Fig. 2

Rab29-dependent LRRK2 activation model. In the presence of GTP-bound Rab29 the equilibrium between monomeric cytosolic LRRK2 and kinase-active dimeric membrane-associated LRRK2 is shifted to the membrane form. 1 Monomeric LRRK2 is recruited to TGN membranes by GTP-bound Rab29. It is not known whether LRRK2 GTP hydrolysis occurs in the cytosol or immediately following membrane recruitment, but the result is an accumulation of monomeric GDP-bound LRRK2 on TGN membranes. 2 The recruitment of LRRK2 to TGN membranes creates a microdomain of high LRRK2 concentration, facilitating LRRK2 dimerisation. 3 While dimerised and kinase-active, LRRK2 releases GDP, 4 GTP exchange occurs, creating dimeric, kinase-active and Rab29-bound LRRK2. 5 Rab29 GTP hydrolysis releases LRRK2 dimers, promoting dissociation from TGN membranes. 6 Decreased LRRK2 concentration in the cytosol favours monomerisation and kinase inactivation. This last step is impaired by pathogenic RocCOR mutations. The representation of LRRK2 as LRR, Roc and COR domains is derived from the LRRK2 GTPase cycle proposed by Deyaert and colleagues, upon which much of this model is built (31).