Rab Proteins and the Compartmentalization of the Endosomal System

Of the approximately 70 human Rab GTPases, nearly three-quarters are involved in endo-cytic trafficking. Significant plasticity in endosomal membrane transport pathways is closely coupled to receptor signaling and Rab GTPase-regulated scaffolds. Here we review current literature pertaining to endocytic RabGTPase localizations, functions, and coordinationwith regulatory proteins and effectors. The roles of RabGTPases in (1) compartmentalization of the endocytic pathway into early, recycling, late, and lysosomal routes; (2) coordination of individual transport steps from vesicle budding to fusion; (3) effector interactomes; and (4) integration of GTPase and signaling cascades are discussed. The general working principle of RabGTPases is that they contribute to the struc-tural and functional identity of intracellular or-ganelles. These functions rely on the versatile GTP/GDP cycle for the assembly of multipro-tein machineries on the cytoplasmic surface of intracellular membranes. Rab GTPase protein assemblies are spatially and temporally regulat-ed, can vary quantitatively over time, and are reversible, thus allowing for a change in the membrane composition and intracellular fate of organelles. Rab proteins belong to the Ras superfam-ily of small GTPases and share properties char-acteristic of small GTPases in common with other subfamilies (Rojas et al. 2012). First, Rab GTPases undergo cycles of GTP binding and hydrolysis to GDP, which serves to drive a reversible conformational change that is de-coded by interacting proteins (Wittinghofer et al. 1993). Guanine-nucleotide exchange fac-tors (GEFs) and GTPase-activating proteins (GAPs) catalyze the exchange and hydrolysis reactions and, therefore, act as regulators of the GTP–GDP cycle (Yoshimura et al. 2010