How does the Bax-α1 targeting sequence interact with mitochondrial membranes? The role of cardiolipin
How does the Bax-α1 targeting sequence interact with mitochondrial membranes? The role of cardiolipin
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DOI：
10.1016/j.bbamem.2008.12.014
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发表时间：
2009-03-01
影响因子：
3.4
通讯作者：
Groebner, Gerhard
中科院分区：
文献类型：
--
作者：
Sani, Marc-Antoine;Dufourc, Erick J.;Groebner, Gerhard
程序性细胞死亡的一个关键事件是凋亡的 Bax 蛋白从细胞质转移到线粒体。位于 Bax N 末端的第一个螺旋 (Bax-alpha 1) 在这里可以充当寻址序列，将激活的 Bax 引导至线粒体表面。使用固态 NMR（核磁共振）、CD（圆二色性）和 ATR（衰减全反射）光谱来阐明 Bax-alpha 1 对线粒体膜系统的识别过程。研究了两种潜在的目标膜，其中线粒体外膜 (OM) 由中性磷脂模拟，而线粒体接触位点 (CS) 含有额外的阴离子心磷脂。 H-1 和 P-31 魔角旋转 (MAS) NMR 显示，仅在存在心磷脂的情况下，Bax-alpha 1 才会在脂质头基区域引起明显的扰动。 Bax-α 1 无法插入 CS 膜，但在浓度升高时，它会插入不含心磷脂的 OM 囊泡的疏水核心，从而采用 β 片层样特征，如 ATR 所证实。 CD研究表明，心磷脂介导的Bax-α1在CS膜表面的静电锁定促进了构象转变为α螺旋状态：这一过程似乎对于诱导激活的Bax中进一步的构象转变事件是必要的，最终在线粒体凋亡期间导致不可逆的膜通透化。 (C) 2008 Elsevier B.V. 保留所有权利。
A key event in programmed cell death is the translocation of the apoptotic Bax protein from the cytosol towards mitochondria. The first helix localized at the N-terminus of Bax (Bax-alpha 1) can act here as an addressing sequence, which directs activated Bax towards the mitochondrial surface. Solid state NMR (nuclear magnetic resonance), CD (circular dichroism) and ATR (attenuated total reflection) spectroscopy were used to elucidate this recognition process of a mitochondrial membrane system by Bax-alpha 1. Two potential target membranes were studied, with the outer mitochondrial membrane (OM) mimicked by neutral phospholipids, while mitochondrial contact sites (CS) contained additional anionic cardiolipin. H-1 and P-31 magic angle spinning (MAS) NMR revealed Bax-alpha 1 induced pronounced perturbations in the lipid headgroup region only in presence of cardiolipin. Bax-alpha 1 could not insert into CS membranes but at elevated concentrations it inserted into the hydrophobic core of cardiolipin-free OM vesicles, thereby adopting beta-sheet-like features, as confirmed by ATR. CD studies revealed, that the cardiolipin mediated electrostatic locking of Bax-alpha 1 at the CS membrane surface promotes conformational changes into an alpha-helical state: a process which seems to be necessary to induce further conformational transition events in activated Bax which finally causes irreversible membrane permeabilization during the mitochondrial apoptosis. (C) 2008 Elsevier B.V. All rights reserved.