Uren Rachel T, Iyer Sweta, Kluck Ruth M
Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, The University of Melbourne, 1G Royal Parade, Parkville, Victoria 3052, Australia.
Department of Medical Biology, The University of Melbourne, 1G Royal Parade, Parkville, Victoria 3052, Australia.
Philos Trans R Soc Lond B Biol Sci. 2017 Aug 5;372(1726). doi: 10.1098/rstb.2016.0218.
Apoptotic cell death via the mitochondrial pathway occurs in all vertebrate cells and requires the formation of pores in the mitochondrial outer membrane. Two Bcl-2 protein family members, Bak and Bax, form these pores during apoptosis, and how they do so has been investigated for the last two decades. Many of the conformation changes that occur during their transition to pore-forming proteins have now been delineated. Notably, biochemical, biophysical and structural studies indicate that symmetric homodimers are the basic unit of pore formation. Each dimer contains an extended hydrophobic surface that lies on the outer membrane, and is anchored at either end by a transmembrane domain. Membrane-remodelling events such as positive membrane curvature have been reported to accompany apoptotic pore formation, suggesting Bak and Bax form lipidic pores rather than proteinaceous pores. However, it remains unclear how symmetric dimers assemble to porate the membrane. Here, we review how clusters of dimers and their lipid-mediated interactions provide a molecular explanation for the heterogeneous assemblies of Bak and Bax observed during apoptosis.This article is part of the themed issue 'Membrane pores: from structure and assembly, to medicine and technology'.
通过线粒体途径的凋亡性细胞死亡发生在所有脊椎动物细胞中，并且需要在线粒体外膜上形成孔道。两种Bcl-2蛋白家族成员Bak和Bax在凋亡过程中形成这些孔道，在过去二十年里人们一直在研究它们是如何做到这一点的。现在已经描绘出了它们转变为成孔蛋白过程中发生的许多构象变化。值得注意的是，生化、生物物理和结构研究表明对称同型二聚体是孔形成的基本单位。每个二聚体都包含一个位于外膜上的延伸疏水表面，并在两端由一个跨膜结构域锚定。据报道，诸如正膜曲率等膜重塑事件伴随着凋亡孔的形成，这表明Bak和Bax形成的是脂质孔而不是蛋白质孔。然而，尚不清楚对称二聚体是如何组装以使膜成孔的。在这里，我们综述二聚体簇及其脂质介导的相互作用如何为凋亡过程中观察到的Bak和Bax的异质组装提供分子解释。本文是主题为“膜孔：从结构与组装到医学与技术”特刊的一部分。
