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

Martin Steger, Francesca Tonelli, Genta Ito, Paul Davies, Matthias Trost, Melanie Vetter, Stefanie Wachter, Esben Lorentzen, Graham Duddy, Stephen Wilson, Marco A S Baptista, Brian K. Fiske, Matthew J. Fell, John A. Morrow, Alastair D. Reith, Dario R. Alessi (Lead / Corresponding author), Matthias Mann (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

368 Citations (Scopus)
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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.

Original languageEnglish
Article numbere12813
Pages (from-to)1-28
Number of pages28
JournaleLife
Volume5
DOIs
Publication statusPublished - 29 Jan 2016

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