolved sophisticated systems for ensuring that metal cofactors are correctly assembled and delivered to their proper destinations. Equally critical in this process are the strategies to avoid the insertion of the wrong metal cofactor into apo-proteins and to avoid the damage that redox-active metals can catalyze in the cellular milieu. Iron and zinc are the most abundant metal cofactors in cells and iron cofactors include heme, iron-sulfur clusters, and mono- and dinuclear iron centers. Systems for the intracellular trafficking of iron cofactors are being characterized. This review focuses on the trafficking of ferrous iron cofactors in the cytosol of mammalian cells, a process that involves specialized iron-binding proteins, termed iron chaperones, of the poly rC-binding protein family.

1）数百种细胞蛋白需要铁辅因子才能进行活性，并且细胞表达用于组装和分布的系统。缺乏用于铁辅因子的胞质铁池的分子细节，但是聚（RC）结合蛋白（PCBP）家族的铁伴侣在亚铁离子分布中起关键作用。在这里，我们表明，在细胞和体外，PCBP1通过保守的半胱氨酸和谷氨酸残基以及非共价结合的谷胱甘肽（GSH）的分子来协调铁。 PCBP1相互作用蛋白的蛋白质组学分析鉴定出BOLA2，该蛋白与GLRX3复合起来，是胞质2FE-2S簇伴侣。 PCBP1复合物与胞质Bola2的Fe-GSH结合形式通过桥接Fe配体。细胞和体外的PCBP1和BOLA2的生化分析表明，PCBP1-FE-GSH-BOLA2用作在Bola2-GlRX3上组装2FE-2S簇所需的中间配合物，从而将细胞中的铁质铁和Fe-S分布系统链接起来。 2）哺乳动物细胞含有数千种金属蛋白，并进化了复杂的系统，以确保将金属辅因子正确组装并传递到适当的目的地。在此过程中同样至关重要的是避免将错误的金属辅因子插入Apo蛋白的策略，并避免氧化还原活性金属可以催化细胞环境中的损害。铁和锌是细胞中最丰富的金属辅因子，铁辅因子包括血红素，铁硫簇以及单核铁中心。铁辅因子的细胞内运输系统正在表征。这篇综述着重于哺乳动物细胞的细胞质中的亚铁辅助因子的运输，该过程涉及多rc结合蛋白家族的专门的铁结合蛋白（称为铁伴侣）。