Dissecting the Activation Pathway of Pro-Apoptotic BAX: Mechanistic Insights and Pharmacologic Opportunities.

Abstract 768

BAX is a pro-apoptotic BCL-2 family member that lies dormant in the cytosol until converted into a killer protein in response to cellular stress. We previously identified an elusive trigger site that mediates BH3-induced direct BAX activation. The continuum of conformational changes that transforms ligand-triggered BAX into a lethal mitochondrial homooligomer remains undefined. Here, we apply NMR and chemical biology methodologies to characterize the key structural alterations and corresponding functional consequences that comprise the direct BAX activation mechanism. Our structure-function analysis reveals a cascade of dynamic changes involving the N-terminal loop, C-terminal helix, and BH3 domain, which convert BAX from an inactive monomer into a toxic oligomer. Our dissection of this seminal pro-apoptotic process highlights new pharmacologic opportunities to modulate cell death in hematologic malignancy by influencing key steps of the BAX activation pathway.