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Structure-guided mutagenesis reveals a hierarchical mechanism of Parkin activation

Author

Listed:
  • 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)

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.

Suggested Citation

  • Matthew Y. Tang & Marta Vranas & Andrea I. Krahn & Shayal Pundlik & Jean- François Trempe & Edward A. Fon, 2017. "Structure-guided mutagenesis reveals a hierarchical mechanism of Parkin activation," Nature Communications, Nature, vol. 8(1), pages 1-14, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14697
    DOI: 10.1038/ncomms14697
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    Cited by:

    1. Michael J. Munson & Benan J. Mathai & Matthew Yoke Wui Ng & Laura Trachsel-Moncho & Laura R. Ballina & Sebastian W. Schultz & Yahyah Aman & Alf H. Lystad & Sakshi Singh & Sachin Singh & Jørgen Wesche , 2021. "GAK and PRKCD are positive regulators of PRKN-independent mitophagy," Nature Communications, Nature, vol. 12(1), pages 1-22, December.
    2. Véronique Sauvé & Eric Stefan & Nathalie Croteau & Thomas Goiran & Rayan Fakih & Nupur Bansal & Adelajda Hadzipasic & Jing Fang & Paramasivam Murugan & Shimin Chen & Edward A. Fon & Warren D. Hirst & , 2024. "Activation of parkin by a molecular glue," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

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