The Parkinson's disease-associated protein, leucine-rich repeat kinase 2 (LRRK2), is an authentic GTPase that stimulates kinase activity

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the leading cause of autosomal dominant Parkinson's disease (PD). LRRK2, a member of the ROCO protein family, contains both Ras GTPase-like (Roc) and kinase (MAPKKK) domains, as well as other functional motifs. Here, we have identif...

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Bibliographic Details
Published in:Experimental cell research 2007-10, Vol.313 (16), p.3658-3670
Main Authors: Guo, Luxuan, Gandhi, Payal N, Wang, Wen, Petersen, Robert B, Wilson-Delfosse, Amy L, Chen, Shu G
Format: Article
Language:English
Subjects:
Cell Line
Enzyme Activation
GTP Phosphohydrolases - metabolism
Guanosine Triphosphate - metabolism
Humans
Hydrolysis
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
Models, Biological
Mutant Proteins - metabolism
Mutation - genetics
Phosphorylation
Protein Structure, Tertiary
Protein-Serine-Threonine Kinases - chemistry
Protein-Serine-Threonine Kinases - metabolism
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Summary:Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the leading cause of autosomal dominant Parkinson's disease (PD). LRRK2, a member of the ROCO protein family, contains both Ras GTPase-like (Roc) and kinase (MAPKKK) domains, as well as other functional motifs. Here, we have identified LRRK2 as the first mammalian ROCO protein that is an authentic and functional GTPase, defined by the ability to bind GTP and undergo intrinsic GTP hydrolysis. Furthermore, the Roc domain is sufficient for this native GTPase activity and binds and hydrolyzes GTP indistinguishably from the Ras-related small GTPase, Rac1. The PD-associated mutation, R1441C, located within the Roc domain, leads to an increase in LRRK2 kinase activity and a decrease in the rate of GTP hydrolysis, compared to the wild-type protein, in an in vitro assay. This finding suggests that the R1441C mutation may help stabilize an activated state of LRRK2. Additionally, LRRK2-mediated phosphorylation is stimulated upon binding of non-hydrolyzable GTP analogs, suggesting that LRRK2 is an MAPKKK-activated intramolecularly by its own GTPase. Since GTPases and MAPKKKs are upstream regulators of multiple signal transduction cascades, LRRK2 may play a central role in integrating pathways involved in neuronal cell signaling and the pathogenesis of PD.
ISSN:0014-4827
1090-2422
DOI:10.1016/j.yexcr.2007.07.007