Cargando…

Rab29 activation of the Parkinson's disease‐associated LRRK2 kinase

Parkinson's disease predisposing LRRK2 kinase phosphorylates a group of Rab GTPase proteins including Rab29, within the effector‐binding switch II motif. Previous work indicated that Rab29, located within the PARK16 locus mutated in Parkinson's patients, operates in a common pathway with L...

Descripción completa

Detalles Bibliográficos
Autores principales: Purlyte, Elena, Dhekne, Herschel S, Sarhan, Adil R, Gomez, Rachel, Lis, Pawel, Wightman, Melanie, Martinez, Terina N, Tonelli, Francesca, Pfeffer, Suzanne R, Alessi, Dario R
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5753036/
https://www.ncbi.nlm.nih.gov/pubmed/29212815
http://dx.doi.org/10.15252/embj.201798099
_version_ 1783290193627840512
author Purlyte, Elena
Dhekne, Herschel S
Sarhan, Adil R
Gomez, Rachel
Lis, Pawel
Wightman, Melanie
Martinez, Terina N
Tonelli, Francesca
Pfeffer, Suzanne R
Alessi, Dario R
author_facet Purlyte, Elena
Dhekne, Herschel S
Sarhan, Adil R
Gomez, Rachel
Lis, Pawel
Wightman, Melanie
Martinez, Terina N
Tonelli, Francesca
Pfeffer, Suzanne R
Alessi, Dario R
author_sort Purlyte, Elena
collection PubMed
description Parkinson's disease predisposing LRRK2 kinase phosphorylates a group of Rab GTPase proteins including Rab29, within the effector‐binding switch II motif. Previous work indicated that Rab29, located within the PARK16 locus mutated in Parkinson's patients, operates in a common pathway with LRRK2. Here, we show that Rab29 recruits LRRK2 to the trans‐Golgi network and greatly stimulates its kinase activity. Pathogenic LRRK2 R1441G/C and Y1699C mutants that promote GTP binding are more readily recruited to the Golgi and activated by Rab29 than wild‐type LRRK2. We identify conserved residues within the LRRK2 ankyrin domain that are required for Rab29‐mediated Golgi recruitment and kinase activation. Consistent with these findings, knockout of Rab29 in A549 cells reduces endogenous LRRK2‐mediated phosphorylation of Rab10. We show that mutations that prevent LRRK2 from interacting with either Rab29 or GTP strikingly inhibit phosphorylation of a cluster of highly studied biomarker phosphorylation sites (Ser910, Ser935, Ser955 and Ser973). Our data reveal that Rab29 is a master regulator of LRRK2, controlling its activation, localization, and potentially biomarker phosphorylation.
format Online
Article
Text
id pubmed-5753036
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher John Wiley and Sons Inc.
record_format MEDLINE/PubMed
spelling pubmed-57530362018-01-05 Rab29 activation of the Parkinson's disease‐associated LRRK2 kinase Purlyte, Elena Dhekne, Herschel S Sarhan, Adil R Gomez, Rachel Lis, Pawel Wightman, Melanie Martinez, Terina N Tonelli, Francesca Pfeffer, Suzanne R Alessi, Dario R EMBO J Articles Parkinson's disease predisposing LRRK2 kinase phosphorylates a group of Rab GTPase proteins including Rab29, within the effector‐binding switch II motif. Previous work indicated that Rab29, located within the PARK16 locus mutated in Parkinson's patients, operates in a common pathway with LRRK2. Here, we show that Rab29 recruits LRRK2 to the trans‐Golgi network and greatly stimulates its kinase activity. Pathogenic LRRK2 R1441G/C and Y1699C mutants that promote GTP binding are more readily recruited to the Golgi and activated by Rab29 than wild‐type LRRK2. We identify conserved residues within the LRRK2 ankyrin domain that are required for Rab29‐mediated Golgi recruitment and kinase activation. Consistent with these findings, knockout of Rab29 in A549 cells reduces endogenous LRRK2‐mediated phosphorylation of Rab10. We show that mutations that prevent LRRK2 from interacting with either Rab29 or GTP strikingly inhibit phosphorylation of a cluster of highly studied biomarker phosphorylation sites (Ser910, Ser935, Ser955 and Ser973). Our data reveal that Rab29 is a master regulator of LRRK2, controlling its activation, localization, and potentially biomarker phosphorylation. John Wiley and Sons Inc. 2017-12-06 2018-01-04 /pmc/articles/PMC5753036/ /pubmed/29212815 http://dx.doi.org/10.15252/embj.201798099 Text en © 2017 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the Creative Commons Attribution 4.0 (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Articles
Purlyte, Elena
Dhekne, Herschel S
Sarhan, Adil R
Gomez, Rachel
Lis, Pawel
Wightman, Melanie
Martinez, Terina N
Tonelli, Francesca
Pfeffer, Suzanne R
Alessi, Dario R
Rab29 activation of the Parkinson's disease‐associated LRRK2 kinase
title Rab29 activation of the Parkinson's disease‐associated LRRK2 kinase
title_full Rab29 activation of the Parkinson's disease‐associated LRRK2 kinase
title_fullStr Rab29 activation of the Parkinson's disease‐associated LRRK2 kinase
title_full_unstemmed Rab29 activation of the Parkinson's disease‐associated LRRK2 kinase
title_short Rab29 activation of the Parkinson's disease‐associated LRRK2 kinase
title_sort rab29 activation of the parkinson's disease‐associated lrrk2 kinase
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5753036/
https://www.ncbi.nlm.nih.gov/pubmed/29212815
http://dx.doi.org/10.15252/embj.201798099
work_keys_str_mv AT purlyteelena rab29activationoftheparkinsonsdiseaseassociatedlrrk2kinase
AT dhekneherschels rab29activationoftheparkinsonsdiseaseassociatedlrrk2kinase
AT sarhanadilr rab29activationoftheparkinsonsdiseaseassociatedlrrk2kinase
AT gomezrachel rab29activationoftheparkinsonsdiseaseassociatedlrrk2kinase
AT lispawel rab29activationoftheparkinsonsdiseaseassociatedlrrk2kinase
AT wightmanmelanie rab29activationoftheparkinsonsdiseaseassociatedlrrk2kinase
AT martinezterinan rab29activationoftheparkinsonsdiseaseassociatedlrrk2kinase
AT tonellifrancesca rab29activationoftheparkinsonsdiseaseassociatedlrrk2kinase
AT pfeffersuzanner rab29activationoftheparkinsonsdiseaseassociatedlrrk2kinase
AT alessidarior rab29activationoftheparkinsonsdiseaseassociatedlrrk2kinase