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 As 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 As Baptista, Brian K Fiske, Matthew J Fell, John A Morrow, Alastair D Reith, Dario R Alessi, Matthias Mann

380 Citations (Scopus)

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
Journal	eLife
Volume	5
ISSN	2050-084X
DOIs	https://doi.org/10.7554/elife.12813
Publication status	Published - 29 Jan 2016
Externally published	Yes

Keywords

Animals
Gene Expression Regulation
Humans
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
Mice, Knockout
Parkinson Disease
Protein Processing, Post-Translational
Proteome
rab GTP-Binding Proteins
Journal Article
Research Support, Non-U.S. Gov't

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http://europepmc.org/articles/pmc4769169?pdf=renderLicence: 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., 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. https://doi.org/10.7554/elife.12813

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title = "Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates a subset of Rab GTPases",

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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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 As} 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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T1 - Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates a subset of Rab GTPases

AU - Steger, Martin

AU - Tonelli, Francesca

AU - Ito, Genta

AU - Davies, Paul

AU - Trost, Matthias

AU - Vetter, Melanie

AU - Wachter, Stefanie

AU - Lorentzen, Esben

AU - Duddy, Graham

AU - Wilson, Stephen

AU - Baptista, Marco As

AU - Fiske, Brian K

AU - Fell, Matthew J

AU - Morrow, John A

AU - Reith, Alastair D

AU - Alessi, Dario R

AU - Mann, Matthias

PY - 2016/1/29

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N2 - 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.

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.

KW - Animals

KW - Gene Expression Regulation

KW - Humans

KW - Leucine-Rich Repeat Serine-Threonine Protein Kinase-2

KW - Mice, Knockout

KW - Parkinson Disease

KW - Protein Processing, Post-Translational

KW - Proteome

KW - rab GTP-Binding Proteins

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.7554/elife.12813

DO - 10.7554/elife.12813

M3 - Journal article

C2 - 26824392

SN - 2050-084X

VL - 5

JO - eLife

JF - eLife

ER -

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

Abstract

Keywords

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