The Rab family of proteins is a member of the Ras superfamily of small G proteins.[1] Approximately 70 types of Rabs have now been identified in humans.[2] Rab proteins generally possess a GTPase fold, which consists of a six-stranded beta sheet which is flanked by five alpha helices.[3] Rab GTPases regulate many steps of membrane trafficking, 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.


The four steps of Rab protein vesicle transport (listed in text)

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'.

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 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.[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. 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.[5]


Choroideremia is caused by a loss-of-function mutation in the CHM gene which codes for Rab 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]

Intellectual disability

Mutations in the GDI1 gene, which encodes a guanosine nucleotide dissociation inhibitor, 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.[4]


Evidence shows that overexpression of Rab GTPases have a striking relationship with carcinogenesis, 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 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.[5]

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.[10]

Types of Rab proteins

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 organisms Saccharomyces cerevisiae [11] and Aspergillus nidulans.[12]

Name Subcellular location
RAB1 (Ypt1, RabO) Golgi complex
RAB2A ER, cis-Golgi network
RAB3A Secretory and synaptic vesicles
RAB4A Recycling endosomes
RAB5A Clathrin-coated vesicles, plasma membranes
RAB5C (Vps21, RabB) Early endosomes
RAB6A (Ypt6, RabC) Golgi and trans-Golgi network
RAB7 (Ypt7, RabS) Late endosomes, vacuoles
RAB8A Basolateral secretory vesicles
RAB9A Late endosome, trans-golgi network
RAB11A (Ypt31, RabE) Recycling endosomes, post-Golgi exocytic carriers
RAB13 Golgi, endosome, cytosol, plasma membrane
RAB14 Early endosomes
RAB17 Endosome
RAB18 Lipid droplets, golgi, endoplasmic reticulum
RAB20 Golgi, mitochondria, early phagosome, early endosome
RAB23 Plasma membrane
RAB25 Small-scale transport, promoter for tumor development[13]
RAB27 Extracellular vesicles, endosome
RAB29 Recruits LRRK2 to TGN
RAB39A Binds Caspase-1 in inflammasome

Other Rab proteins


  1. ^ Stenmark H, Olkkonen VM (2001). "The Rab GTPase family". Genome Biology. 2 (5): REVIEWS3007. doi:10.1186/gb-2001-2-5-reviews3007. PMC 138937. PMID 11387043.
  2. ^ a b Seto, Shintaro; Tsujimura, Kunio; Horii, Toshinobu; Koide, Yukio (2014-01-01), Hayat, M. A. (ed.), "Chapter 10 - Mycobacterial Survival in Alveolar Macrophages as a Result of Coronin-1a Inhibition of Autophagosome Formation", Autophagy: Cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging, Amsterdam: Academic Press, pp. 161–170, doi:10.1016/b978-0-12-405877-4.00010-x, ISBN 978-0-12-405877-4, retrieved 2020-11-19
  3. ^ Hutagalung AH, Novick PJ (January 2011). "Role of Rab GTPases in membrane traffic and cell physiology". Physiological Reviews. 91 (1): 119–49. doi:10.1152/physrev.00059.2009. PMC 3710122. PMID 21248164.
  4. ^ a b c Seabra MC, Mules EH, Hume AN (January 2002). "Rab GTPases, intracellular traffic and disease". Trends in Molecular Medicine. 8 (1): 23–30. doi:10.1016/s1471-4914(01)02227-4. PMID 11796263.
  5. ^ a b Tzeng HT, Wang YC (October 2016). "Rab-mediated vesicle trafficking in cancer". Journal of Biomedical Science. 23 (1): 70. doi:10.1186/s12929-016-0287-7. PMC 5053131. PMID 27716280.
  6. ^ Cremers FP, Armstrong SA, Seabra MC, Brown MS, Goldstein JL (January 1994). "REP-2, a Rab escort protein encoded by the choroideremia-like gene". The Journal of Biological Chemistry. 269 (3): 2111–7. doi:10.1016/S0021-9258(17)42142-9. PMID 8294464.
  7. ^ Seabra MC, Ho YK, Anant JS (October 13, 1995). "Deficient Geranylgeranylation of Ram/Rab27 in Choroideremia". The Journal of Biological Chemistry. 270 (41): 24420–24427. doi:10.1074/jbc.270.41.24420. PMID 7592656.
  8. ^ Johnson IR, Parkinson-Lawrence EJ, Shandala T, Weigert R, Butler LM, Brooks DA (December 2014). "Altered endosome biogenesis in prostate cancer has biomarker potential". Molecular Cancer Research. 12 (12): 1851–62. doi:10.1158/1541-7786.MCR-14-0074. PMC 4757910. PMID 25080433.
  9. ^ Johnson IR, Parkinson-Lawrence EJ, Keegan H, Spillane CD, Barry-O'Crowley J, Watson WR, et al. (November 2015). "Endosomal gene expression: a new indicator for prostate cancer patient prognosis?". Oncotarget. 6 (35): 37919–29. doi:10.18632/oncotarget.6114. PMC 4741974. PMID 26473288.
  10. ^ Lesage S, Bras J, Cormier-Dequaire F, Condroyer C, Nicolas A, Darwent L, Guerreiro R, Majounie E, Federoff M, Heutink P, Wood NW, Gasser T, Hardy J, Tison F, Singleton A, Brice A (June 2015). "Loss-of-function mutations in RAB39B are associated with typical early-onset Parkinson disease". Neurology. Genetics. 1 (1): e9. doi:10.1212/NXG.0000000000000009. PMC 4821081. PMID 27066548.
  11. ^ "Saccharomyces Genome Database (SGD)". Yeast Genome Org. Stanford University.
  12. ^ "Aspergillus Genome Database (AspGD)". Stanford University.
  13. ^ Kessler D, Gruen GC, Heider D, Morgner J, Reis H, Schmid KW, Jendrossek V (2012). "The action of small GTPases Rab11 and Rab25 in vesicle trafficking during cell migration". Cellular Physiology and Biochemistry. 29 (5–6): 647–56. doi:10.1159/000295249. PMID 22613965.