The GTPase function of LRRK2

Abstract

LRRK2 (leucine-rich repeat kinase 2) is a large protein encoding multiple functional domains, including two catalytically active domains, a kinase and a GTPase domain. The LRRK2 GTPase belongs to the Ras-GTPase superfamily of GTPases, more specifically to the ROC (Ras of complex proteins) subfamily. Studies with recombinant LRRK2 protein purified from eukaryotic cells have confirmed that LRRK2 binds guanine nucleotides and catalyses the hydrolysis of GTP to GDP. LRRK2 is linked to PD (Parkinson's disease) and GTPase activity is impaired for several PD mutants located in the ROC and COR (C-terminal of ROC) domains, indicating that it is involved in PD pathogenesis. Ras family GTPases are known to function as molecular switches, and several studies have explored this possibility for LRRK2. These studies show that there is interplay between the LRRK2 GTPase function and its kinase function, with most data pointing towards a role for the kinase domain as an upstream regulator of ROC. The GTPase function is therefore a pivotal functionality within the LRRK2-mediated signalling cascade which includes partners encoded by other LRRK2 domains as well as other cellular signalling partners. The present review examines what is known of the enzymatic properties of the LRRK2 GTPase, the interplay between ROC and other LRRK2 domains, and the interplay between ROC and other cellular proteins with the dual goal to understand how LRRK2 GTPase affects cellular functions and point to future research venues.