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Membrane association but not identity is required for LRRK2 activation and phosphorylation of Rab GTPases
LRRK2 kinase mutations cause familial Parkinson’s disease and increased phosphorylation of a subset of Rab GTPases. Rab29 recruits LRRK2 to the trans-Golgi and activates it there, yet some of LRRK2’s major Rab substrates are not on the Golgi. We sought to characterize the cell biology of LRRK2 activ...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Rockefeller University Press
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6891090/ https://www.ncbi.nlm.nih.gov/pubmed/31624137 http://dx.doi.org/10.1083/jcb.201902184 |
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author | Gomez, Rachel C. Wawro, Paulina Lis, Pawel Alessi, Dario R. Pfeffer, Suzanne R. |
author_facet | Gomez, Rachel C. Wawro, Paulina Lis, Pawel Alessi, Dario R. Pfeffer, Suzanne R. |
author_sort | Gomez, Rachel C. |
collection | PubMed |
description | LRRK2 kinase mutations cause familial Parkinson’s disease and increased phosphorylation of a subset of Rab GTPases. Rab29 recruits LRRK2 to the trans-Golgi and activates it there, yet some of LRRK2’s major Rab substrates are not on the Golgi. We sought to characterize the cell biology of LRRK2 activation. Unlike other Rab family members, we show that Rab29 binds nucleotide weakly, is poorly prenylated, and is not bound to GDI in the cytosol; nevertheless, Rab29 only activates LRRK2 when it is membrane bound and GTP bound. Mitochondrially anchored, GTP-bound Rab29 is both a LRRK2 substrate and activator, and it drives accumulation of active LRRK2 and phosphorylated Rab10 on mitochondria. Importantly, mitochondrially anchored LRRK2 is much less capable of phosphorylating plasma membrane–anchored Rab10 than soluble LRRK2. These data support a model in which LRRK2 associates with and dissociates from distinct membrane compartments to phosphorylate Rab substrates; if anchored, LRRK2 can modify misdelivered Rab substrates that then become trapped there because GDI cannot retrieve them. |
format | Online Article Text |
id | pubmed-6891090 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-68910902020-06-02 Membrane association but not identity is required for LRRK2 activation and phosphorylation of Rab GTPases Gomez, Rachel C. Wawro, Paulina Lis, Pawel Alessi, Dario R. Pfeffer, Suzanne R. J Cell Biol Research Articles LRRK2 kinase mutations cause familial Parkinson’s disease and increased phosphorylation of a subset of Rab GTPases. Rab29 recruits LRRK2 to the trans-Golgi and activates it there, yet some of LRRK2’s major Rab substrates are not on the Golgi. We sought to characterize the cell biology of LRRK2 activation. Unlike other Rab family members, we show that Rab29 binds nucleotide weakly, is poorly prenylated, and is not bound to GDI in the cytosol; nevertheless, Rab29 only activates LRRK2 when it is membrane bound and GTP bound. Mitochondrially anchored, GTP-bound Rab29 is both a LRRK2 substrate and activator, and it drives accumulation of active LRRK2 and phosphorylated Rab10 on mitochondria. Importantly, mitochondrially anchored LRRK2 is much less capable of phosphorylating plasma membrane–anchored Rab10 than soluble LRRK2. These data support a model in which LRRK2 associates with and dissociates from distinct membrane compartments to phosphorylate Rab substrates; if anchored, LRRK2 can modify misdelivered Rab substrates that then become trapped there because GDI cannot retrieve them. Rockefeller University Press 2019-12-02 2019-10-17 /pmc/articles/PMC6891090/ /pubmed/31624137 http://dx.doi.org/10.1083/jcb.201902184 Text en © 2019 Gomez et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Research Articles Gomez, Rachel C. Wawro, Paulina Lis, Pawel Alessi, Dario R. Pfeffer, Suzanne R. Membrane association but not identity is required for LRRK2 activation and phosphorylation of Rab GTPases |
title | Membrane association but not identity is required for LRRK2 activation and phosphorylation of Rab GTPases |
title_full | Membrane association but not identity is required for LRRK2 activation and phosphorylation of Rab GTPases |
title_fullStr | Membrane association but not identity is required for LRRK2 activation and phosphorylation of Rab GTPases |
title_full_unstemmed | Membrane association but not identity is required for LRRK2 activation and phosphorylation of Rab GTPases |
title_short | Membrane association but not identity is required for LRRK2 activation and phosphorylation of Rab GTPases |
title_sort | membrane association but not identity is required for lrrk2 activation and phosphorylation of rab gtpases |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6891090/ https://www.ncbi.nlm.nih.gov/pubmed/31624137 http://dx.doi.org/10.1083/jcb.201902184 |
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