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Structural basis for feedforward control in the PINK1/parkin pathway

Véronique Sauvé, George Sung, Emma MacDougall, Guennadi Kozlov, Anshu Saran, Rayan Fakih, View ORCID ProfileEdward A. Fon, View ORCID ProfileKalle Gehring
doi: https://doi.org/10.1101/2021.08.16.456440
Véronique Sauvé
aDepartment of Biochemistry and Centre de Recherche en Biologie Structurale, McGill University, Montreal, Quebec, Canada
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George Sung
aDepartment of Biochemistry and Centre de Recherche en Biologie Structurale, McGill University, Montreal, Quebec, Canada
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Emma MacDougall
bMcGill Parkinson Program, Neurodegenerative Diseases Group, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
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Guennadi Kozlov
aDepartment of Biochemistry and Centre de Recherche en Biologie Structurale, McGill University, Montreal, Quebec, Canada
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Anshu Saran
aDepartment of Biochemistry and Centre de Recherche en Biologie Structurale, McGill University, Montreal, Quebec, Canada
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Rayan Fakih
aDepartment of Biochemistry and Centre de Recherche en Biologie Structurale, McGill University, Montreal, Quebec, Canada
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Edward A. Fon
bMcGill Parkinson Program, Neurodegenerative Diseases Group, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
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  • ORCID record for Edward A. Fon
Kalle Gehring
aDepartment of Biochemistry and Centre de Recherche en Biologie Structurale, McGill University, Montreal, Quebec, Canada
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  • ORCID record for Kalle Gehring
  • For correspondence: kalle.gehring@mcgill.ca
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ABSTRACT

PINK1 and parkin constitute a mitochondrial quality control system mutated in Parkinson’s disease. PINK1, a kinase, phosphorylates ubiquitin to recruit parkin, an E3 ubiquitin ligase, to mitochondria. PINK1 controls both parkin localization and activity through phosphorylation of both ubiquitin and the ubiquitin-like (Ubl) domain of parkin. Here, we observe that phospho-ubiquitin can bind to two distinct sites on parkin, a high affinity site on RING1 that controls parkin localization, and a low affinity site on RING0 that releases parkin autoinhibition. Surprisingly, NMR titrations and ubiquitin vinyl sulfone assays show that the RING0 site has higher affinity for phospho-ubiquitin than the phosphorylated Ubl. Parkin could be activated by micromolar concentrations of tetra-phospho-ubiquitin chains that mimic a mitochondrion bearing multiple phosphorylated ubiquitins. A chimeric form of parkin with the Ubl domain replaced by ubiquitin was readily activated by PINK1 phosphorylation. In all cases, mutation of the binding site on RING0 abolished parkin activation. The feedforward mechanism of parkin activation confers robustness and rapidity to the PINK1-parkin pathway and likely represents an intermediate step in its evolutionary development.

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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 17, 2021.
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Structural basis for feedforward control in the PINK1/parkin pathway
Véronique Sauvé, George Sung, Emma MacDougall, Guennadi Kozlov, Anshu Saran, Rayan Fakih, Edward A. Fon, Kalle Gehring
bioRxiv 2021.08.16.456440; doi: https://doi.org/10.1101/2021.08.16.456440
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Structural basis for feedforward control in the PINK1/parkin pathway
Véronique Sauvé, George Sung, Emma MacDougall, Guennadi Kozlov, Anshu Saran, Rayan Fakih, Edward A. Fon, Kalle Gehring
bioRxiv 2021.08.16.456440; doi: https://doi.org/10.1101/2021.08.16.456440

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