Molecular mechanism and structure of the cytosolic iron-sulfur protein assembly (CIA) machinery

细胞质铁硫蛋白组装（CIA）机器的分子机制和结构

• 批准号: 298582020
• 负责人: Professor Dr. Roland Lill
• 金额: --
• 依托单位: Institut für Klinische Zytobiologie und Zytopathologie
• 依托单位国家: 德国
• 项目类别: Reinhart Koselleck Projects
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/298582020?language=en
• 关键词: Molecular; mechanism; structure; cytosolic; iron

Iron-sulfur (Fe/S) clusters are essential protein cofactors involved in numerous key biological processes such as metabolism, energy conversion, DNA synthesis and repair, and protein translation. The synthesis of Fe/S clusters and their insertion into target proteins in a living cell is catalyzed by complex machinery. In (non-green) eukaryotes three biogenesis systems have been identified in mitochondria and cytosol with more than 30 known components. Mitochondrial Fe/S proteins require the iron-sulfur cluster (ISC) assembly machinery which was inherited from bacteria during evolution. Biogenesis of cytosolic and nuclear Fe/S proteins also depends on the function of this machinery, yet additionally requires the mitochondrial ISC export apparatus and the cytosolic iron-sulfur protein assembly (CIA) machinery. Hitherto, eleven CIA proteins have been identified and their sequence of action been defined, yet little is known about their biochemical function. This proposal therefore aims to elucidate the molecular mechanisms of three CIA protein complexes. Cell biological and biochemical reconstitution approaches will be combined with ultrastructural und mutational techniques to define the molecular events of how a [4Fe-4S] cluster is initially synthesized on the CIA scaffold complex and then specifically inserted into target apoproteins via the CIA targeting and adapter complexes. Our studies will help resolving the sophisticated molecular mechanisms of a central and conserved process of life.

铁硫（Fe/S）簇是参与代谢、能量转化、DNA合成和修复以及蛋白质翻译等众多关键生物过程的必需蛋白质辅因子。Fe/S簇的合成及其插入活细胞中的靶蛋白是由复杂的机制催化的。在（非绿色）真核生物中，线粒体和胞质溶胶中已经确定了三个生物合成系统，其中有30多种已知成分。线粒体Fe/S蛋白需要铁-硫簇（ISC）组装机制，这是在进化过程中从细菌遗传而来的。细胞质和核Fe/S蛋白的生物发生也依赖于这种机制的功能，但还需要线粒体ISC输出装置和细胞质铁硫蛋白组装（CIA）机制。迄今为止，已经鉴定了11种CIA蛋白，并确定了它们的作用序列，但对它们的生物化学功能知之甚少。因此，该建议旨在阐明三种CIA蛋白复合物的分子机制。细胞生物学和生物化学重建方法将与超微结构和突变技术相结合，以定义[4Fe-4S]簇最初如何在CIA支架复合物上合成，然后通过CIA靶向和衔接子复合物特异性插入靶脱辅基蛋白的分子事件。我们的研究将有助于解决一个中心和保守的生命过程的复杂分子机制。