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

描述(由申请人提供)：金属离子对生命是必不可少的，因为它们增强了氨基酸、蛋白质的化学作用，从而催化了许多困难的生物反应。由于“游离”金属离子有毒且不分青红皂白地反应，关键蛋白质系统已进化为隔离、伴侣和调节金属离子浓度。这些系统的缺陷会导致金属离子代谢疾病，并导致细胞、组织和系统的病理。铁-硫簇组装途径包含一组保守的金属配位蛋白，识别铁-S簇并将其插入载脂金属蛋白中。我们的工作模型是Frataxin(Fxn)结合到一个Nfs1/Isd11/Isu2复合体上，并激活该复合体用于铁-S簇的生物合成。在这项建议中，我们旨在通过进一步发展我们的体外系统，提供组装络合物的结构性质，Fe-S簇合成的机理细节，并确定Friedreich‘s共济失调临床变体功能受损的基础。这项基础性研究将为新的遗传结果和发现建立一个框架，并为理解与人类健康和疾病相关的铁-硫簇代谢缺陷提供基础。

DESCRIPTION (provided by applicant): 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. Our working model is that frataxin (Fxn) binds to a Nfs1/Isd11/Isu2 complex and activates the complex for Fe-S cluster biosynthesis. In this proposal, we aim to build on these results by further developing our in vitro system and providing structural properties for the assembly complexes, mechanistic details for Fe-S cluster synthesis, and determine the basis for the compromised function in Friedreich's ataxia clinical variants. 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.