Bimodal targeting of cytochrome P450s to endoplasmic reticulum and mitochondria: the concept of chimeric signals.
Bimodal targeting of cytochrome P450s to endoplasmic reticulum and mitochondria: the concept of chimeric signals.
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DOI：
10.1111/j.1742-4658.2011.08356.x
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发表时间：
2011-11
期刊：
影响因子：
--
通讯作者：
Bajpai P
中科院分区：
文献类型：
--
作者：
Avadhani NG;Sangar MC;Bansal S;Bajpai P
靶向信号对于蛋白质找到其特定的细胞目的地至关重要。靶向内质网 (ER)、线粒体、过氧化物酶体和细胞核的蛋白质信号是不同的，并且蛋白质跨这些膜区室的易位机制也显着不同。然而，最近，许多蛋白质已被证明存在于多个细胞位点，例如线粒体和内质网、细胞质和线粒体、质膜和线粒体、以及过氧化物酶体和线粒体，这表明在某些情况下存在多模式靶向信号。细胞色素 P450 单加氧酶 (CYP) 在药物和毒素的药代动力学和药效学中发挥着至关重要的作用，是双峰靶向蛋白的原型。据报道，除了 ER 之外，CYP 家族 1、2 和 3 的几个成员现在还与线粒体和质膜相关。本综述重点介绍了 CYP1A1、2B1、2E1 和 2D6 靶向线粒体和 ER 的双模式机制。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。这些多模态信号被适当地称为嵌合信号来描述它们的双重靶向特性。 CYP2B1、2D6、2E1 的神秘线粒体靶向信号需要通过紧邻靶向信号和/或膜锚定区域的 PKA 或 PKC 介导的磷酸化来激活。 CYP1A1 的神秘线粒体靶向信号需要通过胞质内切蛋白酶的内切蛋白水解酶来激活，从而暴露线粒体信号。本综述讨论了双模式靶向机制和线粒体靶向 CYP 蛋白的毒理学后果。
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 PKA or PKC 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.
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DOI：
10.1124/jpet.106.110007
发表时间：
2006-12-01
影响因子：
3.5
作者：
Bai, Jingxiang;Cederbaum, Arthur I.
通讯作者：
Cederbaum, Arthur I.
影响因子：
4.8
作者：
Boopathi, E;Anandatheerthavarada, HK;Avadhani, NG
通讯作者：
Avadhani, NG
影响因子：
4.8
作者：
Dasari, Venkata Ramesh;Anandatheerthavarada, Hindupur K.;Avadhani, Narayan G.
通讯作者：
Avadhani, Narayan G.
影响因子：
4.8
作者：
Devi, Latha;Raghavendran, Vijayendran;Anandatheerthavarada, Hindupur K.
通讯作者：
Anandatheerthavarada, Hindupur K.
影响因子：
64.8
作者：
EILERS, M;SCHATZ, G
通讯作者：
SCHATZ, G