The structural and mechanistic basis for recycling of Rab proteins between membrane compartments

Rab proteins are members of the Ras superfamily of GTPases and are key regulators of intracellular vesicular transport. They undergo a cycle of GTPase activity, and this activity is interconnected to a cycle of reversible attachment to membranes. This cycle is mediated by geranylgeranylation of (usually) two C-terminal cysteines, which in turn is effected by Rab geranylgeranyltransferase in concert with REP (Rab escort protein). After delivery to their respective membranes, Rabs are activated by replacement of GDP by GTP, allowing interaction with a wide variety of effector molecules involved in vesicular transport, in particular with docking of transport vesicles to their specific target membranes. After completion of these events and GTP hydrolysis, Rabs are retrieved by GDI (GDP dissociation inhibitor) and delivered to their starting compartment. Here, the structural and mechanistic basis of events occurring in Rab delivery and cycling, and the differences between REP and GDI are discussed on the basis of recent advances in the field.Received 4 November 2004; received after revision 14 February 2005; accepted 31 March 2005