Rab proteins (also known as Ypt in yeasts and plants) are monomeric GTPases of the Ras superfamily (RAS superfamily). Rabs are present in all eukaryotes and the Rab families in the genomes of several species have been reported. 60 human RAB genes are known in 2005. However, the complexity of the Rab protein family might be even greater as there is evidence that alternative splicing of Rab genes results in the production of functionally distinct isoforms.

Although intrinsically soluble, post-translational addition of isoprenoid moieties (isoprenylation) allows Rabs to associate with the cytoplasmic face of membrane-bound intracellular organelles and vesicles.

Lipid-modified Rabs appear to be targeted to specific membranes and thus display a characteristic pattern of subcellular localization.

Evolutionarily conserved Rabs tend to be expressed in all cell and tissue types and regulate fundamental transport pathways whereas less conserved family members function in the many specialized pathways found in different mammalian cell types.

Members

RAB1

RAB2

RAB3

RAB4

RAB5

RAB6

RAB7

RAB8

RAB9

RAB10

RAB11A

RAB11B

RAB12

RAB13

RAB14

RAB15

RAB16

RAB17

RAB18

RAB19

RAB10

RAB21

RAB22A

RAB22B

RAB22C

RAB23

RAB24

RAB25

RAB26

RAB27A

RAB27B

RAB28

RAB29

RAB30

RAB31

RAB32

RAB33A

RAB33B

RAB34

RAB35

RAB36

RAB37

RAB38

RAB39A

RAB39B

RAB40A

RAB40B

RAB40C

RAB41

RAB42

RAB43

RAB44

RAB45

RAB46

RAB47

RAB48

RAB49

RAB50

Functions

Cellular organelles in the exocytic and endocytic pathways have a distinctive spatial distribution. They communicate through an elaborate system of vesiculo-tubular transport.

RABs proteins and their effectors coordinate consecutive stages of transport, such as vesicle formation, vesicle and organelle motility, and tethering of vesicles to their target compartment.

The human genome is predicted to contain 60 RAB genes, suggesting that future work could reveal further links between Rab dysfunction and disease.

RABs are highly compartmentalized in organelle membranes, making them excellent candidates for determining transport specificity and organelle identity.

A number of processes in eukaryotic cells are believed to be regulated by small, monomeric GTPases belonging to the RAS superfamily, RABs.

A subset of these GTPases (the yeast YPTI/SEC4 gene products and their mammalian counterparts, the RAB proteins) plays a central role in membrane trafficking.

Each of the several proteins of this subfamily that have been identified is thought to regulate vesicular trafficking at a specific subcellular compartment.

The subcellular location of several RAB proteins (RABs) has been determined by immunohistochemical methods:

 RAB2 (MIM.179509) is found in the intermediate recycling pathway between the endoplasmic reticulum and the Golgi complex
 RAB6 (MIM.179513) is distributed in the medial and trans Golgi
 RAB4 (MIM.179511) and RAB5A (MIM.179512) are associated with the plasma membrane and early endosomes

Members

The human genome is predicted to contain 60 RAB genes, suggesting that future work could reveal further links between Rab dysfunction and disease.

RAB1	RAB2	RAB3	RAB4	RAB5A	RAB5B	RAB5C	RAB6	RAB7	RAB8	RAB9
RAB10	RAB11	RAB12	RAB13	RAB14	RAB15	RAB16	RAB17	RAB18	RAB19
RAB20	RAB21	RAB22	RAB23	RAB24	RAB25	RAB26	RAB27	RAB28	RAB29

Functions

Targeting and Fusion of Vesicles with the Target Organelle

The Rab proteins are key regulators of the tethering and fusion of vesicles during vesicle transport. They cycle between forms bound by guanosine triphosphate (GTP) and guanosine diphosphate (GDP) and shift between cellular membranes and the cytoplasm with the help of the Rab GDP-dissociation inhibitor (GDI).

The membrane association of Rab proteins is dependent on hydrophobic modification mediated by Rab escort protein (REP) and an isoprenyl transferase.

The function of Rab guanosine triphosphatases (GTPases) and their effectors is apparently linked to that of the highly conserved membrane-anchored proteins (SNAREs) acting farther downstream in the vesicle fusion process.

The pairing of these proteins on the vesicle and target membranes is needed for bilayer fusion.

Examples of genetic defects that affect the function of Rab proteins include choroideremia, in which Rab escort protein 1 is defective, and X-linked mental retardation, in which the Rab GDP-dissociation inhibitor is defective.

Pathology

 RAB7 : Charcot-Marie-Tooth disease
 RAB27A : Griscelli disease
 germline mutations of RAB23 in acrocephalopolysyndactyly type 2 (Carpenter syndrome ) (MIM.201000) (17503333)
 Rab escort protein-1 (choroideremia)
 Rab geranylgeranyl transferase (Hermansky-Pudlak syndrome)
 Rab GDP dissociation inhibitor-alpha (X-linked mental retardation)
 The tuberous sclerosis 2 gene product, tuberin, functions as a Rab5 GTPase activating protein (GAP) in modulating endocytosis. TSC2 is mutated in tuberous sclerosis.

Physiopathology

Membrane and protein traffic in the secretory and endocytic pathways is mediated by vesicular transport. Rab GTPases are key regulators of vesicular transport. They have linked Rab dysfunction to human disease.

Mutations in RAB27A result in Griscelli syndrome, caused by defects in melanosome transport in melanocytes and loss of cytotoxic killing activity in T cells.

Other genetic diseases are caused by partial dysfunction of multiple Rab proteins resulting from mutations in general regulators of Rab activity; Rab escort protein-1 (choroideremia), Rab geranylgeranyl transferase (Hermansky-Pudlak syndrome) and Rab GDP dissociation inhibitor-alpha (X-linked mental retardation).

Infectious diseases (endocytic Rabs in infectious diseases caused by intracellular microorganisms)

In infectious diseases caused by intracellular microorganisms, the function of endocytic Rabs is altered either as part of host defences or as part of survival strategy of the pathogen.

The human genome is predicted to contain 60 RAB genes, suggesting that future work could reveal further links between Rab dysfunction and disease.

See also

 vesicular transport
 intracellular transport

References

 Cheng KW, Lahad JP, Gray JW, Mills GB. Emerging role of RAB GTPases in cancer and human disease. Cancer Res. 2005 Apr 1;65(7):2516-9. PMID: 15805241

 Seabra MC, Mules EH, Hume AN. Rab GTPases, intracellular traffic and disease. Trends Mol Med. 2002 Jan;8(1):23-30. PMID: 11796263

 Zerial M, McBride H. Rab proteins as membrane organizers. Nat Rev Mol Cell Biol. 2001 Feb;2(2):107-17. PMID: 11252952

 Pfeffer SR. Rab GTPases: specifying and deciphering organelle identity and function. Trends Cell Biol. 2001 Dec;11(12):487-91. PMID: 11719054

 Olkkonen VM, Ikonen E. Genetic defects of intracellular-membrane transport. N Engl J Med. 2000 Oct 12;343(15):1095-104. PMID: 11027745

References

 Jenkins D, Seelow D, Jehee FS, Perlyn CA, Alonso LG, Bueno DF, Donnai D, Josifova D, Mathijssen IM, Morton JE, Orstavik KH, Sweeney E, Wall SA, Marsh JL, Nurnberg P, Passos-Bueno MR, Wilkie AO.RAB23 mutations in Carpenter syndrome imply an unexpected role for hedgehog signaling in cranial-suture development and obesity.Am J Hum Genet. 2007 Jun;80(6):1162-70. PMID: 17503333