The leucine-rich repeat kinase 2 (LRRK2), encoded by the PARK8 gene, is a 2527 amino acid protein kinase that plays an important role in the pathogenesis of familial Parkinson’s disease. Mutations within the functional domains of LRRK2 have been known to cause hereditary PD, indicating that LRRK2’s is significant and maintains the proper function of neurons. LRRK2 possesses seven functional domains including in them a kinase domain, Ras-of-complex (Roc) and the C-terminal-of-Roc (COR) tandem domains. The Roc-COR tandem domains together belong to the Roco family proteins and exhibit GTPase activity. Mutations mapped to the Roc-COR domains are known to confer neurotoxicity, however the mechanism by which the Roc-COR domain is controlled by its upstream regulators is not yet fully understood and the downstream effectors remain mostly unknown. The Rho guanine nucleotide exchange factor 7 (ARHGEF7) has been proposed to interact with the Roc-COR domain of LRRK2, facilitating the release of GDP and to allow binding of GTP.

The objective for this project is to investigate how the binding of ARHGEF7 to the LRRK2 regulates the Roc-COR GTPase activity. Another aspect of my objective is to investigate how the kinase domain might be regulated by the Roc-COR domain of LRRK2 and how ARHGEF7 may indirectly modulate the kinase activity of LRRK2.