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: 10580842
• 负责人: DAVID P BARONDEAU
• 金额: $ 29.13万
• 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/10580842
• 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 离子有毒，不分青红皂白地反应，关键的蛋白质系统已经进化 隔离、伴侣和调节金属离子浓度。这些产品中的缺陷 系统会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 识别和插入Fe-S的一组保守的金属配位蛋白 聚集成载脂蛋白金属蛋白。我们确定了第一个晶体结构 NFS1-ISD11-ACP半胱氨酸脱硫酶，它是这个过程中的一个中心酶 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，三个截然不同的可互换的 α2β22架构现在以半胱氨酸脱硫酶复合体而闻名，该复合体 具有可叠加的原核，但具有明显的蛋白质-蛋白质相互作用。在这 提案，我们的目的是研究它们之间的功能关系 体系结构，阐明硫向不同受体转移的机制细节 并为铁-S簇的组装提供了新的见解 人铁-S簇生物合成的调控机制。这 基础研究将为新出现的遗传结果和 这些发现为理解铁硫团簇中的缺陷提供了基础 新陈代谢与人类健康和疾病有关。