1. Biochemistry
  2. Biophysics and Structural Biology
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Structure of PINK1 and mechanisms of Parkinson's disease associated mutations

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Cite as: eLife 2017;6:e29985 doi: 10.7554/eLife.29985

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.

Article and author information

Author details

  1. Atul Kumar

    Division of Gene Regulation and Expression, University of Dundee, Dundee, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Jevgenia Tamjar

    MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Andrew D Waddell

    MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Helen I Woodroof

    MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Olawale G Raimi

    Division of Gene Regulation and Expression, University of Dundee, Dundee, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Andrew M Shaw

    MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Mark Peggie

    Division of Signal Transduction Therapy, University of Dundee, Dundee, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Miratul MK Muqit

    MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, United Kingdom
    For correspondence
    m.muqit@dundee.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
  9. Daan MF van Aalten

    Division of Gene Regulation and Expression, University of Dundee, Dundee, United Kingdom
    For correspondence
    dmfvanaalten@dundee.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon 0000-0002-1499-6908

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

  1. Tony Hunter, Reviewing Editor, Salk Institute for Biological Studies, United States

Publication history

  1. Received: June 29, 2017
  2. Accepted: October 4, 2017
  3. Accepted Manuscript published: October 5, 2017 (version 1)

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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