Rab (G-protein)

The Rab family of proteins is a member of the Ras superfamily of monomeric G proteins. Approximately 70 types of Rabs have now been identified in humans. Rab proteins generally possess a GTPase fold, which consists of a six-stranded Beta Sheet which is flanked by five alpha helixes. Rab GTPases regulate many steps of membrane traffic, including vesicle formation, vesicle movement along actin and tubulin networks, and membrane fusion. These processes make up the route through which cell surface proteins are trafficked from the Golgi to the plasma membrane and are recycled. Surface protein recycling returns proteins to the surface whose function involves carrying another protein or substance inside the cell, such as the transferrin receptor, or serves as a means of regulating the number of a certain type of protein molecules on the surface.

Rab proteins are peripheral membrane proteins, anchored to a membrane via a lipid group covalently linked to an amino acid. Specifically, Rabs are anchored via prenyl groups on two cysteines in the C-terminus. Rab escort proteins (REPs) deliver newly synthesized and prenylated Rab to its destination membrane by binding the hydrophobic, insoluble prenyl groups and carrying Rab through the cytoplasm. The lipid prenyl groups can then insert into the membrane, anchoring Rab at the cytoplasmic face of a vesicle or the plasma membrane. Because Rab proteins are anchored to the membrane through a flexible C-terminal region, they can be thought of as a 'balloon on a string'.

Like other GTPases, Rabs switch between two conformations, an inactive form bound to GDP (guanosine diphosphate), and an active form bound to GTP (guanosine triphosphate). A GDP/GTP exchange factor (GEF) catalyzes the conversion from GDP-bound to GTP-bound form, thereby activating the Rab. The inherent GTP hydrolysis of Rabs can be enhanced by a GTPase-activating protein (GAP) leading to Rab inactivation. REPs carry only the GDP-bound form of Rab, and Rab effectors, proteins with which Rab interacts and through which it functions, only bind the GTP-bound form of Rab. Rab effectors are very heterogeneous, and each Rab isoform has many effectors through which it carries out multiple functions. The specific binding of the effector to the Rab protein allows the Rab protein to be effective, and conversely, the conformation shift of the Rab protein to the inactive state leads to effector dissociation from the Rab protein.

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