Mechanistic studies of the human FDX2 in Fe-S cluster assembly

人类 FDX2 在 Fe-S 簇组装中的机制研究

• 批准号: 10810130
• 负责人: DAVID P BARONDEAU
• 金额: $ 1.39万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10810130
• 关键词: 4' -phosphopantetheine; Acyl Carrier Protein; Acylation; Address; Aging; Alzheimer' s Disease; Amino Acids; Amyotrophic Lateral Sclerosis; Anabolism; Architecture; Biochemical Process; Biogenesis; Biological; Biological Assay; Cardiovascular Diseases; Catalytic Domain; Cell Death; Cellular Metabolic Process; Clinical; Complex; Coupled; Defect; Development; Disease; Electron Transport; Enzymes; Equilibrium; Eukaryota; Exhibits; Friedreich Ataxia; Genetic; Genomic Instability; Health; Human; Human Activities; In Vitro; Individual; Ions; Iron; Lead; Length; Life; Link; Lipids; Malignant Neoplasms; Mass Spectrum Analysis; Metabolic Diseases; Metabolism; Metalloproteins; Metals; Methods; Mitochondria; Mitochondrial DNA; Modeling; Modification; Molecular Chaperones; Multiple Sclerosis; Neurodegenerative Disorders; Normal Cell; Parkinson Disease; Pathology; Pathway interactions; Phosphorylation; Post-Translational Protein Processing; Protein Chemistry; Proteins; Protomer; Public Health; Reaction; Reactive Oxygen Species; Regulation; Research; Respiration; Role; Structure; Sulfides; Sulfur; System; Time; Tissues; Toxic effect; Transfer RNA; Variant; cofactor; cysteine desulfurase; electron donor; fascinate; frataxin; fundamental research; insight; iron metabolism; mitochondrial dysfunction; molybdenum cofactor; protein protein interaction; self assembly; stoichiometry; trafficking

Metal ions are essential to life as they augment amino acid protein chemistry and thereby catalyze many difficult biological reactions. As “free” metal ions are toxic and indiscriminately reactive, critical protein systems have evolved to sequester, chaperone, and regulate metal ion concentrations. Defects in these systems lead to metal ion metabolic disease and result in cellular, tissue, and systemic pathology. The iron-sulfur cluster assembly pathway contains a conserved set of metallochaperone proteins that recognize and insert Fe-S clusters into apo metalloproteins. We determined the first crystal structure for the NFS1-ISD11-ACP cysteine desulfurase, which is a central enzyme in this pathway that is also implicated in providing sulfur for molybdenum cofactor biosynthesis and tRNA modifications. Interestingly, three distinct interchangeable α2β22 architectures are now known for the cysteine desulfurase complex that have superimposable protomers but distinct protein-protein interactions. In this proposal, we aim to investigate the functional relationship between these architectures, elucidate mechanistic details for sulfur transfer to different acceptor proteins and for Fe-S cluster assembly, and provide new insight into the regulatory control mechanisms for human Fe-S cluster biosynthesis. This fundamental research will establish a framework for emerging genetic results and discoveries and provide a basis for understanding defects in iron-sulfur cluster metabolism relevant to human health and disease.

金属离子在增强氨基酸蛋白时对生命至关重要 化学，从而将许多困难的生物学反应催化为“游离”金属 离子有毒且无毒性，关键蛋白质系统已经发展 隔离，伴侣并调节金属离子概念 系统导致金属离子代谢疾病，并导致细胞，组织和 系统病理学。 识别和插入Fe-S的保守金属伴侣蛋白集 簇进入Apo金属蛋白。 NFS1-ISD11-ACP半胱氨酸脱硫酶，这是其中的中心酶 途径也与为钼辅助因子提供硫 生物合成和tRNA修饰。 α2β22架构是对半胱氨酸脱硫酶复合物的n. 具有叠加的质子，但在此中具有不同的蛋白质蛋白质相互作用 提案，我们旨在调查这些功能关系 体系结构，阐明硫磺的机械细节至不同的受体 蛋白质和Fe-S簇组件，并为您提供新的 人类Fe-S群集生物合成的调节控制机制 基础研究将建立一个新兴遗传结果的框架，并 发现并为了解铁硫簇中的缺陷提供了基础 与人类健康和疾病有关的代谢。