| First Author | Purlyte E | Year | 2018 |
| Journal | EMBO J | Volume | 37 |
| Issue | 1 | Pages | 1-18 |
| PubMed ID | 29212815 | Mgi Jnum | J:351286 |
| Mgi Id | MGI:6730536 | Doi | 10.15252/embj.201798099 |
| Citation | Purlyte E, et al. (2018) Rab29 activation of the Parkinson's disease-associated LRRK2 kinase. EMBO J 37(1):1-18 |
| abstractText | 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. |
