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需要铁辅助因子才能活动，细胞表达了它们的组装和分布系统。用于铁辅因子的细胞质铁池的分子细节尚不清楚，但聚（rC）结合蛋白（PCBP）家族的铁伴侣蛋白在铁离子分布中起关键作用。本研究表明，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）分子来协调铁。对pcbp1相互作用蛋白的蛋白质组学分析发现，BolA2与Glrx3复合物起细胞质2Fe-2S簇伴侣的作用。Fe- gsh结合形式的PCBP1通过桥接Fe配体与细胞质BolA2结合。细胞内和体外对PCBP1和BolA2的生化分析表明，PCBP1- fe - gsh -BolA2作为2Fe-2S簇在BolA2- glrx3上组装所需的中间复合物，从而连接细胞内亚铁和Fe-S分布系统。