期刊
EMBO JOURNAL
卷 37, 期 1, 页码 1-18出版社
WILEY
DOI: 10.15252/embj.201798099
关键词
Golgi; GTPase; PARK genes; phosphorylation; Rab10
资金
- Medical Research Council [MC_UU_12016/2]
- Boehringer-Ingelheim
- GlaxoSmithKline
- Merck KGaA
- U.S. National Institutes of Health [DK37332]
- Michael J. Fox Foundation for Parkinson's research [6986]
- MRC [MC_UU_12016/2, MC_UU_00018/1] Funding Source: UKRI
- Medical Research Council [1836218, MC_UU_12016/2, MC_UU_00018/1] Funding Source: researchfish
Parkinson's disease predisposing LRRK2 kinase phosphorylates a group of Rab GTPase proteins including Rab29, within the effect-orbinding 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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