Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates a subset of Rab GTPases
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...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2016-01-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/12813 |
| _version_ | 1811236868620025856 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Martin Steger |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T12:15:29Z |
| format | Article |
| id | doaj.art-409b18202ccc444788ac40f61b9a7b0c |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T12:15:29Z |
| publishDate | 2016-01-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-409b18202ccc444788ac40f61b9a7b0c2022-12-22T03:33:26ZengeLife Sciences Publications LtdeLife2050-084X2016-01-01510.7554/eLife.12813Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates a subset of Rab GTPasesMartin Steger0Francesca Tonelli1Genta Ito2Paul Davies3Matthias Trost4Melanie Vetter5Stefanie Wachter6Esben Lorentzen7Graham Duddy8Stephen Wilson9Marco AS Baptista10Brian K Fiske11Matthew J Fell12John A Morrow13Alastair D Reith14Dario R Alessi15Matthias Mann16Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, GermanyMedical Research Council Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee, United KingdomMedical Research Council Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee, United KingdomMedical Research Council Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee, United KingdomMedical Research Council Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee, United KingdomDepartment of Structural Cell Biology, Max Planck Institute of Biochemistry, Martinsried, GermanyDepartment of Structural Cell Biology, Max Planck Institute of Biochemistry, Martinsried, GermanyDepartment of Structural Cell Biology, Max Planck Institute of Biochemistry, Martinsried, GermanyMolecular Discovery Research, GlaxoSmithKline Pharmaceuticals R&D, Harlow, United KingdomRD Platform Technology and Science, GlaxoSmithKline Pharmaceuticals R&D, Stevenage, United KingdomThe Michael J. Fox Foundation for Parkinson's Research, New York, United StatesThe Michael J. Fox Foundation for Parkinson's Research, New York, United StatesEarly Discovery Neuroscience, Merck Research Laboratories, Boston, United StatesNeuroscience, Merck Research Laboratories, Westpoint, United StatesNeurodegeneration Discovery Performance Unit, GlaxoSmithKline Pharmaceuticals R&D, Stevenage, United KingdomMedical Research Council Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee, United KingdomDepartment of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, GermanyMutations 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.https://elifesciences.org/articles/12813neurodegenerationphosphoproteomicsLRRK2rabschemical proteomicsparkinson-s disease |
| spellingShingle | 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 Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates a subset of Rab GTPases eLife neurodegeneration phosphoproteomics LRRK2 rabs chemical proteomics parkinson-s disease |
| title | Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates a subset of Rab GTPases |
| title_full | Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates a subset of Rab GTPases |
| title_fullStr | Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates a subset of Rab GTPases |
| title_full_unstemmed | Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates a subset of Rab GTPases |
| title_short | Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates a subset of Rab GTPases |
| title_sort | phosphoproteomics reveals that parkinson s disease kinase lrrk2 regulates a subset of rab gtpases |
| topic | neurodegeneration phosphoproteomics LRRK2 rabs chemical proteomics parkinson-s disease |
| url | https://elifesciences.org/articles/12813 |
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