Structural Insights into the Function of Frataxin

Frataxin 功能的结构见解

• 批准号: 8516019
• 负责人: TIMOTHY Louis STEMMLER
• 金额: $ 35.52万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8516019
• 关键词: Active Sites; Adrenodoxin; Aerobic; Alzheimer' s Disease; Anabolism; Binding; Biochemical; Biochemical Pathway; Cell Maintenance; Cells; Characteristics; Complex; Development; Disease; Disease Association; Dopamine; Eukaryota; Event; Friedreich Ataxia; Funding; Genetic; Goals; Homeostasis; Human; Huntington Disease; Inflammation; Iron; Knowledge; Laboratories; Life; Macromolecular Complexes; Metabolism; Metals; Methods; Mitochondria; Molecular; Molecular Chaperones; Molecular Genetics; Molecular Structure; Multiprotein Complexes; Myelin; Nature; Nervous System Physiology; Neuraxis; Neurodegenerative Disorders; Neurons; Neurotransmitters; Organism; Oxidative Phosphorylation; Oxidative Stress; Oxygen; Parkinson Disease; Pathway interactions; Patients; Phenotype; Play; Production; Proteins; Public Health; Regulation; Role; Scaffolding Protein; Serotonin; Site; Structure; Sulfides; Sulfur; Work; Yeasts; cysteine desulfurase; frataxin; insight; interest; molecular dynamics; novel therapeutic intervention; oxidative damage

DESCRIPTION (provided by applicant): Iron is essential for life and crucial to the human central nervous system (CNS). It is fundamental in biochemical pathways including oxidative phosphorylation, myelin synthesis, neurotransmitter production and the synthesis/metabolism of serotonin and dopamine, all of which are essential for normal CNS function. Since iron is highly reactive towards oxygen in aerobic cells, maintenance of cellular iron homeostasis is vital for normal neuronal function and for overall organism viability. Unfortunately, a growing number of human neurodegenerative disorders (Alzheimer's, Huntington's, Parkinson's, Friedreich's ataxia, etc.) have phenotypes confirming disease association to disruption of iron homeostasis. The long-range goal of the Stemmler laboratory is to characterize the functional role proteins play in regulating cellular iron homeostasis, with special interest regarding iron-sulfur cluster (ISC) bioassembly. In eukaryotes, the mitochondrial ISC assembly pathway provides the bulk of the iron-sulfur (Fe-S) clusters used ubiquitously throughout all cells. In yeast, this pathway proceeds through a coordinated effort between the assembly scaffold protein (Isu1/2), a cysteine desulfurase (Nfs1) that provides sulfur, an accessory protein (Isd11) important in Nfs1 stabilization, an adrenodoxin (Yah1) that may provide reducing equivalents to stabilize sulfide for transfer and the iron chaperone frataxin (Yfh1). The objective of this application is to provid molecular and mechanistic details regarding interactions between these key proteins during Fe-S cluster assembly. Our central hypothesis is frataxin plays a direct role in mitochondrial Fe-S cluster assembly by serving as an iron chaperone to Isu and as a modulator of Nfs activity when bound in a stable multiprotein complex that includes Nfs/Isd11/Isu and Yah. Here we will explore the molecular details of frataxin's interaction with Isu, characterize frataxin's interactin with the Nfs/Isd11 complex which modulates cysteine desulfurase activity, and study the structural and dynamic nature of the macromolecular complex that drives Fe-S cluster assembly.

描述(申请人提供)：铁是生命所必需的，对人类中枢神经系统(CNS)至关重要。它是氧化磷酸化、髓鞘合成、神经递质产生以及5-羟色胺和多巴胺的合成/代谢等生化途径的基础，所有这些都是中枢神经系统正常功能所必需的。由于铁在有氧细胞中对氧气具有高度的反应性，维持细胞铁的稳态对正常的神经元功能和整个生物体的生存至关重要。不幸的是，越来越多的人类神经退行性疾病(阿尔茨海默氏症、亨廷顿氏症、帕金森氏症、弗里德里希共济失调等)有确认疾病与铁稳态紊乱有关的表型。Stemmler实验室的长期目标是表征蛋白质在调节细胞铁稳态中所起的功能作用，特别是关于铁-硫簇(ISC)的生物组装。在真核生物中，线粒体ISC组装途径提供了所有细胞普遍使用的铁-硫簇(Fe-S)的大部分。在酵母中，这一途径继续进行 通过组装支架蛋白(Isu1/2)、提供硫的半胱氨酸脱硫酶(Nfs1)、在Nfs1稳定中重要的辅助蛋白(Isd11)、可以提供还原当量以稳定硫化物进行转移的肾上腺素(Yah1)和铁伴侣蛋白Frataxin(Yfh1)之间的协调作用。本申请的目的是提供关于铁-S簇组装过程中这些关键蛋白之间相互作用的分子和机制细节。我们的中心假设是Frataxin在线粒体Fe-S簇组装中发挥直接作用，当它与一个稳定的多蛋白复合体结合时，它作为ISU的铁伴侣，并作为NFS活性的调节器。在这里，我们将探索Frataxin与ISU相互作用的分子细节，表征Frataxin与调节半胱氨酸脱硫酶活性的NFS/ISD11复合体的相互作用，并研究驱动Fe-S团簇组装的大分子复合体的结构和动力学性质。