Intrinsic apoptosis is orchestrated by a group of proteins that mediate the coordinated disruption of mitochondrial membranes. Bax is a multi-domain protein that, upon activation, disrupts the integrity of the mitochondrial outer membrane by forming pores. We strategically introduced glutamic acids into a short sequence of the Bax protein that constitutively creates membrane pores. The resulting BaxE5 peptide efficiently permeabilizes membranes at acidic pH, showing low permeabilization at neutral pH. Atomic force microscopy (AFM) imaging showed that at acidic pH BaxE5 established several membrane remodeling modalities that progressively disturbed the integrity of the lipid bilayer. The AFM data offers vistas on the membrane disruption process, which starts with pore formation and progresses through localized exposure of membrane monolayers leading to stable and small (height ∼ 16 Å) lipid–peptide complexes. The different types of membrane morphology observed in the presence of BaxE5 suggest that the peptide can establish different types of membrane interactions. BaxE5 adopts a rare unstructured conformation when bound to membranes, which might facilitate the dynamic transition between those different states, and then promote membrane digestion.

中文翻译：

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凋亡蛋白 Bax 修饰片段的可控膜重塑

内在细胞凋亡由一组介导线粒体膜协调破坏的蛋白质精心策划。Bax 是一种多结构域蛋白，激活后通过形成孔破坏线粒体外膜的完整性。我们有策略地将谷氨酸引入 Bax 蛋白的短序列中，该序列构成性地产生膜孔。由此产生的 BaxE5 肽在酸性 pH 值下有效渗透膜，在中性 pH 值下表现出低渗透性。原子力显微镜 (AFM) 成像显示，在酸性 pH 值下，BaxE5 建立了几种膜重塑模式，这些模式逐渐扰乱了脂质双层的完整性。AFM 数据提供了膜破裂过程的前景，它从孔隙形成开始，并通过膜单层的局部暴露进行，从而导致稳定和小（高度~16Å）脂质 - 肽复合物。在存在 BaxE5 的情况下观察到的不同类型的膜形态表明该肽可以建立不同类型的膜相互作用。BaxE5 在与膜结合时采用一种罕见的非结构化构象，这可能促进这些不同状态之间的动态转换，进而促进膜消化。