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

Steger, M., Tonelli, F., Ito, G., Davies, P., Trost, M., Vetter, M., et al. (2016). Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates a subset of Rab GTPases. ELIFE, 5: e12813. doi:10.7554/eLife.12813.

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 Creators:
Steger, Martin1, Author              
Tonelli, Francesca2, Author
Ito, Genta2, Author
Davies, Paul2, Author
Trost, Matthias2, Author
Vetter, Melanie3, Author              
Wachter, Stefanie3, Author              
Lorentzen, Esben3, Author              
Duddy, Graham2, Author
Wilson, Stephen2, Author
Baptista, Marco A. S.2, Author
Fiske, Brian K.2, Author
Fell, Matthew J.2, Author
Morrow, John A.2, Author
Reith, Alastair D.2, Author
Alessi, Dario R.2, Author
Mann, Matthias1, Author              
Affiliations:
1Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565159              
2external, ou_persistent22              
3Lorentzen, Esben / Intraflagellar Transport, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565157              

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Free keywords: GENOME-WIDE ASSOCIATION; ALPHA-SYNUCLEIN; IN-VIVO; CYTOPLASMIC LOCALIZATION; DOPAMINERGIC-NEURONS; 14-3-3 BINDING; PROTEIN; PHOSPHORYLATES; MUTATIONS; NEURODEGENERATION
 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.

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Language(s): eng - English
 Dates: 2016
 Publication Status: Published online
 Pages: 28
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: ISI: 000373801500001
DOI: 10.7554/eLife.12813
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Title: ELIFE
Source Genre: Journal
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Publ. Info: SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND : ELIFE SCIENCES PUBLICATIONS LTD
Pages: - Volume / Issue: 5 Sequence Number: e12813 Start / End Page: - Identifier: ISSN: 2050-084X