Disruption of the autoinhibited state primes the E3 ligase parkin for activation and catalysis

• DOI: 10.15252/embj.201592337
• Publication Date: 2015-08-08T02:09:19Z
• Authors: Atul Kumar; Jacob D Aguirre; Tara EC Condos; R Julio Martinez‐...; Viduth K Chaugule; Rachel Toth; Ramasubramanian S...; Pascal Mercier; Axel Knebel; Donald E Spratt; Kathryn R Barber; Gary S Shaw; Helen Walden
• Keywords: HEK 293 cells

Abstract The PARK 2 gene is mutated in 50% of autosomal recessive juvenile parkinsonism ( ARJP ) cases. It encodes parkin, an E3 ubiquitin ligase the RBR family. Parkin exists autoinhibited state that activated by phosphorylation its N‐terminal ubiquitin‐like (Ubl) domain and binding phosphoubiquitin. We describe 1.8 Å crystal structure human parkin fully inhibited identify key interfaces to maintain inhibition. phosphoubiquitin‐binding interface, provide a model for phosphoubiquitin–parkin complex show how Ubl primes optimal phosphoubiquitin binding. Furthermore, we demonstrate addition leads displacement through loss structure, unveiling ubiquitin‐binding site used E2~Ub conjugate, thus leading active parkin. find role prevent activity absence signals, propose inhibition, optimization recruitment, release inhibition engagement with conjugate. Taken together, this provides mechanistic framework activating