Structural Insights into the Function of Frataxin

描述（由申请人提供）：Frataxin是一种已知参与调节细胞铁稳态的线粒体蛋白，最近被认为是血红素和Fe-S簇生物合成的线粒体铁伴侣。frataxin水平的降低是常染色体隐性神经退行性疾病弗里德赖希共济失调（FRDA）的主要原因，这种疾病在5万人中有1人患病。Frataxin已被证明与催化血红素2Fe-2S簇产生的蛋白质相互作用，表明Frataxin在fe辅助因子的产生中起直接作用。酵母frataxin （Yfh1p）与蛋白质Hem15p和Isu1p之间的相互作用被认为分别促进铁的传递和血红素和2Fe-2S簇的细胞合成，但是对于这些蛋白质如何相互作用以及铁在复合物形成过程中如何传递和转移几乎一无所知。本应用程序的目的是表征在血红素和Fe-S簇生物合成途径中fraataxins的作用。我们的中心

DESCRIPTION (provided by applicant): Frataxin, a mitochondrial protein known to participate in regulating cellular iron homeostasis, has recently been suggested to act as a mitochondrial iron chaperone for heme and Fe-S cluster biosynthesis. A reduced level of frataxin is the principal cause of the autosomal recessive neurodegenerative disorder Friedreich's ataxia (FRDA), which affects 1 in 50,000 humans. Frataxin has been shown to interact with the proteins that catalyze heme 2Fe-2S cluster production, suggesting frataxin plays a direct role in Fe-cofactor production. The interaction between yeast frataxin (Yfh1p) and the proteins Hem15p and Isu1p are believed to promote iron delivery and the cellular synthesis of heme and 2Fe-2S clusters, respectively, however almost nothing is known about how these proteins interact and how iron is delivered and transferred during complex formation. The objective of this application is to characterize frataxins role in both the heme and Fe-S cluster biosynthetic pathways. Our central hypothesis is that monomeric frataxins binds ferrous iron, protects the bound Fe(II) against oxidation in the potentially oxygen rich environment of the mitochondrion and then delivers reduced metal to target proteins involved in both the heme and Fe-S assembly pathways. This hypothesis is based on our laboratories biochemical and structural characterization of monomeric Yfh1p, as well as published reports of frataxins in vitro iron delivery activity. The rationale for our proposed studies is if we can distinguish frataxins role in regulating cellular iron homeostasis, we can help elucidate what pathways are deficient in FRDA patients, and we expect this information will lead to more successful treatment strategies for the disorder. We are in an excellent position to complete this work as we have recently cloned, expressed and solved the solution structure of yeast frataxin, and our laboratory has begun to characterize how Yfh1p binds iron and interacts with its protein binding partners. In addition, we have begun to test the physological significance of our findings both in vitro and in vivo.