Flavin nucleotides act as electron shuttles mediating reduction of the [2Fe-2S] clusters in mitochondrial outer membrane protein mitoNEET.
Flavin nucleotides act as electron shuttles mediating reduction of the [2Fe-2S] clusters in mitochondrial outer membrane protein mitoNEET.
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DOI：
10.1016/j.freeradbiomed.2016.12.001
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发表时间：
2017-01
影响因子：
7.4
通讯作者：
Ding, Huangen
中科院分区：
文献类型：
--
作者：
Landry, Aaron P.;Wang, Yiming;Cheng, Zishuo;Crochet, Robert B.;Lee, Yong-Hwan;Ding, Huangen
MitoNEET是II型糖尿病药物吡格列酮的主要靶点，在调节能量代谢、铁稳态和线粒体中活性氧的产生方面具有重要作用。在结构上，线粒体通过其N端跨膜α-螺旋与线粒体外膜连接。MitoNEET的C-末端胞液结构域通过三个半胱氨酸和一个组氨酸残基拥有氧化还原活性的[2Fe-2S]簇。在这里，我们报告了还原的黄素核苷酸可以在厌氧或有氧条件下迅速还原mitoNEET[2Fe-2S]簇。在NADH和黄素还原酶存在下，在有氧条件下，大约1个黄素核苷酸分子足以在4分钟内还原100个mitoNEET[2Fe-2S]簇。电子顺磁共振(EPR)测量表明，黄素单核苷酸(FMN)而不是黄素腺嘌呤二核苷酸(FAD)与mitoNEET有特异性的相互作用。分子对接模型进一步表明，黄素单核苷酸在N端跨膜α-螺旋和[2Fe-2S]簇结合域之间与mitoNEET结合。在mitoNEET中，[2Fe-2S]簇与结合的黄素单核苷酸之间的最近距离约为10？，这可能有助于电子从还原的黄素核苷酸快速转移到mitoNEET中的[2Fe-2S]簇。这些结果表明，黄素核苷酸可能作为电子穿梭来减少人细胞中的mitoNEET[2Fe-2S]簇并调节线粒体的功能。
MitoNEET, a primary target of type II diabetes drug pioglitazone, has an essential role in regulating energy metabolism, iron homeostasis, and production of reactive oxygen species in mitochondria. Structurally, mitoNEET is anchored to the mitochondrial outer membrane via its N-terminal transmembrane α-helix. The C-terminal cytosolic domain of mitoNEET hosts a redox active [2Fe-2S] cluster via three cysteine and one histidine residues. Here we report that the reduced flavin nucleotides can rapidly reduce the mitoNEET [2Fe-2S] clusters under anaerobic or aerobic conditions. In the presence of NADH and flavin reductase, about 1 molecule of flavin nucleotide is sufficient to reduce 100 molecules of the mitoNEET [2Fe-2S] clusters in 4 minutes under aerobic conditions. The electron paramagnetic resonance (EPR) measurements show that flavin mononucleotide (FMN), but not flavin adenine dinucleotide (FAD), has a specific interaction with mitoNEET. Molecular docking models further reveal that flavin mononucleotide binds mitoNEET at the region between the N-terminal transmembrane α-helix and the [2Fe-2S] cluster binding domain. The closest distance between the [2Fe-2S] cluster and the bound flavin mononucleotide in mitoNEET is about 10 Å, which may facilitate rapid electron transfer from the reduced flavin nucleotide to the [2Fe-2S] cluster in mitoNEET. The results suggest that flavin nucleotides may act as electron shuttles to reduce the mitoNEET [2Fe-2S] clusters and regulate mitochondrial functions in human cells.
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