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首页> 外文期刊>The FEBS journal >Bimodal targeting of cytochrome P450s to endoplasmic reticulum and mitochondria: the concept of chimeric signals. [Review]
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Bimodal targeting of cytochrome P450s to endoplasmic reticulum and mitochondria: the concept of chimeric signals. [Review]

机译：细胞色素P450对内质网和线粒体的双峰靶向：嵌合信号的概念。 [评论]

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摘要

Targeting signals are critical for proteins to find their specific cellular destination. Signals for protein targeting to the endoplasmic reticulum (ER), mitochondria, peroxisome and nucleus are distinct and the mechanisms of protein translocation across these membrane compartments also vary markedly. Recently, however, a number of proteins have been shown to be present in multiple cellular sites such as mitochondria and ER, cytosol and mitochondria, plasma membrane and mitochondria, and peroxisome and mitochondria suggesting the occurrence of multimodal targeting signals in some cases. Cytochrome P450 monooxygenases (CYPs), which play crucial roles in pharmacokinetics and pharmacodynamics of drugs and toxins, are the prototype of bimodally targeted proteins. Several members of family 1, 2 and 3 CYPs have now been reported to be associated with mitochondria and plasma membrane in addition to the ER. This review highlights the mechanisms of bimodal targeting of CYP1A1, 2B1, 2E1 and 2D6 to mitochondria and ER. The bimodal targeting of these proteins is driven by their N-terminal signals which carry essential elements of both ER targeting and mitochondria targeting signals. These multimodal signals have been termed chimeric signals appropriately to describe their dual targeting property. The cryptic mitochondrial targeting signals of CYP2B1, 2D6, 2E1 require activation by protein kinase A or protein kinase C mediated phosphorylation at sites immediately flanking the targeting signal and/or membrane anchoring regions. The cryptic mitochondria targeting signal of CYP1A1 requires activation by endoproteolytic cleavage by a cytosolic endoprotease, which exposes the mitochondrial signal. This review discusses both mechanisms of bimodal targeting and toxicological consequences of mitochondria targeted CYP proteins
机译：靶向信号对于蛋白质找到其特定的细胞目的地至关重要。蛋白质靶向内质网（ER），线粒体，过氧化物酶体和细胞核的信号是截然不同的，并且跨这些膜区室的蛋白质转运机制也有显着差异。然而，近来，已显示许多蛋白质存在于多个细胞部位，例如线粒体和ER，胞质和线粒体，质膜和线粒体以及过氧化物酶体和线粒体，提示在某些情况下多峰靶向信号的出现。细胞色素P450单加氧酶（CYP）是双峰靶向蛋白的原型，在药物和毒素的药代动力学和药效学中起着至关重要的作用。据报道，除了ER外，家族1、2和3种CYP的一些成员还与线粒体和质膜有关。这篇综述强调了CYP1A1、2B1、2E1和2D6对线粒体和ER的双峰靶向机制。这些蛋白质的双峰靶向是由其N端信号驱动的，这些信号携带ER靶向和线粒体靶向信号的基本元素。这些多峰信号已适当地称为嵌合信号，以描述其双重靶向特性。 CYP2B1、2D6、2E1的隐蔽线粒体靶向信号需要被蛋白激酶A或蛋白激酶C介导的磷酸化激活，该磷酸化作用立即位于靶向信号和/或膜锚定区域的两侧。 CYP1A1的线粒体靶向信号需要通过胞质内切蛋白酶进行内切蛋白水解来激活，从而暴露出线粒体信号。这篇综述讨论了双峰靶向机制和线粒体靶向CYP蛋白的毒理学后果

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