Structure and Mechanism of the Human FE-S Cluster Assembly Complex

人类FE-S簇组装复合物的结构和机制

• 批准号: 10299047
• 负责人: DAVID P BARONDEAU
• 金额: $ 29.31万
• 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/10299047
• 关键词: 4' -phosphopantetheine; Acyl Carrier Protein; 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; Crystallization; 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; base; cofactor; cysteine desulfurase; electron donor; fascinate; frataxin; fundamental research; insight; iron metabolism; mitochondrial dysfunction; molybdenum cofactor; protein protein interaction; 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.

金属离子是生命所必需的，因为它们增加了氨基酸蛋白质 化学，从而催化许多困难的生物反应。作为“自由”金属 离子是有毒的和不加选择的反应，关键的蛋白质系统已经进化 螯合、陪伴和调节金属离子浓度。这些缺陷 系统导致金属离子代谢疾病，并导致细胞、组织和 系统病理学铁硫簇组装途径包含一个 识别并插入Fe-S的保守的金属伴侣蛋白 聚集成载脂蛋白金属蛋白。我们确定了第一个晶体结构， NFS 1-ISD 11-ACP半胱氨酸脱硫酶，这是一个中心酶，在这个过程中， 也涉及为钼辅因子提供硫的途径 生物合成和tRNA修饰。有趣的是，三个不同的可互换的 现在已知α2β2 β2 α 2结构用于半胱氨酸脱硫酶复合物， 具有可重叠的原聚体，但具有不同的蛋白质-蛋白质相互作用。在这 建议，我们的目的是调查这些之间的功能关系 结构，阐明硫转移到不同受体的机理细节 蛋白质和Fe-S簇组装，并提供新的见解， 人类Fe-S簇生物合成的调控机制。这 基础研究将为新兴的遗传学成果建立一个框架， 为理解铁硫团簇中的缺陷提供了依据 与人体健康和疾病有关的代谢。