Inducible fold‐switching as a mechanism to fibrillate pro‐apoptotic BCL‐2 proteins. Issue 10 (25th March 2021)

• Record Type: Journal Article
• Authors: Morris, Daniel L.; Tjandra, Nico
• Other Names: LiWang Andy guestEditor.; Porter Lauren L. guestEditor.; Wang Lee‐Ping guestEditor.
• Is Part Of: Biopolymers. Volume 112:Issue 10(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-03-25
• Subjects: amyloid -- apoptosis -- BAX -- BID -- conformational change -- electron microscopy -- fibrils -- fold‐switching -- humanin -- mitochondrial outer membrane permeabilization -- β‐sheet; Biopolymers -- Periodicals; Peptides -- Periodicals; Spectrum analysis -- Periodicals; 572.33
• DOI: 10.1002/bip.23424
• Languages: English
• ISSNs: 0006-3525

Abstract

Abstract: 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. Abstract :