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的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者的研究机构。 铁硫（Fe/S）簇是许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组装并整合到活细胞中的脱辅基蛋白中。Fe/S簇蛋白的缺乏可导致细胞功能障碍甚至死亡。在人类中，存在一些与Fe/S簇蛋白有关的疾病，如X-连锁铁粒幼细胞性贫血、X-连锁铁粒幼细胞性贫血伴共济失调和弗里德赖希共济失调。Frataxin是Fe/S簇组装蛋白之一，由于发现Frataxin缺陷与Friedreich共济失调有关，这是一种以神经损伤、心肌病和糖尿病为特征的进行性疾病，因此一直是深入研究的主题。在体内，frataxin通过向亚铁螯合酶提供铁来促进血红素的生物合成，通过与铁-硫支架蛋白IscU的相互作用来组装铁-硫簇，以及修复铁-硫簇如顺乌头酸酶。Frataxin还在保护免受氧化应激中起主要作用。在酵母中，铁依赖性寡聚化的共济失调蛋白已被证明形成24亚基复合物，其功能类似于铁蛋白作为铁储存单位。在人共济失调蛋白中，N-末端区域是共济失调蛋白寡聚化所必需的。我们的研究结果表明，人类共济失调蛋白形成更大（可能48个亚基）的复合物。我们已经获得了单体全长人共济失调蛋白的初步SAXS数据。SAXS模型表明，额外的N-末端区域可能涉及与IscU和共济失调蛋白寡聚化的相互作用。我们正试图了解frataxin与IscU和IscS的相互作用和功能。我们还想研究Fe/S簇组装机制的蛋白质复合物。

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.