Apoptotic pore formation is associated with in-plane insertion of Bak or Bax central helices into the mitochondrial outer membrane
Apoptotic pore formation is associated with in-plane insertion of Bak or Bax central helices into the mitochondrial outer membrane
复制标题
DOI：
10.1073/pnas.1415142111
复制
发表时间：
2014-09-30
影响因子：
11.1
通讯作者：
Kluck, Ruth M.
中科院分区：
文献类型：
--
作者：
Westphal, Dana;Dewson, Grant;Kluck, Ruth M.
B细胞淋巴瘤-2(Bcl2)家族成员Bak或Bax的寡聚体对线粒体外膜(MOM)的通透性是线粒体凋亡途径中的关键步骤。然而，它们是如何破坏母亲的诚信还不得而知。一个长期存在的模型是，活化的Bak和Bax在MOM上插入两个α-螺旋，α5和α6，作为发夹，但最近对齐聚物结构的见解对这一模型提出了质疑。我们已经阐明了这些螺旋是如何促进MOM穿孔的，方法是确定在寡聚体中，Bakα5(像Baxα5)仍然是蛋白质核心的一部分，并且不透膜的半胱氨酸试剂可以标记放置在Bak和Bax的α5和α6的许多位置的半胱氨酸。结果与发夹插入模型不一致，但支持平面内模型，即α5和α6塌陷到膜上并浅插入以驱动蛋白脂孔的形成。
The pivotal step on the mitochondrial pathway to apoptosis is permeabilization of the mitochondrial outer membrane (MOM) by oligomers of the B-cell lymphoma-2 (Bcl-2) family members Bak or Bax. However, how they disrupt MOM integrity is unknown. A longstanding model is that activated Bak and Bax insert two alpha-helices, alpha 5 and alpha 6, as a hairpin across the MOM, but recent insights on the oligomer structures question this model. We have clarified how these helices contribute to MOM perforation by determining that, in the oligomers, Bak alpha 5 (like Bax alpha 5) remains part of the protein core and that a membrane-impermeable cysteine reagent can label cysteines placed at many positions in alpha 5 and alpha 6 of both Bak and Bax. The results are inconsistent with the hairpin insertion model but support an in-plane model in which alpha 5 and alpha 6 collapse onto the membrane and insert shallowly to drive formation of proteolipidic pores.