BIM is a key apoptotic protein, participating in diverse cellular processes. Interestingly, recent studies have hypothesized that BIM is associated with the extensive neuronal cell death encountered in protein misfolding diseases, such as Alzheimer’s disease. Here, we report that the core pro-apoptotic domain of BIM, the BIM-BH3 motif, forms ubiquitous amyloid fibrils. The BIM-BH3 fibrils exhibit cytotoxicity, disrupt mitochondrial functions, and modulate the structures and dynamics of mitochondrial membrane mimics. Interestingly, a slightly longer peptide in which BIM-BH3 was flanked by four additional residues, widely employed as a model of the pro-apoptotic core domain of BIM, did not form fibrils, nor exhibited cell disruptive properties. The experimental data suggest a new mechanistic role for the BIM-BH3 domain, and demonstrate, for the first time, that an apoptotic peptide forms toxic amyloid fibrils.

BIM 是一种关键的凋亡蛋白，参与多种细胞过程。有趣的是，最近的研究假设 BIM 与蛋白质错误折叠疾病（例如阿尔茨海默病）中遇到的广泛神经元细胞死亡有关。在这里，我们报告 BIM 的核心促凋亡结构域 BIM-BH3 基序形成普遍存在的淀粉样原纤维。 BIM-BH3 原纤维表现出细胞毒性，破坏线粒体功能，并调节线粒体膜模拟物的结构和动力学。有趣的是，一种稍长的肽（其中 BIM-BH3 两侧有四个附加残基）被广泛用作 BIM 促凋亡核心结构域的模型，它不会形成原纤维，也不会表现出细胞破坏特性。实验数据表明 BIM-BH3 结构域具有新的机制作用，并首次证明凋亡肽形成有毒的淀粉样原纤维。