Mitochondrial outer membrane permeabilization, which is a critical step in apoptosis, is initiated upon transmembrane insertion of the C-terminal α-helix (α9) of the pro-apoptotic Bcl-2 family protein BAX. The isolated α9 fragment (residues 173-192) is also competent to disrupt model membranes, and the structures of its membrane-associated oligomers are of interest in understanding the potential roles of this sequence in apoptosis. Here, we used ultrafast two-dimensional infrared (2D IR) spectroscopy, thioflavin T binding, and transmission electron microscopy to show that the synthetic BAX α9 peptide (α9p) forms amyloid aggregates in solution and on the surfaces of anionic small unilamellar vesicles (SUVs). Its inherent amyloidogenicity was predicted by sequence analysis, and 2D IR spectra reveal that SUVs modulate the β-sheet structures of the resulting amyloid species. These results contradict prior models of transmembrane α9p pores and motivate further examination of the formation or suppression of BAX amyloids in apoptosis.

中文翻译：

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人BAXα9（173-192）的膜依赖性淀粉样蛋白聚集

线粒体外膜通透性是细胞凋亡的关键步骤，它是在促细胞凋亡的Bcl-2家族蛋白BAX的C端α-螺旋（α9）跨膜插入后启动的。分离的α9片段（残基173-192）也具有破坏模型膜的能力，并且其膜相关寡聚物的结构对于了解该序列在凋亡中的潜在作用也很重要。在这里，我们使用超快二维红外（2D IR）光谱，硫黄素T结合和透射电子显微镜显示合成的BAXα9肽（α9p）在溶液中以及阴离子小单层囊泡（SUVs）的表面上形成淀粉样聚集体。 ）。通过序列分析可以预测其固有的淀粉样蛋白形成性，和2D IR光谱表明SUV可以调节所得淀粉样蛋白的β-折叠结构。这些结果与跨膜α9p孔的先前模型相矛盾，并促使进一步检查凋亡中BAX淀粉样蛋白的形成或抑制。