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; Matthias Mann

doi:10.7554/eLife.12813

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)

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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 language	English
Article number	e12813
Pages (from-to)	1-28
Number of pages	28
Journal	eLife
Volume	5
DOIs	https://doi.org/10.7554/eLife.12813
Publication status	Published - 29 Jan 2016

ASJC Scopus subject areas

General Biochemistry,Genetics and Molecular Biology
General Immunology and Microbiology
General Medicine
General Neuroscience

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10.7554/eLife.12813Licence: CC BY

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© 2016, Steger et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Final published version, 4.2 MBLicence: CC BY

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Steger, M., Tonelli, F., Ito, G., Davies, P., Trost, M., Vetter, M., Wachter, S., Lorentzen, E., Duddy, G., Wilson, S., Baptista, M. A. S., Fiske, B. K., Fell, M. J., Morrow, J. A., Reith, A. D., Alessi, D. R., & Mann, M. (2016). Phosphoproteomics reveals that Parkinson’s disease kinase LRRK2 regulates a subset of Rab GTPases. eLife, 5, 1-28. Article e12813. https://doi.org/10.7554/eLife.12813

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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{\textquoteright}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.",

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

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AU - Steger, Martin

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AU - Trost, Matthias

AU - Vetter, Melanie

AU - Wachter, Stefanie

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AU - Duddy, Graham

AU - Wilson, Stephen

AU - Baptista, Marco A S

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AU - Mann, Matthias

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

Abstract

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Role of fbx07 in Parkinson's Disease (Studentship)

Aref#d: 21286. Mass Spectrometry-Based Global Analysis of Protein Phosphorylation in Cells and Tissue Extracts with Altered PINK1 Catalytic Activity: A Novel Screen for PINK1 Substrates

Alessi, Dario

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

Abstract

ASJC Scopus subject areas

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Role of fbx07 in Parkinson's Disease (Studentship)

Aref#d: 21286. Mass Spectrometry-Based Global Analysis of Protein Phosphorylation in Cells and Tissue Extracts with Altered PINK1 Catalytic Activity: A Novel Screen for PINK1 Substrates

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Alessi, Dario

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