Inducible fold-switching as a mechanism to fibrillate pro-apoptotic BCL-2 proteins.

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.