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

Kumar, A. et al. (2015) Disruption of the autoinhibited state primes the E3 ligase parkin for activation and catalysis. EMBO Journal, 34(20), pp. 2506-2521. (doi: 10.15252/embj.201592337) (PMID:26254304) (PMCID:PMC4609183)

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The PARK2 gene is mutated in 50% of autosomal recessive juvenile parkinsonism (ARJP) cases. It encodes parkin, an E3 ubiquitin ligase of the RBR family. Parkin exists in an autoinhibited state that is activated by phosphorylation of its N‐terminal ubiquitin‐like (Ubl) domain and binding of phosphoubiquitin. We describe the 1.8 Å crystal structure of human parkin in its fully inhibited state and identify the key interfaces to maintain parkin inhibition. We identify the phosphoubiquitin‐binding interface, provide a model for the phosphoubiquitin–parkin complex and show how phosphorylation of the Ubl domain primes parkin for optimal phosphoubiquitin binding. Furthermore, we demonstrate that the addition of phosphoubiquitin leads to displacement of the Ubl domain through loss of structure, unveiling a ubiquitin‐binding site used by the E2~Ub conjugate, thus leading to active parkin. We find the role of the Ubl domain is to prevent parkin activity in the absence of the phosphorylation signals, and propose a model for parkin inhibition, optimization for phosphoubiquitin recruitment, release of inhibition by the Ubl domain and engagement with an E2~Ub conjugate. Taken together, this model provides a mechanistic framework for activating parkin.

Item Type:Articles
Additional Information:This work was supported by Cancer Research UK (A17739), the EMBO Young Investigator Programme and the Medical Research Council (HW), and by a Burroughs Wellcome Fund Collaborative Research Travel Grant (GSS, HW).
Glasgow Author(s) Enlighten ID:Chaugule, Dr Viduth and Walden, Professor Helen
Authors: Kumar, A., Aguirre, J. D., Condos, T. E.C., Martinez-Torres, R. J., Chaugule, V. K., Toth, R., Sundaramoorthy, R., Mercier, P., Knebel, A., Spratt, D. E., Barber, K. R., Shaw, G. S., and Walden, H.
College/School:College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
Journal Name:EMBO Journal
Publisher:EMBO Press
ISSN (Online):1460-2075
Published Online:07 August 2015
Copyright Holders:Copyright © 2015 The Authors
First Published:First published in EMBO Journal 34(20):2506-2521
Publisher Policy:Reproduced under a Creative Commons License

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