Format

Send to

Choose Destination
EMBO J. 2018 Jan 4;37(1):1-18. doi: 10.15252/embj.201798099. Epub 2017 Dec 6.

Rab29 activation of the Parkinson's disease-associated LRRK2 kinase.

Author information

1
MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, UK.
2
Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA.
3
The Michael J. Fox Foundation for Parkinson's Research, New York, NY, USA.
4
MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, UK f.tonelli@dundee.ac.uk pfeffer@stanford.edu d.r.alessi@dundee.ac.uk.
5
Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA f.tonelli@dundee.ac.uk pfeffer@stanford.edu d.r.alessi@dundee.ac.uk.

Abstract

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.

KEYWORDS:

GTPase; Golgi; PARK genes; Rab10; phosphorylation

PMID:
29212815
PMCID:
PMC5753036
DOI:
10.15252/embj.201798099
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center