The molecular mechanism behind reactive aldehyde action on transmembrane translocations of proton and potassium ions.
The molecular mechanism behind reactive aldehyde action on transmembrane translocations of proton and potassium ions.
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DOI：
10.1016/j.freeradbiomed.2015.10.422
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发表时间：
2015-12
影响因子：
7.4
通讯作者：
Pohl EE
中科院分区：
文献类型：
--
作者：
Jovanovic O;Pashkovskaya AA;Annibal A;Vazdar M;Burchardt N;Sansone A;Gille L;Fedorova M;Ferreri C;Pohl EE
膜转运蛋白参与许多生理和病理过程。在氧化应激下，它们成为导致蛋白质损伤和/或影响蛋白质功能的活性氧及其衍生物的靶标。这种相互作用的分子机制知之甚少。在这里，我们描述了一种新的脂质介导的机制，生物学上重要的反应性醛（RA; 4-羟基-2-壬烯醛，4-羟基-2-己烯醛和4-氧代-2-壬烯醛）修改几种膜转运蛋白的活性。我们发现，研究RA共价修饰膜脂质磷脂酰乙醇胺（PE），导致形成不同的膜活性加合物。分子动力学模拟表明，锚定的PE-RA加合物的脂质头基区域是主要负责的脂质膜的性质，如膜序参数，边界电位和膜曲率的变化。这些导致线粒体解偶联蛋白1、钾载体缬氨霉素和离子载体CCCP的转运活性改变。与此相反，既不直接蛋白质修饰RA如先前所示的胞质蛋白，也不RA插入到膜双层的影响所研究的转运蛋白。我们的研究结果解释了醛作用于细胞蛋白质的多样性，并在生物学上重要的RA对膜受体，通道和转运蛋白的脂质介导的影响的调查开辟了一个新的领域。
Membrane transporters are involved in enormous number of physiological and pathological processes. Under oxidative stress they become targets for reactive oxygen species and its derivatives which cause protein damage and/or influence protein function(s). The molecular mechanisms of this interaction are poorly understood. Here we describe a novel lipid-mediated mechanism by which biologically important reactive aldehydes (RAs; 4-hydroxy-2-nonenal, 4-hydroxy-2-hexenal and 4-oxo-2-nonenal) modify the activity of several membrane transporters. We revealed that investigated RAs covalently modify the membrane lipid phosphatidylethanolamine (PE), that lead to the formation of different membrane active adducts. Molecular dynamic simulations suggested that anchoring of PE-RA adducts in the lipid headgroup region is primarily responsible for changes in the lipid membrane properties, such as membrane order parameter, boundary potential and membrane curvature. These caused the alteration of transport activity of mitochondrial uncoupling protein 1, potassium carrier valinomycin and ionophore CCCP. In contrast, neither direct protein modification by RA as previously shown for cytosolic proteins, nor RAs insertion into membrane bilayers influenced the studied transporters. Our results explain the diversity of aldehyde action on cell proteins and open a new field in the investigation of lipid-mediated effects of biologically important RA on membrane receptors, channels and transporters.
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影响因子：
5.5
作者：
Hess, Berk;Kutzner, Carsten;Lindahl, Erik
通讯作者：
Lindahl, Erik
影响因子：
3.3
作者：
Klauda, Jeffery B.;Venable, Richard M.;Freites, J. Alfredo;O'Connor, Joseph W.;Tobias, Douglas J.;Mondragon-Ramirez, Carlos;Vorobyov, Igor;MacKerell, Alexander D., Jr.;Pastor, Richard W.
通讯作者：
Pastor, Richard W.
影响因子：
4.3
作者：
Beck, Valeri;Jaburek, Martin;Pohl, Elena E.
通讯作者：
Pohl, Elena E.
影响因子：
4.4
作者：
JORGENSEN, WL;CHANDRASEKHAR, J;KLEIN, ML
通讯作者：
KLEIN, ML
影响因子：
4.4
作者：
ESSMANN, U;PERERA, L;PEDERSEN, LG
通讯作者：
PEDERSEN, LG