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)数以百计的细胞蛋白质需要铁辅因子的活动，细胞表达系统的组装和分布。用于铁辅因子的细胞溶质铁池的分子细节缺乏，但聚（rC）结合蛋白（PCBP）家族的铁伴侣在亚铁离子分布中起着关键作用。在这里，我们表明，在细胞和体外，PCBP 1通过保守的半胱氨酸和谷氨酸残基和非共价结合的谷胱甘肽（GSH）的分子协调铁。PCBP 1相互作用蛋白的蛋白质组学分析确定BolA 2，其功能，在复杂的Glrx 3，作为一个细胞溶质2Fe-2S簇伴侣。PCBP 1的Fe-GSH结合形式通过桥接Fe配体与胞质BolA 2复合。PCBP 1和BolA 2在细胞内和体外的生化分析表明，PCBP 1-Fe-GSH-BolA 2作为2Fe-2S簇在BolA 2-Glrx 3上组装所需的中间复合物，从而连接细胞中的亚铁和Fe-S分布系统。 2)哺乳动物细胞含有数千种金属蛋白，并进化出复杂的系统，以确保金属辅因子正确组装并运送到正确的目的地。在这一过程中，同样关键的是避免将错误的金属辅因子插入脱辅基蛋白和避免氧化还原活性金属在细胞环境中催化的损害的策略。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、单核和双核铁中心。铁辅因子的细胞内运输系统的特点。这篇评论的重点是贩运的亚铁辅助因子在哺乳动物细胞的胞质溶胶中，一个过程，涉及专门的铁结合蛋白，称为铁伴侣，聚rC结合蛋白家族。