Structure-guided mutagenesis reveals a hierarchical mechanism of Parkin activation

Matthew Y. Tang, Marta Vranas, Andrea I. Krahn, Shayal Pundlik, Jean- François Trempe () and Edward A. Fon ()
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Matthew Y. Tang: McGill Parkinson Program, Neurodegenerative Diseases Group, Montreal Neurological Institute, McGill University
Marta Vranas: Groupe de Recherche Axé sur la Structure des Protéines, McGill University
Andrea I. Krahn: McGill Parkinson Program, Neurodegenerative Diseases Group, Montreal Neurological Institute, McGill University
Shayal Pundlik: McGill Parkinson Program, Neurodegenerative Diseases Group, Montreal Neurological Institute, McGill University
Jean- François Trempe: Groupe de Recherche Axé sur la Structure des Protéines, McGill University
Edward A. Fon: McGill Parkinson Program, Neurodegenerative Diseases Group, Montreal Neurological Institute, McGill University

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract Parkin and PINK1 function in a common pathway to clear damaged mitochondria. Parkin exists in an auto-inhibited conformation stabilized by multiple interdomain interactions. The binding of PINK1-generated phospho-ubiquitin and the phosphorylation of the ubiquitin-like (Ubl) domain of Parkin at Ser65 release its auto-inhibition, but how and when these events take place in cells remain to be defined. Here we show that mutations that we designed to activate Parkin by releasing the Repressor Element of Parkin (REP) domain, or by disrupting the interface between the RING0:RING2 domains, can completely rescue mutations in the Parkin Ubl that are defective in mitochondrial autophagy. Using a FRET reporter assay we show that Parkin undergoes a conformational change upon phosphorylation that can be mimicked by mutating Trp403 in the REP. We propose a hierarchical model whereby pUb binding on mitochondria enables Parkin phosphorylation, which, in turn, leads to REP removal, E3 ligase activation and mitophagy.

Date: 2017
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DOI: 10.1038/ncomms14697

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