1. Biochemistry
  2. Cell Biology
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Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates a subset of Rab GTPases

  1. Martin Steger
  2. Francesca Tonelli
  3. Genta Ito
  4. Paul Davies
  5. Matthias Trost
  6. Melanie Vetter
  7. Stefanie Wachter
  8. Esben Lorentzen
  9. Graham Duddy
  10. Stephen Wilson
  11. Marco AS Baptista
  12. Brian K Fiske
  13. Matthew J Fell
  14. John A Morrow
  15. Alastair D Reith
  16. Dario R Alessi
  17. Matthias Mann Is a corresponding author
  1. Max Planck Institute of Biochemistry, Germany
  2. University of Dundee, United Kingdom
  3. The Wellcome Trust Sanger Institute, United Kingdom
  4. GlaxoSmithKline Pharmaceuticals R&D, United Kingdom
  5. The Michael J. Fox Foundation for Parkinson's Research, United States
  6. Merck Research Laboratories, United States
Research Article
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Cite as: eLife 2016;5:e12813 doi: 10.7554/eLife.12813

Abstract

Mutations in Park8, encoding for the multidomain Leucine-rich repeat kinase 2 (LRRK2) protein, comprise the predominant genetic cause of Parkinson's disease (PD). G2019S, the most common amino acid substitution activates the kinase two to three-fold. This has motivated the development of LRRK2 kinase inhibitors; however, poor consensus on physiological LRRK2 substrates has hampered clinical development of such therapeutics. We employ a combination of phosphoproteomics, genetics and pharmacology to unambiguously identify a subset of Rab GTPases as key LRRK2 substrates. LRRK2 directly phosphorylates these both in vivo and in vitro on an evolutionary conserved residue in the switch II domain. Pathogenic LRRK2 variants mapping to different functional domains increase phosphorylation of Rabs and this strongly decreases their affinity to regulatory proteins including Rab GDP dissociation inhibitors (GDIs). Our findings uncover a key class of bona-fide LRRK2 substrates and a novel regulatory mechanism of Rabs that connects them to PD.

Article and author information

Author details

  1. Martin Steger

    1. Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany
    Competing interests
    No competing interests declared.
  2. Francesca Tonelli

    1. Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee, United Kingdom
    Competing interests
    No competing interests declared.
  3. Genta Ito

    1. Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee, United Kingdom
    Competing interests
    No competing interests declared.
  4. Paul Davies

    1. Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee, United Kingdom
    Competing interests
    No competing interests declared.
  5. Matthias Trost

    1. Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee, United Kingdom
    Competing interests
    No competing interests declared.
  6. Melanie Vetter

    1. Department of Structural Cell Biology, Max Planck Institute of Biochemistry, Martinsried, Germany
    Competing interests
    No competing interests declared.
  7. Stefanie Wachter

    1. Department of Structural Cell Biology, Max Planck Institute of Biochemistry, Martinsried, Germany
    Competing interests
    No competing interests declared.
  8. Esben Lorentzen

    1. Department of Structural Cell Biology, Max Planck Institute of Biochemistry, Martinsried, Germany
    Competing interests
    No competing interests declared.
  9. Graham Duddy

    1. The Wellcome Trust Sanger Institute, Hinxton, United Kingdom
    Competing interests
    No competing interests declared.
  10. Stephen Wilson

    1. RD Platform Technology and Science, GlaxoSmithKline Pharmaceuticals R&D, Stevenage, United Kingdom
    Competing interests
    Stephen Wilson, Employees of GlaxoSmithKline, a global healthcare company that may conceivably benefit financially through this publication.
  11. Marco AS Baptista

    1. The Michael J. Fox Foundation for Parkinson's Research, New York, United States
    Competing interests
    No competing interests declared.
  12. Brian K Fiske

    1. The Michael J. Fox Foundation for Parkinson's Research, New York, United States
    Competing interests
    No competing interests declared.
  13. Matthew J Fell

    1. Early Discovery Neuroscience, Merck Research Laboratories, Boston, United States
    Competing interests
    Matthew J Fell, Employee of Merck, a global healthcare company that may conceivably benefit financially through this publication..
  14. John A Morrow

    1. Neuroscience, Merck Research Laboratories, Westpoint, United States
    Competing interests
    John A Morrow, employees of Merck Research Laboratories.
  15. Alastair D Reith

    1. Neurodegeneration Discovery Performance Unit, GlaxoSmithKline Pharmaceuticals R&D, Stevenage, United Kingdom
    Competing interests
    Alastair D Reith, Employee of GlaxoSmithKline, a global healthcare company that may conceivably benefit financially through this publication.
  16. Dario R Alessi

    1. Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee, United Kingdom
    Competing interests
    No competing interests declared.
  17. Matthias Mann

    1. Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany
    For correspondence
    1. mmann@biochem.mpg.de
    Competing interests
    No competing interests declared.

Ethics

Animal experimentation: All animal studies were ethically reviewed and carried out in accordance with Animals (Scientific Procedures) Act 1986, the GSK Policy on the Care, Welfare and Treatment of Animals, regulations set by the University of Dundee and the U.K. Home Office. Animal studies and breeding were approved by the University of Dundee ethical committee and performed under a U.K. Home Office project license.

Reviewing Editor

  1. Ivan Dikic, Reviewing Editor, Goethe University Medical School, Germany

Publication history

  1. Received: November 3, 2015
  2. Accepted: January 21, 2016
  3. Accepted Manuscript published: January 29, 2016 (version 1)
  4. Version of Record published: February 16, 2016 (version 2)

Copyright

© 2016, Steger 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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