STRUCTURAL AND FUNCTIONAL STUDIES ON IRON-SULFUR CLUSTER BIOGENESIS IN EUKARYOTE

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。 铁-硫(Fe/S)簇是众多蛋白质的重要辅因子。Fe/S簇需要一组复杂的蛋白质才能在活细胞中组装并并入脱辅基蛋白。铁/S簇蛋白的缺失可能导致细胞功能障碍甚至死亡。在人类中，存在一些与Fe/S簇蛋白相关的疾病，如X连锁铁粒母细胞贫血、X连锁铁粒母细胞贫血伴共济失调和Friedreich共济失调。Frataxin是Fe/S簇组装蛋白之一，因为发现Frataxin缺陷与Friedreich共济失调有关，Friedreich共济失调是一种以神经功能障碍、心肌病和糖尿病为特征的进行性疾病。在体内，Frataxin通过向铁络合酶捐献铁，通过与铁硫支架蛋白IscU相互作用组装铁硫簇，以及修复乌头酸酶等铁硫簇来促进血红素的生物合成。Frataxin在对抗氧化应激的保护中也起着主要作用。在酵母中，Frataxin的铁依赖寡聚已被证明形成24个亚基复合体，其功能类似于铁蛋白作为铁存储单元。在人类Frataxin中，Frataxin寡聚需要N-末端区域。我们的结果表明，人类Frataxin形成更大的(可能是48个亚基)复合体。我们已经获得了单体全长人类Frataxin的SAXS初步数据。SAXS模型表明，额外的N末端区域可能涉及与IscU和Frataxin齐聚的相互作用。我们正在努力了解Frataxin与ISCU和ISCS的相互作用和功能。我们还研究了铁/S团簇组装机的蛋白质复合体。

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. Iron-sulfur (Fe/S) clusters are important cofactors of numerous proteins. Fe/S clusters required a complex set of proteins to become assembled and incorporated into apoproteins in a living cell. The deficiency of Fe/S cluster proteins may cause cell malfunction and even death. In human, there are some diseases related to Fe/S cluster proteins such as X-linked sideroblastic anemia, X-linked sideroblastic anemia with ataxia and Friedreich ataxia. Frataxin, one of the Fe/S cluster assembly proteins has been the subject of intense investigation due to the discovery that frataxin defects are linked to Friedreich ataxia, a progressive disorder characterized by neurological impairment, cardiomyopathy, and diabetes. In vivo, frataxin promotes the biosynthesis of hemes by donating iron to ferrochelatase, the assembly of iron-sulfur clusters through interactions with the iron-sulfur scaffolding protein IscU, and the repair of iron-sulfur clusters such as aconitase. Frataxin also plays a primary role in the protection against oxidative stress. In yeast, Fe-dependent oligomerization of frataxin has been shown to form 24 subunit complexes that may function similarly to ferritin as iron-storage units. In human frataxin, N-terminal region is required for fratxin oligolmerization. Our results suggest that human frataxin forms larger (possibly 48 subunit) complexes. We have got the initial SAXS data for monomeric full-length human frataxin. The SAXS model suggests the extra N-terminal region might involve the interactions with IscU and frataxin oligomerization. We are trying to understand the interactions and functions of frataxin with IscU and IscS. We also like to investigate the protein complex of Fe/S cluster assembly machinery.