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 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.

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Function

Rab proteins are peripheral membrane proteins, meaning they are 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 forms, and GTP hydrolysis to GDP is catalyzed by a GTPase-activating protein (GAP). 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.

After membrane fusion, Rab is recycled back to its membrane of origin. A GDP dissociation inhbitor (GDI) binds the prenyl groups of the inactive, GDP-bound form of Rab, inhibits the exchange of GDP for GTP (which would reactivate the Rab) and delivers Rab to its original membrane.

Clinical significance

Defects in protein prenylation can cause pathologies such as choroideremia.

Types of Rab proteins

There are approximately 70 different Rabs, mostly involved in vesicle trafficking. Their complexity can be understood if thought of as address labels for vesicle trafficking, defining the identity and routing of vesicles.

Other Rab proteins

• Rab6 Rab6a Online 'Mendelian Inheritance in Man' (OMIM) 179513, Ran6b, Rab6c
• Rab13
• Rab27

References

• Stenmark H, Olkkonen VM (2001). "The Rab GTPase family". Genome Biol 2 (5): REVIEWS307.1-7. PMID 11387043.