Rab family of GTPases

Abstract

Rab proteins represent the largest branch of the Ras-like small GTPase superfamily and there are 66 Rab genes in the human genome. They alternate between GTP- and GDP-bound states, which are facilitated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), and function as molecular switches in regulation of intracellular membrane trafficking in all eukaryotic cells. Each Rab targets to an organelle and specify a transport step along exocytic, endocytic, and recycling pathways as well as the crosstalk between these pathways. Through interactions with multiple effectors temporally, a Rab can control membrane budding and formation of transport vesicles, vesicle movement along cytoskeleton, and membrane fusion at the target compartment. The large number of Rab proteins reflects the complexity of the intracellular transport system, which is essential for the localization and function of membrane and secretory proteins such as hormones, growth factors, and their membrane receptors. As such, Rab proteins have emerged as important regulators for signal transduction, cell growth, and differentiation. Altered Rab expression and/or activity have been implicated in diseases ranging from neurological disorders, diabetes to cancer.

Fig. 1

The mammalian and yeast Rab/Ypt homologs. Data from Diekmann et al. and Klöpper et al. [1, 2] reveal six major groups of Rab GTPases from the LECA to mammals. Shown are only the mammalian Rabs with yeast Rab/Ypt homologs. RabX1 is not present in mammalian cells, while there are no members of group VI, including Rab28, found in yeast

Fig. 2

Rabs throughout the mammalian cell. Rabs are found in virtually every membranous compartment in eukaryotic cells. Above is a schematic representation of intracellular localization of the Rabs from Fig. 1 and discussed in this volume of MiMB

Fig. 3

The Rab GTPase cycle coupled with membrane targeting. Inactive GDP-bound Rabs are found in the cytosol bound to GDI. Upon approaching the target membrane, GDF may interact with the Rab to facilitate GDI dissociation and Rab insertion into the membrane. On the membrane, GEF catalyzes GDP dissociation, allowing for GTP binding and subsequent activation of the Rab, which in turn interacts with multiple effectors to promote vesicle budding, movement, and fusion. Then GTP hydrolysis by the Rab, accelerated by a cognate GAP, converts it to inactive GDP-bound state. The inactive Rab can be removed from the membrane by GDI and recycled back to the donor compartment

Fig. 4

Rab activation cascades. The GTP loading and activation of a Rab can be regulated as part of an activation cascade from an upstream Rab. (a) Rab activation cascades are evolutionarily conserved from yeast to mammals. During polarized exocytosis in S. cerevisiae, activated Ypt32 recruits Sec2, a Sec4 GEF, to the membrane of secretory vesicles destined for exocytosis. Sec2 in turn leads to the recruitment and activation of Sec4. The same cascade is seen in mammalian cells with Rab11, Rabin8 (Rab8 GEF), and Rab8. (b) On the Golgi membrane, active Rab33B recruits the Ric1–Rgp1 complex (Rab6 GEF), which activates Rab6. (c) On late endosomes, Rab9 recruits Bloc-3 (Rab32/33 GEF) to the membrane and activates Rab32 as they move toward lysosomes or melanosomes. (d) Active Rab22 binds and recruits Rabex-5 (Rab5 GEF) and activates Rab5 on early endosomes. Active Rab5 in turn binds Sand1 (Mon1 in Yeast) –Ccz1 complex (Rab7 GEF), which recruits and activates Rab7 to facilitate transition to late endosomes. Upon dissociation of Rab22 and Rabex-5, Rab5 is inactivated by GTP hydrolysis and converted to GDP bound state, which is then removed from the membrane by GDI