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: 8668076
• 负责人: DAVID P BARONDEAU
• 金额: $ 26.94万
• 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 2017-04-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8668076
• 关键词: Aging; Alzheimer' s Disease; Amino Acids; Amyotrophic Lateral Sclerosis; Anabolism; Architecture; Binding; Biochemical Process; Biochemical Reaction; Biogenesis; Biological; Calcium; Cardiovascular Diseases; Cells; Cellular biology; Cessation of life; Chemicals; Clinical; Code; Complex; Cues; Defect; Development; Disease; Electron Transport; Environment; Eukaryota; Free Radicals; Friedreich Ataxia; Genes; Genetic; Genomic Instability; Health; Homeostasis; Housing; Human; In Vitro; Inherited; Introns; Ions; Iron; Lead; Life; Lipids; Malignant Neoplasms; Mediating; Metabolic Diseases; Metabolism; Metalloproteins; Metals; Mitochondria; Mitochondrial DNA; Modeling; Molecular Chaperones; Multiple Sclerosis; Mutation; Neurodegenerative Disorders; Parkinson Disease; Pathology; Pathway interactions; Patients; Production; Property; Protein Chemistry; Proteins; Public Health; Reaction; Research; Research Personnel; Role; Scaffolding Protein; Solutions; Solvents; Structure; Sulfides; Sulfur; System; Tissues; Toxic effect; Trinucleotide Repeats; Variant; Work; base; catalyst; cofactor; cysteine desulfurase; frataxin; fundamental research; iron metabolism; loss of function mutation; mitochondrial dysfunction; research study; scaffold

DESCRIPTION (provided by applicant): 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. Our working model is that frataxin (Fxn) binds to a Nfs1/Isd11/Isu2 complex and activates the complex for Fe-S cluster biosynthesis. In this proposal, we aim to build on these results by further developing our in vitro system and providing structural properties for the assembly complexes, mechanistic details for Fe-S cluster synthesis, and determine the basis for the compromised function in Friedreich's ataxia clinical variants. 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.

描述（由申请人提供）：金属离子对生命至关重要，因为它们会增强氨基酸蛋白化学，从而催化许多困难的生物学反应。由于“游离”金属离子是有毒的，而且反应性不加区分，因此关键的蛋白质系统已演变为隔离，伴侣和调节金属离子浓度。这些系统的缺陷导致金属离子代谢疾病，并导致细胞，组织和全身病理。铁硫簇组装途径包含一组保守的金属伴侣蛋白，该蛋白识别并插入Fe-S簇中的Apo金属蛋白。我们的工作模型是，Frataxin（FXN）与NFS1/ISD11/ISU2复合物结合，并激活Fe-S簇生物合成的复合物。在此提案中，我们旨在通过进一步开发我们的体外系统并为组装络合物提供结构特性，Fe-S群集合成的机理细节，并确定Friedreich的Hataxia临床临床变体中受损功能的基础。这项基本研究将建立一个框架，以建立新兴的遗传结果和发现，并为了解与人类健康和疾病有关的铁硫簇代谢缺陷提供了基础。