Structure of PINK1 and mechanisms of Parkinson's disease associated mutations
- University of Dundee, United Kingdom
Abstract
Mutations in the human kinase PINK1 (hPINK1) are associated with autosomal recessive early-onset Parkinson's disease (PD). hPINK1 activates Parkin E3 ligase activity, involving phosphorylation of ubiquitin and the Parkin ubiquitin-like (Ubl) domain via as yet poorly understood mechanisms. hPINK1 is unusual amongst kinases due to the presence of three loop insertions of unknown function. We report the structure of Tribolium castaneum PINK1 (TcPINK1), revealing several unique extensions to the canonical protein kinase fold. The third insertion, together with autophosphorylation at residue Ser205, contributes to formation of a bowl-shaped binding site for ubiquitin. We also define a novel structural element within the second insertion that is held together by a distal loop that is critical for TcPINK1 activity. The structure of TcPINK1 explains how PD-linked mutations that lie within the kinase domain result in hPINK1 loss-of-function and provides a platform for the exploration of small molecule modulators of hPINK1.
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Article and author information
Author details
Daan MF van Aalten
Funding
Wellcome (110061)
- Daan MF van Aalten
Parkinson's UK (G-1506)
- Miratul MK Muqit
- Daan MF van Aalten
Wellcome (101022/Z/13/Z)
- Miratul MK Muqit
Medical Research Council
- Andrew M Shaw
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Tony Hunter, Salk Institute for Biological Studies, United States
Version history
- Received: June 29, 2017
- Accepted: October 4, 2017
- Accepted Manuscript published: October 5, 2017 (version 1)
- Version of Record published: November 9, 2017 (version 2)
Copyright
© 2017, Kumar et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Structure of PINK1 and mechanisms of Parkinson's disease associated mutations
eLife 6:e29985.
https://doi.org/10.7554/eLife.29985
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