The Rab GTPase family

Abstract

The Rab family is part of the Ras superfamily of small GTPases. There are at least 60 Rab genes in the human genome, and a number of Rab GTPases are conserved from yeast to humans. The different Rab GTPases are localized to the cytosolic face of specific intracellular membranes, where they function as regulators of distinct steps in membrane traffic pathways. In the GTP-bound form, the Rab GTPases recruit specific sets of effector proteins onto membranes. Through their effectors, Rab GTPases regulate vesicle formation, actin- and tubulin-dependent vesicle movement, and membrane fusion.

Figure 1

The Rab GTPase cycle. The Rab GTPase switches between GDP- and GTP-bound forms, which have different conformations. Conversion from the GDP- to the GTP-bound form is caused by nucleotide exchange, catalyzed by a GDP/GTP exchange factor (GEF). Conversion from the GTP-to the GDP-bound form occurs by GTP hydrolysis, facilitated by a GTPase-activating protein (GAP). The GTP-bound form interacts with effector molecules, whereas the GDP-bound form interacts with Rab escort protein (REP) and GDP dissociation inhibitor (GDI). Pi, inorganic phosphate.

Figure 2

Phylogenetic tree of human Rab GTPases. Adapted with permission from [4].

Figure 3

Structural features of Rab GTPases. (a) Ribbon drawing of Rab3A complexed with the GTP analog GppNHp (reproduced with permission from [9]). Purple, bound nucleotide; orange sphere, Mg²⁺ ion; blue, switch I and II regions; green, α helices and β sheets; yellow, loops. (b) A profile amino-acid sequence of the Rab GTPase subfamily generated using the hidden Markov model (HMM) method (modified from [6]). The uppercase/lowercase coding represents outcome of the profile HMM method. Upper-case characters, residues found in the profile with a probability of p > 0.5; red, Rab-specific residues (RabF1-5); dark blue, subfamily-specific motifs (RabSF1-4); cyan, highly conserved nucleotide-binding motifs; G, guanine-base-binding motif; PM, phosphate/magnesium-binding motif. The secondary structure units (α helices, β strands, and loops, λ) are indicated above the sequence.

Figure 4

Intracellular vesicle transport pathways and localization of selected Rabs. The biosynthetic pathway transports proteins from the endoplasmic reticulum (ER) through the Golgi complex to the cell surface. In the trans-Golgi network (TGN), molecules can enter either constitutive secretory vesicles (CV) or regulated secretory granules/vesicles (RV). In specialized cells melanosomes (M) are a lysosome-related compartment that moves within the cell in an actin- and myosin-dependent manner, generating pigmentation. Material internalized from outside the cell reaches the early endosomes (EE) first and can be recycled back to the surface, either directly or via a perinuclear recycling endosome (RE) compartment, or transported to late endosomes (LE) and lysosomes. The biosynthetic and endocytic circuits (arrows) exchange material at the level of the Golgi apparatus and the endosomal elements. The localization of selected mammalian Rab proteins in the membrane compartments participating in these transport processes is indicated.