TheRab family ofproteins is a member of theRas superfamily of smallG proteins.^[1] Approximately 70 types of Rabs have now been identified inhumans.^[2] Rab proteins generally possess aGTPase fold, which consists of a six-strandedbeta sheet which is flanked by fivealpha helices.^[3]

Rab GTPases regulate many steps of membrane trafficking, including vesicle formation, vesicle movement alongactin andtubulin 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 areperipheral membrane proteins, anchored to a membrane via a lipid group covalently linked to an amino acid. Specifically, Rabs are anchored viaprenyl groups on twocysteines in the C-terminus. Rab escort proteins (REPs) deliver newly synthesized and prenylated Rab to its destination membrane by binding thehydrophobic, insoluble prenyl groups and carrying Rab through the cytoplasm. Thelipidprenyl 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'.

Rabs switch between two conformations, an inactive form bound to GDP (guanosine diphosphate), and an active form bound to GTP (guanosine triphosphate). A guanine nucleotide 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 aGTPase-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.^[4]

Effector proteins have one of four different functions.

1. Cargo budding, selection, and coating
2. Vesicle transport
3. Vesicle uncoating and tethering
4. Vesicle fusion^[4]

After membrane fusion and effector dissociation, Rab is recycled back to its membrane of origin. AGDP dissociation inhibitor (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.

Rab proteins and their functions are essential to properorganelle function, and as such, when any deviation is introduced to the Rab protein cycle, physiological disease states ensue.^[5]

Choroideremia is caused by a loss-of-function mutation in theCHM gene which codes forRab escort protein (REP-1). REP-1 and REP-2 (a REP-1 like protein) both help with the prenylation and transport of Rab proteins.^[6] Rab27 has been found to preferentially depend on REP-1 for prenylation, which could be the underlying cause of choroideremia.^[7]

Mutations in theGDI1 gene, which encodes a guanosine nucleotide dissociation inhibitor, have been shown to lead toX-linked nonspecificintellectual disability. In a study done on mice, carriers for a deletion of theGDI1 gene have shown marked abnormalities inshort-term memory formation and social interaction patterns. It is noted that the social and behavioral patterns exhibited in mice that are carriers of the GDI1 protein are similar to those observed in humans with the same deletion. The loss of theGDI1 gene has been shown through brain extracts of the mutant mice to lead to the accumulation of the Rab4 and Rab5 proteins, thus inhibiting their function.^[4]

Evidence shows that overexpression of Rab GTPases have a striking relationship withcarcinogenesis, such as in prostate cancer.^[8][9] There are many mechanisms by which Rab protein dysfunction has been shown to cause cancer. To name a few, elevated expression of the oncogenic Rab1, along with Rab1A proteins, promote the growth of tumors, often with a poor prognosis. The overexpression of Rab23 has been linked togastric cancer. In addition to directly causing cancer, dysregulation of Rab proteins has also been linked to progression of already existent tumors, and contributing to their malignancy.^[5]

Mutations of the Rab39b protein have been linked to X-linked intellectual disability and also to a rare form ofParkinson's disease.^[10]

There are approximately 70 different Rabs that have been identified in humans thus far.^[2] They are 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. Shown in parentheses are the equivalent names in the model organismsSaccharomyces cerevisiae^[11] andAspergillus nidulans.^[12]

• RABIF

• rab+G-Proteins at the U.S. National Library of MedicineMedical Subject Headings (MeSH)

• G proteins
• Peripheral membrane proteins

• Articles with short description
• Short description is different from Wikidata