Structure and Mechanism of the Human FE-S Cluster Assembly Complex

金属离子对生命至关重要，因为它们可以增加氨基酸蛋白质 化学，从而催化许多困难的生物反应。作为“自由”金属 离子是有毒的并且具有不加区别的反应性，关键的蛋白质系统已经进化 螯合、陪伴和调节金属离子浓度。这些方面的缺陷 系统导致金属离子代谢疾病并导致细胞、组织和 系统病理学。铁硫簇组装途径包含 一组保守的金属伴侣蛋白，可识别并插入 Fe-S 聚集成apo金属蛋白。我们确定了第一个晶体结构 NFS1-ISD11-ACP 半胱氨酸脱硫酶，这是该过程中的核心酶 还涉及为钼辅因子提供硫的途径 生物合成和 tRNA 修饰。有趣的是，三种不同的可互换 α2β22 结构现在因半胱氨酸脱硫酶复合物而闻名， 具有可叠加的原聚体，但具有不同的蛋白质-蛋白质相互作用。在这个 建议，我们的目的是研究这些之间的功能关系 架构，阐明硫转移到不同受体的机制细节 蛋白质和 Fe-S 簇组装，并提供新的见解 人类Fe-S簇生物合成的调控机制。这个 基础研究将为新兴遗传成果建立一个框架 发现并为理解铁硫团簇的缺陷提供了基础 新陈代谢与人类健康和疾病有关。

Metal ions are essential to life as they augment amino acid protein chemistry and thereby catalyze many difficult biological reactions. As “free” metal ions are toxic and indiscriminately reactive, critical protein systems have evolved to sequester, chaperone, and regulate metal ion concentrations. Defects in these systems lead to metal ion metabolic disease and result in cellular, tissue, and systemic pathology. The iron-sulfur cluster assembly pathway contains a conserved set of metallochaperone proteins that recognize and insert Fe-S clusters into apo metalloproteins. We determined the first crystal structure for the NFS1-ISD11-ACP cysteine desulfurase, which is a central enzyme in this pathway that is also implicated in providing sulfur for molybdenum cofactor biosynthesis and tRNA modifications. Interestingly, three distinct interchangeable α2β22 architectures are now known for the cysteine desulfurase complex that have superimposable protomers but distinct protein-protein interactions. In this proposal, we aim to investigate the functional relationship between these architectures, elucidate mechanistic details for sulfur transfer to different acceptor proteins and for Fe-S cluster assembly, and provide new insight into the regulatory control mechanisms for human Fe-S cluster biosynthesis. This fundamental research will establish a framework for emerging genetic results and discoveries and provide a basis for understanding defects in iron-sulfur cluster metabolism relevant to human health and disease.