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首页> 外文期刊>Journal of chemical neuroanatomy >Mapping the protein phosphorylation sites in human mitochondrial complex I (NADH: Ubiquinone oxidoreductase): A bioinformatics study with implications for brain aging and neurodegeneration
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Mapping the protein phosphorylation sites in human mitochondrial complex I (NADH: Ubiquinone oxidoreductase): A bioinformatics study with implications for brain aging and neurodegeneration

机译：将蛋白质磷酸化位点映射在人体线粒体络合物I（NADH：ubiquinone氧化还原酶）中：具有对脑老化和神经变性的影响的生物信息学研究

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In eukaryotes, mitochondrial complex I (NADH: ubiquinone oxidoreductase; CI) is central to oxidative phosphorylation (OXPHOS). Mammalian CI is a 45 subunit complex that forms supercomplexes with other OXPHOS complexes. Since CI defects are associated with aging and neurodegeneration, it is pertinent to understand its structure-function relationship. Although genetic mutations could lower CI activity causing mitochondria] dysfunction in several pathologies, post-translational modifications (PTMs) have emerged as a key mechanism contributing to altered CI activity. Among non-oxidative PTMs, protein phosphorylation is the most intricate regulatory mechanism controlling CI structure and function during normal physiology, aging and neurodegeneration. To comprehend this, we carried out a comprehensive bioinformatics analysis of protein phosphorylation of human CI subunits using software-based prediction of phosphorylation (phospho) sites and associated kinases. Phosphorylation was higher among core subunits and active domains of the complex. Among the subunits, NDUFS1 displayed significantly higher number as well as percent phospho sites compared to others. Analysis of the subunits containing iron-sulfur (Fe-S) cluster, NADH and FMN binding sites and quinone binding sites indicated the presence of phospho sites in close proximity to the binding sites of these cofactors with potential functional implications. Phosphoproteomics experiment in rat and human muscle mitochondria identified specific phospho sites in CI subunits, thereby validating the bioinformatic analysis. Molecular modeling of CI subunits indicated structural implications following phosphorylation. We surmise that protein phosphorylation, a transient and regulatory event could influence the structure-function relationship of CI thereby impinging on bioenergetics and ultimately contributing to aging and neurodegeneration.
机译：在真核生物中，线粒体复合物I（NADH：ubiquinone氧化还原酶; CI）是氧化磷酸化（毒物）的中心。哺乳动物CI是一种45亚基复合物，其与其他汤膦络合物形成超复杂。由于CI缺陷与老化和神经变性相关，因此有关了解其结构功能关系。虽然遗传突变可以降低CI活性，导致线粒体的功能障碍在几种病理中的功能障碍，翻译后修饰（PTMS）作为有助于改变CI活性的关键机制。在非氧化性PTMS中，蛋白质磷酸化是在正常生理，老化和神经变性期间控制CI结构和功能的最复杂的调节机制。为了理解这一点，我们使用基于软件的磷酸化（磷酸盐）位点和相关激酶的软件的预测来对人CI亚基的蛋白质磷酸化进行综合生物信息分析。核心亚基和复合物的活性结构域中的磷酸化较高。在亚基中，与他人相比，NDUFS1显示出显着更高的数量以及磷酸盐百分比。分析含铁硫（Fe-S）簇，NADH和FMN结合位点和醌结合位点的亚基表明存在磷磷位点紧密到这些辅助actor的结合位点，具有潜在的功能意义。大鼠和人肌肉线粒体的磷蛋白质试验鉴定了CI亚基的特异性磷光位点，从而验证了生物信息分析。 CI亚基的分子建模表明磷酸化后的结构意义。我们猜测蛋白质磷酸化，瞬态和调节事件可能影响CI的结构功能关系，从而抵抗生物终体和最终导致老化和神经变性。

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