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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.
Contents
Function
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.
Effector proteins have one of four different functions.
- Cargo budding, selection, and coating
- Vesicle Transport
- Vesicle Uncoating and Tethering
- Vesicle Fusion
After membrane fusion and effector dissociation, Rab is recycled back to its membrane of origin. A GDP 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.
Clinical significance
Rab proteins and their functions are essential to proper organelle function, and as such, when any deviation is introduced to the Rab protein cycle, physiological disease states ensue.
Choroideremia
Choroideremia has been linked to a loss-of-function mutation in the Rab Escort Protein (REP-1) gene. This loss-of-function mutation causes the body to be unable to use REP-1. In most tissues of the body, Rab Escort Protein-2 is abundant, and can be used interchangeably with REP-1. However, there are only limited amounts of REP-2 protein in the retina, leading to choroideremia. In addition, loss of the ability to prenylate Rab27A has been linked to choroideremia.
Intellectual Disability
Mutations in the GDI1 gene have been shown to lead to X-linked nonspecific intellectual disability. In a study done on mice, carriers for a deletion of the GDI1 gene have shown marked abnormalities in short-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 the GDI1 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.
Cancer/Carcinogenesis
Evidence shows that overexpression of Rab GTPases have a striking relationship with carcinogenesis. 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 to gastric 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.
Parkinson's Disease
Mutations of the Rab39b protein have been linked to X-linked intellectual disability and also to a rare form of Parkinson's disease.
Types of Rab proteins
There are approximately 70 different Rabs that have been identified in humans thus far. 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 parenthesis are the equivalent names in the model organisms Saccharomyces cerevisiae and Aspergillus nidulans.