A hypothetical model of cargo-selective rab recruitment during organelle maturation

Rabs constitute a group of small GTPases that confer directionality to intracellular vesicle transport by promoting on the membrane of transport vesicles in the formation of specific protein complexes allowing for efficient fusion with a selected set of target organelles. The molecular mechanism controlling recruitment of the correct Rab at the right time is not fully understood. We propose a model according to which the residence time of a given Rab on the membrane of an organelle is determined by its transient trapping into a Rab effector complex (REC) composed of cargo receptor, SNAREs and further effectors. The stability of REC is controlled by the conformational state of the receptor which may change due to binding and release of cargo or changes in the luminal ion milieu. We use a conceptual mathematical model to calculate temporal changes in the Rab decoration of an organelle brought about by exchange with a cytosolic pool of Rabs or alternatively by budding and uptake of Rab-carrying vesicles. Considering the time-dependent drop in pH as one crucial factor for the conformational change of endocytic cargo receptors, our model provides a good quantitative description of the switch from Rab5 to Rab7 during the early-to-late endosome transition and correctly explains the arrest of this transition at insufficient luminal acidification. Model simulations suggest that a switch from one Rab to another may be continuous or abrupt. We discuss mechanisms, e.g. specific signalling pathways, which may restore an arrested organelle maturation.