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RABs

Wednesday 29 October 2003

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