GTPase function of Leucine rich repeat kinase 2

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As well as being a kinase associated with age-dependent penetrant forms of Parkinsons disease, Leucine-rich repeat kinase 2 (LRRK2) is also an authentic GTP binding protein. There are mutations in the GTP-binding ROC (Ras of complex proteins) domain and the adjacent COR (C-terminal of ROC) in LRRK2 that cause Parkinsons disease. The aim of this project is to understand why LRRK2 and related homologue LRRK1 bind GTP and what effect this has on the protein. We have previously shown that ROC domain mutations such as R1441C have structural effects on the ROC domain that decrease the already weak GTPase activity of the protein. It has been suggested that the COR domain, where the mutation Y1699C is found, stimulates GTPase activity, perhaps by mediating the formation of dimers. We have recently shown that Y1699C weakens ROC:COR interactions and thereby leads to lower GTPase activity. We have argued that, along with data suggesting that the kinase domain of LRRK2 phosphorylates its own ROC domain, understanding the GTP-bound form of LRRK2 may be crucial for understanding pathogenesis. Furthermore, the available evidence suggests that LRRK2 mutations may cause a persistence of function that becomes pathogenic in the context of an aging nervous system. Our current work on this project is aimed at understanding this phenomenon further by identifying binding partners of the ROC and COR domains in human LRRK2. Some of the candidates that we are considering may influence the cellular function of LRRK2, which may be related to endosome trafficking. Ongoing work includes defining the action of LRRK2 and binding partners in neurons.