Inhibition of BAK apoptotic activity by Parkin-mediated ubiquitination

Abstract

Abstract BAK permeabilizes mitochondrial outer membrane, resulting in apoptosis. This apoptotic activity of BAK is stimulated by binding prodeath activators and must be tightly controlled, otherwise it leads to cancers or neurodegenerative diseases. The Parkinson's disease-related E3 ubiquitin (Ub) ligase Parkin ubiquitinates BAK and inhibits the apoptotic activity. However, the molecular mechanism of how ubiquitination inhibits BAK remains uncharacterized. Here, we verify the Ub modification at BAK K113 by Parkin, and further resolve the solution structure of K113-ubiquitinated BAK complex. The conjugated Ub subunit employs its classical L8-I44-H68-V70 hydrophobic patch to bind within the canonical hydrophobic groove of BAK. This groove-harbored Ub occludes the binding of prodeath BID activators, impairs BID-triggered BAK activation and membrane permeabilization. Loosing Ub association with BAK allows BID to activate the K113-ubiquitinated BAK. Together with structure and function evidence, our study now provide mechanistic insights into the ubiquitination regulatory modality wherein Parkin targets BAK to fine-tune apoptosis.