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Synergistic Recruitment of UbcH7~Ub and Phosphorylated Ubl Domain Triggers Parkin Activation

Tara EC Condos, Karen M Dunkerley, E Aisha Freeman, Kathryn Barber, Jacob Aguirre, View ORCID ProfileViduth Chaugule, Yiming Xiao, Lars Konermann, View ORCID ProfileHelen Walden, Gary S. Shaw
doi: https://doi.org/10.1101/344952
Tara EC Condos
University of Western Ontario;
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Karen M Dunkerley
University of Western Ontario;
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E Aisha Freeman
University of Western Ontario;
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Kathryn Barber
University of Western Ontario;
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Jacob Aguirre
University of Western Ontario;
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Viduth Chaugule
Glasgow University;
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Yiming Xiao
University of Western Ontario;
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Lars Konermann
University of Western Ontario;
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Helen Walden
University of Glasgow
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Gary S. Shaw
University of Western Ontario;
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  • For correspondence: gshaw1@uwo.ca
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Abstract

The mechanism of activation and ubiquitin conjugation by the E3 ligase parkin is pivotal to understand the molecular pathology of early-onset Parkinson's disease. Parkin is normally autoinhibited but is activated by the kinase PINK1 that phosphorylates parkin's N-terminal ubiquitin-like (pUbl) domain and ubiquitin. How these alter the structure of parkin to allow recruitment of an E2~Ub conjugate to enhance ubiquitination is an unresolved question. We present the structure of an incoming E2~Ub conjugate with the phospho-ubiquitin bound C-terminus of parkin (R0RBR). We show the UbcH7~Ub conjugate is recruited by R0RBR parkin in the open state whereby conjugated ubiquitin binds to the RING1/IBR interface. Further, NMR experiments indicate there is re-modelling near the RING0/RING2 interface remote from the E2-binding site. This, and parkin phosphorylation lead to rapid reactivity of the RING2(Rcat) catalytic cysteine in parkin, needed for ubiquitin transfer. Parkin phosphorylation also leads to relocation and weak interaction of the pUbl domain with the RING0 domain that is enhanced upon E2~Ub recruitment indicating these events act synergistically to drive parkin activity.

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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 June 12, 2018.
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Synergistic Recruitment of UbcH7~Ub and Phosphorylated Ubl Domain Triggers Parkin Activation
Tara EC Condos, Karen M Dunkerley, E Aisha Freeman, Kathryn Barber, Jacob Aguirre, Viduth Chaugule, Yiming Xiao, Lars Konermann, Helen Walden, Gary S. Shaw
bioRxiv 344952; doi: https://doi.org/10.1101/344952
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Synergistic Recruitment of UbcH7~Ub and Phosphorylated Ubl Domain Triggers Parkin Activation
Tara EC Condos, Karen M Dunkerley, E Aisha Freeman, Kathryn Barber, Jacob Aguirre, Viduth Chaugule, Yiming Xiao, Lars Konermann, Helen Walden, Gary S. Shaw
bioRxiv 344952; doi: https://doi.org/10.1101/344952

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