Structural model of active Bax at the membrane.
Structural model of active Bax at the membrane.
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DOI：
10.1016/j.molcel.2014.09.022
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发表时间：
2014-11-20
期刊：
影响因子：
16
通讯作者：
Bordignon E
中科院分区：
文献类型：
--
作者：
Bleicken S;Jeschke G;Stegmueller C;Salvador-Gallego R;García-Sáez AJ;Bordignon E
Bax在细胞凋亡的线粒体途径中起核心作用。在激活时，胞质Bax单体在线粒体表面寡聚化并一致地改变构象以在外膜中穿孔。细胞色素c的随后释放引发细胞死亡。然而，膜插入Bax的结构及其作用机制在很大程度上仍然未知。在这里，我们提出了一个3D模型的基础上，在脂质体和分离的线粒体的双电子-电子共振（DEER）光谱的膜上的活性Bax。我们发现，活跃的Bax是组织在膜上的二聚体的组件。除了稳定的二聚化结构域之外，每个单体还包含参与二聚体间相互作用和孔形成的更灵活的刺穿结构域。Bax激活过程中最重要的结构变化是由螺旋5和6形成的发夹的开放，其采用了对线粒体透化机制至关重要的钳状构象。
Bax plays a central role in the mitochondrial pathway of apoptosis. Upon activation, cytosolic Bax monomers oligomerize on the surface of mitochondria and change conformation concertedly to punch holes into the outer membrane. The subsequent release of cytochrome c initiates cell death. However, the structure of membrane-inserted Bax and its mechanism of action remain largely unknown. Here, we propose a 3D model of active Bax at the membrane based on double electron-electron resonance (DEER) spectroscopy in liposomes and isolated mitochondria. We show that active Bax is organized at the membrane as assemblies of dimers. In addition to a stable dimerization domain, each monomer contains a more flexible piercing domain involved in interdimer interactions and pore formation. The most important structural change during Bax activation is the opening of the hairpin formed by helices 5 and 6, which adopts a clamp-like conformation central to the mechanism of mitochondrial permeabilization.