Molecular mechanism of cardiolipin-mediated assembly of respiratory chain supercomplexes.
Molecular mechanism of cardiolipin-mediated assembly of respiratory chain supercomplexes.
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DOI：
10.1039/c5sc04664e
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发表时间：
2016-07-01
期刊：
影响因子：
8.4
通讯作者：
Periole X
中科院分区：
文献类型：
--
作者：
Arnarez C;Marrink SJ;Periole X
我们揭示了心磷脂将呼吸复合体粘合成超复合体的分子机制。这一机制定义了一种新的蛋白质-脂质相互作用的生物物理-化学途径，对拥挤细胞膜的动态组织具有广泛的普遍意义。线粒体通过细胞内膜上的呼吸链产生细胞消耗的大部分ATP。这一过程涉及将蛋白质复合体组装成更大的结构，即呼吸超复合体(SCs)。心磷脂(CL)是线粒体标志性的磷脂，对这些干细胞的结构和功能的完整性至关重要，但它的作用机制尚不清楚。我们的数据揭示了块状CL粘合SCs、引导其形成的机制，并暗示了它可能如何稳定特定的界面。我们描述了9个细胞色素Bc1(CIII)二聚体和27个细胞色素c氧化酶(CIV)单体的自组装分子动力学模拟，目的是模拟线粒体膜的拥挤和复杂性。模拟显示了大量不同的界面，包括现有的实验CIII/CIV SC模型的界面，以及一个旋转180°的CIV替代界面。SC界面包含4到12个CL，∼是散装的10倍。其中一半的CLS络合物利用两个络合物表面上的CL结合位点粘合在一起。自由能计算表明，与其他线粒体脂质相比，CL结合强度更大，这是这些结合位点所特有的，是非加性静电和范德华力的结果。这项研究提供了一个关键的例子，脂类通过改变所有作用力范围，润滑蛋白质界面，并作为交通控制剂将蛋白质聚集在一起，选择性地调节蛋白质-蛋白质的相互作用。
We reveal the molecular mechanism by which cardiolipin glues respiratory complexes into supercomplexes. This mechanism defines a new biophysico-chemical pathway of protein–lipid interplay, with broad general implications for the dynamic organization of crowded cell membranes. Mitochondria produce most of the ATP consumed by cells through the respiratory chain in their inner membrane. This process involves protein complexes assembled into larger structures, the respiratory supercomplexes (SCs). Cardiolipin (CL), the mitochondrial signature phospholipid, is crucial for the structural and functional integrity of these SCs, but it is as yet unclear by what mechanism it operates. Our data disclose the mechanism for bulk CL in gluing SCs, steering their formation, and suggest how it may stabilize specific interfaces. We describe self-assembly molecular dynamics simulations of 9 cytochrome bc1 (CIII) dimers and 27 cytochrome c oxidase (CIV) monomers from bovine heart mitochondria embedded in a CL-containing model lipid bilayer, aimed at mimicking the crowdedness and complexity of mitochondrial membranes. The simulations reveal a large diversity of interfaces, including those of existing experimental CIII/CIV SC models and an alternative interface with CIV rotated by 180°. SC interfaces enclose 4 to 12 CLs, a ∼10 fold enrichment from the bulk. Half of these CLs glue complexes together using CL binding sites at the surface of both complexes. Free energy calculations demonstrate a larger CL binding strength, compared to other mitochondrial lipids, that is exclusive to these binding sites and results from non-additive electrostatic and van der Waals forces. This study provides a key example of the ability of lipids to selectively mediate protein–protein interactions by altering all ranges of forces, lubricate protein interfaces and act as traffic control agents steering proteins together.
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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：
4.6
作者：
Arnarez, C.;Marrink, S. J.;Periole, X.
通讯作者：
Periole, X.
DOI：
10.1073/pnas.1107819108
发表时间：
2011-09-13
影响因子：
11.1
作者：
Dudkina, Natalya V.;Kudryashev, Mikhail;Boekema, Egbert J.
通讯作者：
Boekema, Egbert J.
影响因子：
2.9
作者：
Gao, XG;Wen, XL;Xia, D
通讯作者：
Xia, D
DOI：
10.1073/pnas.1413855111
发表时间：
2014-11-04
影响因子：
11.1
作者：
Blaza, James N.;Serreli, Riccardo;Hirst, Judy
通讯作者：
Hirst, Judy