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

Elena Purlyte, Herschel S. Dhekne, Adil R. Sarhan, Rachel Gomez, Pawel Lis, Melanie Wightman, Terina N. Martinez, Francesca Tonelli (Lead / Corresponding author), Suzanne R. Pfeffer (Lead / Corresponding author), Dario R. Alessi (Lead / Corresponding author)

Research output: Contribution to journalArticle

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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.
Original languageEnglish
Article numbere201798099
Pages (from-to)3549-3681
Number of pages18
JournalEMBO Journal
Volume36
Issue number24
Early online date6 Dec 2017
DOIs
Publication statusPublished - 15 Dec 2017

Fingerprint

Phosphorylation
Parkinson Disease
Phosphotransferases
Chemical activation
Biomarkers
Guanosine Triphosphate
rab GTP-Binding Proteins
Ankyrins
Switches
Mutation
Proteins

Keywords

  • Golgi
  • GTPase
  • PARK genes
  • Phosphorylation
  • Rab10

Cite this

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. In: EMBO Journal. 2017 ; Vol. 36, No. 24. pp. 3549-3681.
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Purlyte, E, Dhekne, HS, Sarhan, AR, Gomez, R, Lis, P, Wightman, M, Martinez, TN, Tonelli, F, Pfeffer, SR & Alessi, DR 2017, 'Rab29 activation of the Parkinson's disease-associated LRRK2 kinase', EMBO Journal, vol. 36, no. 24, e201798099, pp. 3549-3681. https://doi.org/10.15252/embj.201798099

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 (Lead / Corresponding author); Pfeffer, Suzanne R. (Lead / Corresponding author); Alessi, Dario R. (Lead / Corresponding author).

In: EMBO Journal, Vol. 36, No. 24, e201798099, 15.12.2017, p. 3549-3681.

Research output: Contribution to journalArticle

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T1 - Rab29 activation of the Parkinson's disease-associated LRRK2 kinase

AU - Purlyte, Elena

AU - Dhekne, Herschel S.

AU - Sarhan, Adil R.

AU - Gomez, Rachel

AU - Lis, Pawel

AU - Wightman, Melanie

AU - Martinez, Terina N.

AU - Tonelli, Francesca

AU - Pfeffer, Suzanne R.

AU - Alessi, Dario R.

N1 - Michael J. Fox Foundation for Parkinson's Research (GrantNumber(s): 6986) Medical Research Council (GrantNumber(s): MC_UU_12016/2) National Institutes of Health (GrantNumber(s): DK37332)

PY - 2017/12/15

Y1 - 2017/12/15

N2 - 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.

AB - 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.

KW - Golgi

KW - GTPase

KW - PARK genes

KW - Phosphorylation

KW - Rab10

U2 - 10.15252/embj.201798099

DO - 10.15252/embj.201798099

M3 - Article

C2 - 29212815

VL - 36

SP - 3549

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JO - EMBO Journal

JF - EMBO Journal

SN - 0261-4189

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Purlyte E, Dhekne HS, Sarhan AR, Gomez R, Lis P, Wightman M et al. Rab29 activation of the Parkinson's disease-associated LRRK2 kinase. EMBO Journal. 2017 Dec 15;36(24):3549-3681. e201798099. https://doi.org/10.15252/embj.201798099