Phosphoproteomics reveals that Parkinson’s disease kinase LRRK2 regulates a subset of Rab GTPases Martin Steger1, Francesca Tonelli2, Genta Ito2, Paul Davies2, Matthias Trost2, Melanie Vetter3, Stefanie Wachter3, Esben Lorentzen3, Graham Duddy4,ǂ, Stephen Wilson5, Marco A. S. Baptista6, Brian K. Fiske6, Matthew J. Fell7, John A. Morrow8, Alastair D. Reith9, Dario R. Alessi2,* and Matthias Mann1,* 1Department of Proteomics and Signal Transduction, Max-Planck-Institute of Biochemistry, Martinsried, Germany 2Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK 3Department of Structural Cell Biology, Max-Planck-Institute of Biochemistry, Martinsried, Germany 4Molecular Discovery Research, GlaxoSmithKline Pharmaceuticals R&D, New Frontiers Science Park, Harlow, Essex CM19 5AD, UK 5RD Platform Technology & Science, GlaxoSmithKline Pharmaceuticals R&D, Medicines Research Centre, Stevenage, UK 6The Michael J. Fox Foundation for Parkinson’s Research, Grand Central Station, P.O. Box 4777, New York, NY 10163, USA 7Merck Research Laboratories, Early Discovery Neuroscience, Boston, MA, 02115 USA 8Merck Research Laboratories, Neuroscience, West Point, PA, 19486 USA 9Neurodegeneration Discovery Performance Unit, RD Neurosciences, GlaxoSmithKline Pharmaceuticals R&D, Stevenage, UK ǂPresent address: The Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK * Correspondence to D.R.A. (
[email protected]) or M.M. (
[email protected]) 1 1 Abstract 2 Mutations in Park8, encoding for the multidomain Leucine-rich repeat kinase 2 3 (LRRK2) protein, comprise the predominant genetic cause of Parkinson’s disease (PD). 4 G2019S, the most common amino acid substitution activates the kinase two to three- 5 fold. This has motivated the development of LRRK2 kinase inhibitors; however, poor 6 consensus on physiological LRRK2 substrates has hampered clinical development of 7 such therapeutics.