Neurodegenerative diseases often are associated with cellular dysregulation that results in premature cell death or apoptosis. A common example is the accumulation of amyloid plaques that promotes the excessive expression of p38 mitogen-activated protein kinase. The increased abundance of this enzyme leads to mass phosphorylation and activation of a protein from the B-cell lymphoma 2 (BCL-2) family, BAX. BAX is the central regulatory protein for mitochondrial outer membrane permeabilization (MOMP), a poration process that commits cells to apoptosis by releasing death-propagating factors from the mitochondria. Recent reports identify a naturally occurring peptide, Humanin (HN), that could block amyloid-beta-associated neuronal apoptosis by interacting with BCL-2 proteins. We recently showed humanin interaction leads to the amyloid-like fibrillation of BAX and a second BCL-2 family member, BID. We proposed this as a novel anti-apoptotic mechanism that inhibits pro-apoptotic BCL-2 proteins from initiating MOMP by sequestering them into fibrils, a heretofore unprecedented phenomenon that involves refolding globular BCL-2 proteins rapidly into fibrils where they undergo significant alpha-helix to beta-sheet fold-switching. Here we seek to further characterize the fibrillation and fold-switch in conditions that are known to induce amyloid fibrillation.

中文翻译：

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诱导型折叠转换作为原纤维化促凋亡 BCL-2 蛋白的机制

神经退行性疾病通常与导致细胞过早死亡或凋亡的细胞失调有关。一个常见的例子是淀粉样斑块的积累，它促进了 p38 丝裂原活化蛋白激酶的过度表达。这种酶的丰度增加导致来自 B 细胞淋巴瘤 2 (BCL-2) 家族的蛋白质 BAX 的大量磷酸化和活化。BAX 是线粒体外膜透化 (MOMP) 的中心调节蛋白，MOMP 是一种通过从线粒体释放死亡传播因子来使细胞凋亡的穿孔过程。最近的报告确定了一种天然存在的肽 Humanin (HN)，它可以通过与 BCL-2 蛋白相互作用来阻断淀粉样蛋白-β 相关的神经元凋亡。我们最近表明，humanin 相互作用导致 BAX 和第二个 BCL-2 家族成员 BID 的淀粉样蛋白样纤颤。我们提出这是一种新的抗凋亡机制，通过将促凋亡 BCL-2 蛋白隔离成原纤维来抑制促凋亡 BCL-2 蛋白启动 MOMP，这是迄今为止前所未有的现象，涉及将球状 BCL-2 蛋白迅速重新折叠成原纤维，在那里它们经历显着的 α-螺旋到β-折叠折叠切换。在这里，我们寻求进一步表征已知诱导淀粉样蛋白纤颤的条件下的纤颤和折叠转换。一种前所未有的现象，涉及将球状 BCL-2 蛋白快速重新折叠成原纤维，在那里它们经历显着的 α-螺旋到 β-折叠折叠转换。在这里，我们寻求进一步表征已知诱导淀粉样蛋白纤颤的条件下的纤颤和折叠转换。一种前所未有的现象，涉及将球状 BCL-2 蛋白快速重新折叠成原纤维，在那里它们经历显着的 α-螺旋到 β-折叠折叠转换。在这里，我们寻求进一步表征已知诱导淀粉样蛋白纤颤的条件下的纤颤和折叠转换。