Structural Insights into the Function of Frataxin

描述（由申请人提供）：铁是生命所必需的，对人体中枢神经系统（CNS）至关重要。它是生化途径的基础，包括氧化磷酸化、髓磷脂合成、神经递质产生、血清素和多巴胺的合成/代谢，所有这些都是正常中枢神经系统功能所必需的。由于铁在有氧细胞中对氧具有高度反应性，因此维持细胞铁稳态对于正常的神经元功能和整个生物体的生存能力至关重要。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症等）的表型证实了这些疾病与铁稳态破坏有关。Stemmler实验室的长期目标是表征蛋白质在调节细胞铁稳态中发挥的功能作用，特别关注铁硫簇（ISC）生物组装。在真核生物中，线粒体ISC组装途径提供了在所有细胞中普遍使用的铁硫（Fe-S）簇的大部分。在酵母中，这一途径继续进行

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.