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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.·2019·Journal of Cell Biology
DOI 10.1083/jcb.201902184PMC PMC6891090
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Abstract

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.

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  • RAB29-mediated recruitment stimulates LRRK2 kinase activity and causes accumulation of phospho-RABs in the same membrane compartment, likely because phospho-proteins are unable to be extracted by GDI.

    “Such recruitment stimulates the LRRK2 kinase activity and causes an accumulation of phospho-RABs in the same membrane compartment, likely because the phospho-proteins are unable to be extracted by GDI [56,57].”

    From Distinct Roles for RAB10 and RAB29 in Pathogenic LRRK2-Mediated Endolysosomal Trafficking Alterations (2020) · cites this paper as [57]

  • Most endogenous LRRK2 is not present on the Golgi complex, and phospho-RAB8A/RAB10 is not trapped on the Golgi complex under normal conditions.

    “This is consistent with findings indicating that most endogenous LRRK2 is not present on the Golgi complex, and that phospho-RAB8A/RAB10 is not trapped on the Golgi complex under normal conditions either [39,55,57].”

    From Distinct Roles for RAB10 and RAB29 in Pathogenic LRRK2-Mediated Endolysosomal Trafficking Alterations (2020) · cites this paper as [57]

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Research works printed but not linked: 36

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Metadata

Authors
Gomez, R. C., Wawro, P., Lis, P., Alessi, D. R., & Pfeffer, S. R.
Affiliations
  • Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 1
  • Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, UK 2
ORCID
Venue
Journal of Cell Biology
Publisher
Rockefeller University Press
Published
2019-10-17
Volume
218
Issue
12
Pages
4157-4170
ISSN
  • 0021-9525
  • 1540-8140
DOI
10.1083/jcb.201902184
PMC
PMC6891090
Cited by
111
References
2
Language
en
Licence
Funders
  • National Institutes of Health (DK37332)
  • Michael J. Fox Foundation for Parkinson’s Research
  • Medical Research Council (MC_UU_12016/2)
  • National Science Foundation (DGE-114747)

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