Bax monomers form dimer units in the membrane that further self-assemble into multiple oligomeric species.
Bax monomers form dimer units in the membrane that further self-assemble into multiple oligomeric species.
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DOI：
10.1038/ncomms9042
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发表时间：
2015-08-14
影响因子：
16.6
通讯作者：
García-Sáez AJ
中科院分区：
文献类型：
--
作者：
Subburaj Y;Cosentino K;Axmann M;Pedrueza-Villalmanzo E;Hermann E;Bleicken S;Spatz J;García-Sáez AJ
Bax是细胞凋亡的关键调节因子，其在孔形成之前通过线粒体外膜中的寡聚化介导细胞色素c释放到胞质溶胶中。然而，Bax组装和其他Bcl-2成员调控的分子机制仍然不清楚。在这里，通过在单分子水平上分析Bax寡聚体的化学计量，我们发现Bax以单体状态结合到膜上，然后在<1分钟内自组装。引人注目的是，活性Bax并不以独特的寡聚状态存在，而是以基于二聚体单元的几种不同物质存在。此外，我们表明，cBid激活Bax而不影响其组装，而Bcl-xL诱导Bax寡聚体的解离。在我们的实验数据和理论模型的基础上，我们提出了一个新的机制Bax组装的分子途径，形成凋亡孔。 促凋亡蛋白Bax通过在线粒体外膜中形成孔来触发细胞死亡。使用单粒子TIRF成像，作者表明Bax在形成二聚体和二聚体的多聚体之前以单体状态结合膜，这些二聚体被存活蛋白Bcl-xL分解。
Bax is a key regulator of apoptosis that mediates the release of cytochrome c to the cytosol via oligomerization in the outer mitochondrial membrane before pore formation. However, the molecular mechanism of Bax assembly and regulation by other Bcl-2 members remains obscure. Here, by analysing the stoichiometry of Bax oligomers at the single-molecule level, we find that Bax binds to the membrane in a monomeric state and then self-assembles in <1 min. Strikingly, active Bax does not exist in a unique oligomeric state, but as several different species based on dimer units. Moreover, we show that cBid activates Bax without affecting its assembly, while Bcl-xL induces the dissociation of Bax oligomers. On the basis of our experimental data and theoretical modelling, we propose a new mechanism for the molecular pathway of Bax assembly to form the apoptotic pore. The proapoptotic protein Bax triggers cell death by forming pores in the outer mitochondrial membrane. Using single-particle TIRF imaging, the authors show that Bax binds the membrane in a monomeric state before forming dimers and multimers of dimers, which are disassembled by the survival protein Bcl-xL.