2. Academic Validation
  3. Rab29 activation of the Parkinson's disease-associated LRRK2 kinase

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

  • EMBO J. 2018 Jan 4;37(1):1-18. doi: 10.15252/embj.201798099.
Elena Purlyte 1,  Herschel S Dhekne 2,  Adil R Sarhan 1,  Rachel Gomez 2,  Pawel Lis 1,  Melanie Wightman 1,  Terina N Martinez 3,  Francesca Tonelli 4,  Suzanne R Pfeffer 5,  Dario R Alessi 4
Affiliations

Affiliations

  • 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 [email protected] [email protected] [email protected].
  • 5 Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA [email protected] [email protected] [email protected].
PMID: 29212815 DOI: 10.15252/embj.201798099
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.

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