Bak凋亡孔涉及一个灵活的C末端区域以及C末端跨膜结构域的并置。

Bak apoptotic pores involve a flexible C-terminal region and juxtaposition of the C-terminal transmembrane domains.

作者信息

Iyer S, Bell F, Westphal D, Anwari K, Gulbis J, Smith B J, Dewson G, Kluck R M

机构信息

The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia.

Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.

出版信息

Cell Death Differ. 2015 Oct;22(10):1665-75. doi: 10.1038/cdd.2015.15. Epub 2015 Mar 6.

Abstract

Bak and Bax mediate apoptotic cell death by oligomerizing and forming a pore in the mitochondrial outer membrane. Both proteins anchor to the outer membrane via a C-terminal transmembrane domain, although its topology within the apoptotic pore is not known. Cysteine-scanning mutagenesis and hydrophilic labeling confirmed that in healthy mitochondria the Bak α9 segment traverses the outer membrane, with 11 central residues shielded from labeling. After pore formation those residues remained shielded, indicating that α9 does not line a pore. Bak (and Bax) activation allowed linkage of α9 to neighboring α9 segments, identifying an α9:α9 interface in Bak (and Bax) oligomers. Although the linkage pattern along α9 indicated a preferred packing surface, there was no evidence of a dimerization motif. Rather, the interface was invoked in part by Bak conformation change and in part by BH3:groove dimerization. The α9:α9 interaction may constitute a secondary interface in Bak oligomers, as it could link BH3:groove dimers to high-order oligomers. Moreover, as high-order oligomers were generated when α9:α9 linkage in the membrane was combined with α6:α6 linkage on the membrane surface, the α6-α9 region in oligomerized Bak is flexible. These findings provide the first view of Bak carboxy terminus (C terminus) membrane topology within the apoptotic pore.

摘要

Bak和Bax通过寡聚化并在线粒体外膜上形成孔道来介导凋亡性细胞死亡。这两种蛋白质都通过C端跨膜结构域锚定在外膜上,尽管其在凋亡孔道中的拓扑结构尚不清楚。半胱氨酸扫描诱变和亲水标记证实,在健康的线粒体中,Bak的α9片段穿过外膜,其中央的11个残基被屏蔽而无法被标记。在孔道形成后,这些残基仍然被屏蔽,这表明α9并不构成孔道的内衬。Bak(和Bax)的激活使得α9与相邻的α9片段相连,从而确定了Bak(和Bax)寡聚体中的α9:α9界面。尽管沿着α9的连接模式表明存在一个优先的堆积表面,但没有证据表明存在二聚化基序。相反,该界面部分是由Bak构象变化引起的,部分是由BH3:凹槽二聚化引起的。α9:α9相互作用可能构成Bak寡聚体中的二级界面,因为它可以将BH3:凹槽二聚体连接成高阶寡聚体。此外,当膜中的α9:α9连接与膜表面的α6:α6连接相结合时会产生高阶寡聚体,因此寡聚化的Bak中的α6-α9区域是灵活的。这些发现首次揭示了凋亡孔道内Bak羧基末端(C末端)的膜拓扑结构。

文献AI研究员

20分钟写一篇综述,助力文献阅读效率提升50倍

立即体验

用中文搜PubMed

大模型驱动的PubMed中文搜索引擎

马上搜索