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Evolutionary Origin of the Mitochondrial Cholesterol Transport Machinery Reveals a Universal Mechanism of Steroid Hormone Biosynthesis in Animals

机译：线粒体胆固醇运输机制的进化起源揭示了动物体内类固醇激素生物合成的普遍机制。

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摘要

Steroidogenesis begins with the transport of cholesterol from intracellular stores into mitochondria via a series of protein-protein interactions involving cytosolic and mitochondrial proteins located at both the outer and inner mitochondrial membranes. In adrenal glands and gonads, this process is accelerated by hormones, leading to the production of high levels of steroids that control tissue development and function. A hormone-induced multiprotein complex, the transduceosome, was recently identified, and is composed of cytosolic and outer mitochondrial membrane proteins that control the rate of cholesterol entry into the outer mitochondrial membrane. More recent studies unveiled the steroidogenic metabolon, a bioactive, multimeric protein complex that spans the outer-inner mitochondrial membranes and is responsible for hormone-induced import, segregation, targeting, and metabolism of cholesterol by cytochrome P450 family 11 subfamily A polypeptide 1 (CYP11A1) in the inner mitochondrial membrane. The availability of genome information allowed us to systematically explore the evolutionary origin of the proteins involved in the mitochondrial cholesterol transport machinery (transduceosome, steroidogenic metabolon, and signaling proteins), trace the original archetype, and predict their biological functions by molecular phylogenetic and functional divergence analyses, protein homology modeling and molecular docking. Although most members of these complexes have a history of gene duplication and functional divergence during evolution, phylogenomic analysis revealed that all vertebrates have the same functional complex members, suggesting a common mechanism in the first step of steroidogenesis. An archetype of the complex was found in invertebrates. The data presented herein suggest that the cholesterol transport machinery is responsible for steroidogenesis among all vertebrates and is evolutionarily conserved throughout the entire animal kingdom.
机译：类固醇生成始于胆固醇通过一系列蛋白质-蛋白质相互作用（从位于线粒体外膜和内膜的胞浆和线粒体蛋白）从细胞内储存物转运至线粒体。在肾上腺和性腺中，激素会加速这一过程，导致产生高水平的类固醇，从而控制组织的发育和功能。最近发现了一种激素诱导的多蛋白复合物，transduceosome，它由控制胆固醇进入线粒体外膜的速率的胞质和线粒体外膜蛋白组成。最近的研究揭示了类固醇生成代谢物，一种生物活性的多聚体蛋白复合物，横跨线粒体内外膜，负责激素引起的细胞色素P450家族11亚家族A多肽1（CYP11A1）的导入，分离，靶向和代谢胆固醇。 ）在内线粒体膜中。基因组信息的可用性使我们能够系统地探索线粒体胆固醇转运机制所涉及的蛋白质（转导体，类固醇生成代谢素和信号传导蛋白质）的进化起源，追踪原始原型并通过分子系统发育和功能差异预测其生物学功能分析，蛋白质同源性建模和分子对接。尽管这些复合物的大多数成员在进化过程中都有基因复制和功能差异的历史，但系统进化分析表明，所有脊椎动物都具有相同的功能复合物成员，这表明类固醇形成的第一步具有共同的机制。在无脊椎动物中发现了复合物的原型。本文提供的数据表明，胆固醇运输机制负责所有脊椎动物中的类固醇生成，并且在整个动物界中都是进化保守的。

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    Jinjiang Fan; Vassilios Papadopoulos;

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  • 年(卷),期 -1(8),10
  • 年度 -1
  • 页码 e76701
  • 总页数 20
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