STRUCTURE AND MECHANISTIC STUDIES OF HUMAN FE-S CLUSTER BIOSYNTHESIS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 Friedreich-S共济失调是最常见的遗传性共济失调，是由于蛋白质Frataxin功能丧失所致。Frataxin参与了铁的稳态，特别是铁硫蛋白的生物合成。Frataxin专门与支架蛋白IscU相互作用，并为铁-硫簇组装提供铁。虽然人类Frataxin的结构已知，但Frataxin的铁结合部位、人类IscU的结构以及Frataxin：IscU复合体的细节仍不清楚。此外，人类Frataxin的临床突变已被鉴定(如D122Y、G130V、I154F、W155R)，但没有结构或功能特征。这项建议的目标是确定(I)人Frataxin与铁的结晶学结构；(Ii)Frataxin的临床突变体；(Iii)人IscU；以及(Iv)Frataxin：Iscu复合体。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Friedreich?s ataxia is the most common inherited ataxia and results from the loss of function for the protein frataxin. Frataxin has been implicated in iron homeostasis and, particularly, in iron-sulfur protein biosynthesis. Frataxin specifically interacts with the scaffold protein IscU and delivers iron for iron-sulfur cluster assembly. Although the structure of human frataxin is known, the frataxin iron binding site, the structure of human IscU, and details for the frataxin:IscU complex remain elusive. In addition, clinical mutants of human frataxin have been identified (such as D122Y, G130V, I154F, W155R) but not structurally or functionally characterized. The objectives of this proposal are to determine crystallographic structures of (i) human frataxin with iron; (ii) clinical mutants of frataxin; (iii) human IscU; and (iv) the frataxin:IscU complex.