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)

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 > School of Molecular Biosciences
• 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

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
301102		Mechanisms of ubiquitin signalling in Parkinson's Disease	Helen Walden	Wellcome Trust (WELLCOTR)	209347/Z/17/Z	Institute of Molecular, Cell & Systems Biology