Understanding the Mechanism of [4Fe-4S] Cluster Assembly on Eukaryotic Mitochondrial and Cytosolic Aconitase,Inorganic Chemistry

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Understanding the Mechanism of [4Fe-4S] Cluster Assembly on Eukaryotic Mitochondrial and Cytosolic Aconitase
Inorganic Chemistry ( IF 4.3 ) Pub Date : 2019-08-22 , DOI: 10.1021/acs.inorgchem.9b01278
Christine Wachnowsky _{1,

2} , Amber L. Hendricks ₁ , Nathaniel A. Wesley ₁ , Connor Ferguson ₁ , Insiya Fidai _{1,

3} , J. A. Cowan _{1,

2,

3}

Affiliation

Iron–sulfur (Fe–S) clusters are common prosthetic groups that are found within a variety of proteins responsible for functions that include electron transfer, regulation of gene expression, and substrate binding and activation. Acquisition of a [4Fe-4S] cluster is essential for the functionality of many such roles, and dysfunctions in Fe–S cluster synthesis and trafficking often result in human disease, such as multiple mitochondrial dysfunctions syndrome. While the topic of [2Fe-2S] cluster biosynthesis and trafficking has been relatively well studied, the understanding of such processes involving [4Fe-4S] centers is less developed. Herein, we focus on the mechanism of the assembly of [4Fe-4S] clusters on two members of the aconitase family, differing also in organelle placement (mitochondrion and cytosol) and biochemical function. Two mechanistic models are evaluated by a combination of kinetic and spectroscopic models, namely, a consecutive model (I), in which two [2Fe-2S] clusters are sequentially delivered to the target, and a prereaction equilibrium model (II), in which a [4Fe-4S] cluster transiently forms on a donor protein before transfer to the target. The paper also addresses the issue of cluster nuclearity for functionally active forms of ISCU, NFU, and ISCA trafficking proteins, each of which has been postulated to exist in both [2Fe-2S] and [4Fe-4S] bound states. By the application of kinetic assays and electron paramagnetic resonance spectroscopy to examine delivery pathways from a variety of potential [2Fe-2S] donor proteins to eukaryotic forms of both aconitase and iron regulatory protein, we conclude that a consecutive model following the delivery of [2Fe-2S] clusters from NFU1 is the most likely mechanism for these target proteins.

中文翻译：

理解[4Fe-4S]簇组装对真核线粒体和胞质乌头酸酶的作用机理

铁-硫（Fe-S）簇是常见的修复基团，存在于各种蛋白质中，这些蛋白质负责的功能包括电子转移，基因表达调节以及底物结合和激活。[4Fe-4S]簇的获得对于许多这样的角色的功能至关重要，而Fe–S簇合成和运输中的功能障碍通常会导致人类疾病，例如线粒体功能障碍综合症。虽然[2Fe-2S]团簇生物合成和运输的主题已得到相对较好的研究，但对涉及[4Fe-4S]中心的此类过程的了解却很少。在这里，我们集中在乌头酸酶家族的两个成员上[4Fe-4S]簇的组装机制，在细胞器位置（线粒体和胞质溶胶）和生化功能上也有所不同。通过动力学模型和光谱模型的组合来评估两个力学模型，即连续模型（I）和预反应平衡模型（II），其中两个[2Fe-2S]团簇被顺序传递至目标； [4Fe-4S]簇在转移至靶标之前在供体蛋白上短暂形成。本文还讨论了功能性活性形式的ISCU，NFU和ISCA转运蛋白的簇核问题，假定每种蛋白都以[2Fe-2S]和[4Fe-4S]结合状态存在。通过应用动力学分析和电子顺磁共振波谱研究从各种潜在的[2Fe-2S]供体蛋白到乌头酸酶和铁调节蛋白的真核形式的传递途径，

更新日期：2019-08-23

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