FIGURE 1 

Reaction scheme of membrane recruitment and GDP/GTP cycle of two Rab GTPases, Rab5 and Rab7. Early endosomes progressively accumulate cargo destined for degradation in the Rab5 domain while recycling cargo to the cell surface through fission of Rab4 and Rab11 domains (Zerial and McBride, 2001; Rink et al, 2005). Large Rab5-positive early endosomes at the peak of degradable cargo accumulation eventually undergo conversion into Rab7-positive late endosomes (Rink et al, 2005). In this case, the entire Rab5 domain is replaced by the Rab7 domain. This is in contrast to the alternative mechanism of fission between two coexisting Rab domains on the same endosome (Vonderheit and Helenius, 2005). The scheme shows that, during the conversion process, the two Rab GTPases form, together with GEFs, GAPs and effectors, two interconnected modules on the same endosome membrane. Initially, the endosome membrane is enriched in Rab5 and depleted of Rab7. Upon conversion, the membrane composition is reversed, that is, Rab7 prevails over Rab5. Such conversion results from programmed changes in the nucleotide cycle of the two Rab GTPases, which shuttle between inactive GDP-bound (blue) and active GTP-bound (red) conformations. GEFs catalyse the exchange of GDP with GTP, and GAPs catalyse the hydrolysis of GTP into GDP (Vetter and Wittinghofer, 2001), acting upon the respective Rab proteins (GEF5 for Rab5, GEF7 for Rab7, GAP5 for Rab5, GAP7 for Rab7). GEFs and GAPs acting on one Rab protein may also be part of effector complexes (e.g. Rabaptin-5/Rabex-5 for Rab5, Class C VPS/HOPS complex for Rab7), binding the active conformation of the same or the other Rab species. For example, GEF5 (Rabaptin-5/Rabex-5 complex) is both recruited by and acts upon Rab5, thus causing a positive feedback on Rab5 activation. However, the Class C VPS/HOPS complex is a GEF7 and effector of Rab7 but also an effector of Rab5 (Rink et al, 2005), thereby coupling the activity of Rab5 to activation of Rab7. Black curved arrows denote known (biochemically demonstrated) feedback mechanisms on Rab activation whereas grey arrows represent potential, but yet hypothetical, negative feedback mechanisms. The - and + signs denote a decrease or increase in the reactions.