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Elife. 2017 Nov 10;6. pii: e31012. doi: 10.7554/eLife.31012.

Systematic proteomic analysis of LRRK2-mediated Rab GTPase phosphorylation establishes a connection to ciliogenesis.

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, School of Life Sciences, University of Dundee, Dundee, United Kingdom.
3
Department of Biochemistry, Stanford University School of Medicine, Stanford, United States.
4
The Michael J. Fox Foundation for Parkinson's Research, New York, United States.
5
Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
#
Contributed equally

Abstract

We previously reported that Parkinson's disease (PD) kinase LRRK2 phosphorylates a subset of Rab GTPases on a conserved residue in their switch-II domains (Steger et al., 2016) (PMID: 26824392). Here, we systematically analyzed the Rab protein family and found 14 of them (Rab3A/B/C/D, Rab5A/B/C, Rab8A/B, Rab10, Rab12, Rab29, Rab35 and Rab43) to be specifically phosphorylated by LRRK2, with evidence for endogenous phosphorylation for ten of them (Rab3A/B/C/D, Rab8A/B, Rab10, Rab12, Rab35 and Rab43). Affinity enrichment mass spectrometry revealed that the primary ciliogenesis regulator, RILPL1 specifically interacts with the LRRK2-phosphorylated forms of Rab8A and Rab10, whereas RILPL2 binds to phosphorylated Rab8A, Rab10, and Rab12. Induction of primary cilia formation by serum starvation led to a two-fold reduction in ciliogenesis in fibroblasts derived from pathogenic LRRK2-R1441G knock-in mice. These results implicate LRRK2 in primary ciliogenesis and suggest that Rab-mediated protein transport and/or signaling defects at cilia may contribute to LRRK2-dependent pathologies.

KEYWORDS:

LRRK2; Parkinson's disease; Rab GTPases; biochemistry; ciliogenesis; human; mass spectrometry; mouse; proteomics

PMID:
29125462
PMCID:
PMC5695910
DOI:
10.7554/eLife.31012
[Indexed for MEDLINE]
Free PMC Article

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