Mutations in LRRK2 all cause inherited Parkinsons disease but are spread out amongst different functional domains of the protein. Thus, while some mutations are found in the kinase domain, others are found in regions that are associated with GTP binding (the ROC domain) or functional regulators of that activity (the COR domain). We are therefore interested in the GTP-binding properties of LRRK2, particularly in understanding what regulates it and what effects it has on the protein overall. In recent work, we have shown that mutations in the ROC domain change local folding of LRRK2. This likely underlies previous observations that the same mutations cause a decrease in GTPase activity. This is an inherently weak activity and it is unclear if this is physiologically important, but mutations abolish what little there is. To follow up this observation, we are currently exploring the possibility that there might be GTP-dependent interactors of LRRK2 using several screening techniques.
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