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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·2018·The EMBO Journal
DOI 10.15252/embj.201798099PMC PMC5753036
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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.

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Authors
Purlyte, E., Dhekne, H. S., Sarhan, A. R., Gomez, R., Lis, P., Wightman, M., Martinez, T. N., Tonelli, F., Pfeffer, S. R., & Alessi, D. R.
ORCID
Venue
The EMBO Journal
Publisher
Springer Science and Business Media LLC
Published
2017-12-06
Volume
37
Issue
1
Pages
1-18
ISSN
  • 0261-4189
  • 1460-2075
DOI
10.15252/embj.201798099
PMC
PMC5753036
Cited by
336
References
0
Language
en
Update notices
Licence
Funders
  • Michael J. Fox Foundation for Parkinson's Research (6986)
  • RCUK | Medical Research Council (MC_UU_12016/2)
  • HHS | National Institutes of Health (DK37332)

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