A mechanistic review of Parkin activation

Gundogdu, M., Tadayon, R., Salzano, G. , Shaw, G. S. and Walden, H. (2021) A mechanistic review of Parkin activation. Biochimica et Biophysica Acta. General Subjects, 1865(6), 129894. (doi: 10.1016/j.bbagen.2021.129894) (PMID:33753174)

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Abstract

Parkin and phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1) constitute a feed-forward signalling pathway that mediates autophagic removal of damaged mitochondria (mitophagy). With over 130 mutations identified to date in over 1000 patients with early onset parkinsonism, Parkin is considered a hot spot of signalling pathways involved in PD aetiology. Parkin is an E3 ligase and how its activity is regulated has been extensively studied: inter-domain interactions exert a tight inhibition on Parkin activity; binding to phospho-ubiquitin relieves this auto-inhibition; and phosphorylation of Parkin shifts the equilibrium towards maximal Parkin activation. This review focusses on recent, structural findings on the regulation of Parkin activity. What follows is a mechanistic introduction to the family of E3 ligases that includes Parkin, followed by a brief description of structural elements unique to Parkin that lock the enzyme in an autoinhibited state, contrasted with emerging models that have shed light on possible mechanisms of Parkin activation.

Item Type:Articles
Additional Information:GSS was funded by Canadian Institutes of Health Research (CIHR) - PJT-166019. HW was funded by Wellcome Trust Investigator Award (209347/Z/17/Z)
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Salzano, Dr Giulia and Tadayon, Dr Roya and Gundogdu, Dr Mehmet and Walden, Professor Helen
Authors: Gundogdu, M., Tadayon, R., Salzano, G., Shaw, G. S., and Walden, H.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:Biochimica et Biophysica Acta. General Subjects
Publisher:Elsevier
ISSN:0304-4165
ISSN (Online):1872-8006
Published Online:20 March 2021
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in Biochimica et Biophysica Acta. General Subjects 1865(6):129894
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
301102Mechanisms of ubiquitin signalling in Parkinson's DiseaseHelen WaldenWellcome Trust (WELLCOTR)209347/Z/17/ZInstitute of Molecular, Cell & Systems Biology