rab proteins consist of a large family of small GTPases related to the oncogene ras. rab stands for ras in the brain, and rabs define a group of membrane associated proteins that localize to discrete subcellular compartments (Figure 1).

   Figure 1. Rab are associated with distinct cellular trafficking pathways. This figure, adapted from a review by H Stenmark and V Olkkonen (Genome Biology 2:3007) shows the trafficking pathways that a numberous different rabs are associated with.

In vertebrates the rab family consists of more than 60 members. In C. elegans over 20 members have been identified (see list of C. elegans rabs), though only a few of them have been well characterized.

Basic Properties of Rab proteins

rab proteins are small proteins with a protein folding structure very similar to ras (figure 1). They are found in the cell in two conformations, bound to GTP and associated with membranes, and bound to GDP and associated with Guanine Dissociation Inhibitor (GDI), a general rab-GDP binding protein (Figure 3). Two types of protein regulator the switch of rab proteins between these two forms. Guanine nucleotide Exchange Factors (GEFs) catalyze the exchange of GTP for GDP and membrane targeting of rabs, and GTPase Activating Proteins (GAPs) stimulate the native GTPase activity of rabs causing the hydrolyis of GTP to GDP and Pi. By contrast with GDI, GAPs and GEFs are specific for distinct rabs or families or related RABs. And also in contrast to rab proteins which are highly conserved, GAPs and GEFs that regulate specific Rabs share little homology with GAPs and GEFs that regulate other Rab families.
   Figure 3. A simple diagram showing the action of GAPs and GEFs on the state of rab3. GAPs stimulate the GTPase activity of rab3 leading to its extraction from membranes and solubilization. GEFs stimulate exchange of GTP for GDP leading to membrane localization of rab3

 

Rab Effectors

While Rab 'activity' is regulated by GAPs and GEFs, rab proteins are thought to exert their effects on the secretory pathway via proteins which bind rab proteins specifically in the GTP bound state. These are generally called effectors. And similarly to GAPs and GEFs, these proteins are not conserved in structure or function from rab to rab.

Rab3 components in C. elegans

We have identified and characterized mutants in several rab3 pathway components. These include RAB-3, the rab3 GEF AEX-3, the rab3 GAP catalytic subunit RBG-1, and the RAB-3 effectors rabphilin and RIM. Several surprises have come from this work. First, we have documented that C. elegans rabphilin actually is a RAB-27, not a RAB-3 effector. Second, the rab3 GEF works on both RAB-3 and RAB-27. Third ,rab3 GAP seems to be insequential to C. elegans RAB-3 pathway function. Much of this work remains unpublished.