FIGURE 8.

Hypothetical model of LRRK2 kinase activation. A major fraction of LRRK2 protein in cells may reside in large oligomers with low or no kinase activity. LRRK2 oligomers are dissociated through conformational changes induced by GTP binding within the ROC GTPase domain, which may lead to the formation of a dimer structure initially stabilized by a ROC-ROC interaction that unmasks kinase activity and the potential for autophosphorylation. LRRK2 autophosphorylation activity may lead to the stabilization of the kinase-active dimer, which can be destabilized by competing phosphatase activity, GTPase hydrolytic activity, or stochastic interactions with LRRK2 oligomers. In this model, kinase activity is dependent on GTPase activity, whereas GTPase activity is not dependent on kinase activity but must be influenced by changes induced by autophosphorylation. Thus, this model predicts a reciprocal interaction whereby kinase activity and autophosphorylation stabilize lower molecular weight conformations and decrease the reversion to high molecular weight oligomers.