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Structure of PINK1 reveals autophosphorylation dimer and provides insights into binding to the TOM complex

View ORCID ProfileShafqat Rasool, View ORCID ProfileSimon Veyron, View ORCID ProfileNaoto Soya, View ORCID ProfileMohamed Eldeeb, View ORCID ProfileGergely L. Lukacs, View ORCID ProfileEdward A. Fon, View ORCID ProfileJean-François Trempe
doi: https://doi.org/10.1101/2021.08.05.455304
Shafqat Rasool
1Department of Pharmacology & Therapeutics and Centre de Recherche en Biologie Structurale, McGill University, Montreal, Quebec, Canada
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Simon Veyron
1Department of Pharmacology & Therapeutics and Centre de Recherche en Biologie Structurale, McGill University, Montreal, Quebec, Canada
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Naoto Soya
2Department of Physiology and Centre de Recherche en Biologie Structurale, McGill University, Montreal, Quebec, Canada
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Mohamed Eldeeb
3McGill Parkinson Program and Neurodegenerative Diseases Group, Montreal Neurological Institute and Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada
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Gergely L. Lukacs
2Department of Physiology and Centre de Recherche en Biologie Structurale, McGill University, Montreal, Quebec, Canada
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Edward A. Fon
3McGill Parkinson Program and Neurodegenerative Diseases Group, Montreal Neurological Institute and Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada
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Jean-François Trempe
1Department of Pharmacology & Therapeutics and Centre de Recherche en Biologie Structurale, McGill University, Montreal, Quebec, Canada
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  • For correspondence: jeanfrancois.trempe@mcgill.ca
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Summary

Mutations in PINK1 causes autosomal-recessive Parkinson’s disease. Mitochondrial damage results in PINK1 import arrest on the Translocase of the Outer Mitochondrial Membrane (TOM) complex, resulting in the activation of its ubiquitin kinase activity by autophosphorylation and initiation of Parkin-dependent mitochondrial clearance. Herein we report crystal structures of the entire cytosolic domain of insect PINK1. Our structures reveal a dimeric autophosphorylation complex targeting phosphorylation at the invariant Ser205 (human Ser228). The dimer interface requires insert 2, which is unique to PINK1. The structures also reveal how an N-terminal helix binds to the C-terminal extension and provide insights into stabilization of PINK1 on the core TOM complex.

Competing Interest Statement

J.-F.Trempe is a member of the scientific advisory board of Mitokinin Inc.

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Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted August 05, 2021.
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Structure of PINK1 reveals autophosphorylation dimer and provides insights into binding to the TOM complex
Shafqat Rasool, Simon Veyron, Naoto Soya, Mohamed Eldeeb, Gergely L. Lukacs, Edward A. Fon, Jean-François Trempe
bioRxiv 2021.08.05.455304; doi: https://doi.org/10.1101/2021.08.05.455304
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Structure of PINK1 reveals autophosphorylation dimer and provides insights into binding to the TOM complex
Shafqat Rasool, Simon Veyron, Naoto Soya, Mohamed Eldeeb, Gergely L. Lukacs, Edward A. Fon, Jean-François Trempe
bioRxiv 2021.08.05.455304; doi: https://doi.org/10.1101/2021.08.05.455304

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