Functional spectrum and specificity of mitochondrial ferredoxins FDX1 and FDX2
Functional spectrum and specificity of mitochondrial ferredoxins FDX1 and FDX2
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DOI：
10.1038/s41589-022-01159-4
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发表时间：
2022-10-24
影响因子：
14.8
通讯作者：
Lill, Roland
中科院分区：
文献类型：
--
作者：
Schulz, Vinzent;Basu, Somsuvro;Lill, Roland
铁氧还蛋白包括在多种生物过程中穿梭电子的铁-硫（Fe-S）蛋白的大家族。人线粒体含有两种[2Fe-2S]铁氧化还原酶亚型，FDX 1（又名肾上腺素）和FDX 2，在细胞色素P450依赖性类固醇转化和Fe-S蛋白生物合成中具有已知功能。在这里，我们表明，只有FDX 2，而不是FDX 1，参与Fe-S蛋白的成熟。反之亦然，FDX 1不仅对类固醇生成具有特异性，而且对血红素a和硫辛酰辅因子生物合成也具有特异性。在后一种途径中，FDX 1提供电子以启动由硫辛酰合酶催化的自由基链式反应。我们还确定了脂酰化作为毒性抗肿瘤铜离子载体elesclomol的目标。最后，每个铁氧还蛋白的显著靶特异性被分配给小的保守序列基序。交换这些基序改变了这些电子供体的靶特异性。总之，我们的研究结果确定了线粒体铁氧还蛋白的新的生化任务，并提供了其功能特异性的结构见解。
Ferredoxins comprise a large family of iron-sulfur (Fe-S) proteins that shuttle electrons in diverse biological processes. Human mitochondria contain two isoforms of [2Fe-2S] ferredoxins, FDX1 (aka adrenodoxin) and FDX2, with known functions in cytochrome P450-dependent steroid transformations and Fe-S protein biogenesis. Here, we show that only FDX2, but not FDX1, is involved in Fe-S protein maturation. Vice versa, FDX1 is specific not only for steroidogenesis, but also for heme a and lipoyl cofactor biosyntheses. In the latter pathway, FDX1 provides electrons to kickstart the radical chain reaction catalyzed by lipoyl synthase. We also identified lipoylation as a target of the toxic antitumor copper ionophore elesclomol. Finally, the striking target specificity of each ferredoxin was assigned to small conserved sequence motifs. Swapping these motifs changed the target specificity of these electron donors. Together, our findings identify new biochemical tasks of mitochondrial ferredoxins and provide structural insights into their functional specificity.