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Elife. 2016 Jan 29;5. pii: e12813. doi: 10.7554/eLife.12813.

Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates a subset of Rab GTPases.

Author information

1
Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany.
2
Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee, United Kingdom.
3
Department of Structural Cell Biology, Max Planck Institute of Biochemistry, Martinsried, Germany.
4
Molecular Discovery Research, GlaxoSmithKline Pharmaceuticals R&D, Harlow, United Kingdom.
5
RD Platform Technology and Science, GlaxoSmithKline Pharmaceuticals R&D, Stevenage, United Kingdom.
6
The Michael J. Fox Foundation for Parkinson's Research, New York, United States.
7
Early Discovery Neuroscience, Merck Research Laboratories, Boston, United States.
8
Neuroscience, Merck Research Laboratories, Westpoint, United States.
9
Neurodegeneration Discovery Performance Unit, GlaxoSmithKline Pharmaceuticals R&D, Stevenage, United Kingdom.

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 threefold. 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.

KEYWORDS:

LRRK2; biochemistry; cell biology; chemical proteomics; human; mouse; neurodegeneration; parkinson-s disease; phosphoproteomics; rabs

PMID:
26824392
PMCID:
PMC4769169
DOI:
10.7554/eLife.12813
[Indexed for MEDLINE]
Free PMC Article

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