- Protein family review
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The Rab GTPase family
Genome Biologyvolume 2, Article number: reviews3007.1 (2001)
The Rab family is part of the Ras superfamily of small GTPases. There are at least 60 Rab genes in the human genome, and a number of Rab GTPases are conserved from yeast to humans. The different Rab GTPases are localized to the cytosolic face of specific intracellular membranes, where they function as regulators of distinct steps in membrane traffic pathways. In the GTP-bound form, the Rab GTPases recruit specific sets of effector proteins onto membranes. Through their effectors, Rab GTPases regulate vesicle formation, actin- and tubulin-dependent vesicle movement, and membrane fusion.
The compartmentalization of eukaryotic cells requires the transport of lipids and proteins between distinct membrane-bounded organelles. This transport is tightly regulated and typically occurs through transport vesicles that bud from a donor compartment and fuse with an acceptor compartment. Rab GTPases ('Ras-related in brain' ), which belong to the Ras superfamily of small GTPases, have emerged as central regulators of vesicle budding, motility and fusion. Like other regulatory GTPases, the Rab proteins switch between two distinct conformations, one GTP-bound and the other GDP-bound (see Figure 1). The GTP-bound conformation is generally regarded as 'active' , as this is the form that interacts with downstream effector proteins .
Gene organization and evolutionary history
A recent analysis of the sequenced human genome and expressed sequence tags indicates that humans have at least 60 different Rab family members (Figure 2) . This must be regarded as a minimum estimate, as a small part of the genome still remains to be sequenced and sequence annotations are still incomplete. Rab genes are widely distributed over the human chromosomes . Rab GTPases have been found in all eukaryotes investigated, including Saccharomyces cerevisiae (11 members), Caenorhabditis elegans (29 members) and Drosophila melanogaster (26 members) ; this large number and wide distribution underlines their importance in eukaryotic cell biology. Most, but not all, of the yeast Rab GTPases (mostly called Ypt proteins) have one or more putative mammalian homologs. In several cases, a mammalian Rab can functionally replace its yeast counterpart, demonstrating conservation of functions of the proteins within the eukaryotes.
Many Rab GTPases seem to be products of gene duplications, given that several subfamilies of closely related Rab GTPases ('isoforms') with 75-95% sequence identity and overlapping functions can be identified (Figure 2) . Ten subfamilies - Rab1, Rab3, Rab4, Rab5, Rab6, Rab8, Rab11, Rab22, Rab27 and Rab40 - have also been defined based on distinct subfamily-specific sequence motifs, but a number of Rab proteins cannot be grouped in these subfamilies [5,6] (see later). In general, Rab GTPases differ most in their carboxyl termini, which have been implicated in subcellular targeting , whereas regions involved in guanine-nucleotide binding (see below) are most conserved. Furthermore, mammalian Rab genes generally consist of several exons, and alternative splicing has been reported .
Characteristic structural features
High-resolution structural information obtained by X-ray crystallography currently available for four Rab GTPases: mouse Rab3a [9,10], Plasmodium falciparum Rab6 , and S. cerevisiae Ypt51p  and Sec4p . The Rabs share a fold that is, in gross terms, common to all small GTPases of the Ras superfamily. The fold consists of a six-stranded β sheet, comprising five parallel strands and one antiparallel one, surrounded by five α helices. In these structures the elements responsible for guanine nucleotide and Mg2+ binding, as well as GTP hydrolysis, are located in five loops that connect the α helices and β strands. The amino-acid residues that come together in space to form this active site are closely associated with either the phosphate groups of the bound nucleotide and Mg2+ or the guanine base (Figure 3) and are highly conserved within the entire Ras superfamily; they can easily be used to recognize any small GTPase.
Crystallographic analysis of p21Ras  and also recently of the yeast Rab Sec4p  in the GDP- and GTP-bound states shows that the proteins adopt two different conformations, with the major nucleotide-induced differences occurring in regions denoted switch I and switch II . In the amino-acid sequence these switch regions are located in the loop 2 region and the loop 4-α2-loop 5 region, respectively, and in the three-dimensional structure they are found on the surface of the molecule. Numerous mutagenesis studies have shown that the putative switch regions are crucial for the interaction of Rab proteins with regulatory protein partners such as GDP/GTP exchange factors and GTPase-activating proteins (see 'Localization and function'). Furthermore, the crystal structure of a complex of Rab3a and its effector molecule rabphilin-3a shows that the switch regions form an important part of the binding interface between the two proteins .
A recent extensive sequence-analysis study shows the presence of five distinct amino-acid stretches that are characteristic of the Rab GTPases (Figure 3b) . These so-called RabF regions (shown in red in Figure 3b) cluster in and around switch regions I and II and are suggested to provide a means of unequivocally identifying Rab proteins. In addition, four regions (RabSF regions, shown in dark blue in Figure 3b) have been identified that can be used to define the ten subfamilies of Rab GTPases mentioned above [6,7]. The RabSF regions are on two different surfaces of the GTPases; they probably allow specific binding of downstream effector molecules, which must recognize a specific Rab or Rab subfamily in addition to detecting the nucleotide-binding state. In support of this, the crystallographic study by Ostermeier and Brunger  showed that the well-characterized effector of Rab3a, rabphilin-3A, occupies two major binding interfaces on the surface of the GTPase. These regions of Rab3a have been named Rab complementarity-determining regions, and they involve both the switch regions and Rab superfamily-specific motifs . A model has therefore been suggested in which effectors and regulators bind both to the RabF motifs in the switch I and II regions, to discriminate between active and inactive conformations, and to RabSF regions for specificity.
Localization and function
Localization and regulation
Some Rabs are expressed ubiquitously in human tissues, whereas others are tissue-specific (Table 1). Within cells, they are localized to the cytosolic face of distinct intracellular membranes (see Figure 4 and Table 1). Their reversible membrane localization depends on the post-translational modification of a cysteine motif at the very carboxyl terminus (CXXX, CC, CXC, CCXX or CCXXX where X is any amino acid), with one or two highly hydrophobic geranylgeranyl groups . This post-translational modification requires the initial recognition of the newly synthesized Rab protein by a Rab escort protein (REP), which presents the Rab protein to the geranylgeranyl transferase. REP then functions as a chaperone that keeps the hydrophobic, geranylgeranylated Rab soluble and delivers it to the appropriate membrane . The specific targeting of Rab GTPases is thought to rely on membrane receptors that recognize the complex between REP and specific Rabs , but so far no such receptors have been identified at the molecular level.
The REP-associated Rab GTPases are thought to be in the GDP-bound form, whereas membrane delivery is accompanied by the exchange of GDP with GTP, catalyzed by a GDP/GTP exhange factor (GEF), and the release of REP . Upon GTP hydrolysis, which is catalyzed by a GTPase-activating protein (GAP), the Rab GTPase may be released from the membrane. This is mediated by Rab GDP-dissociation inhibitor (GDI), which is capable of retrieving the geranylgeranylated, GDP-bound Rab from intracellular membranes . GDI has structural similarity to REP  and, like REP, GDI can present geranylgeranylated, GDP-bound Rab proteins to specific membranes . GDI, which is more abundant than REP, thus serves as a recycling factor that allows several rounds of membrane association and retrieval of the Rab GTPases.
A wealth of genetic and biochemical studies indicate that Rab GTPases function as regulators of specific intracellular traffic pathways (for a recent review, see ). The key to their function is the recruitment of effector molecules that bind exclusively to their GTP-bound form. Rab effectors are a very heterogeneous group of proteins: some are coiled-coil proteins involved in membrane tethering or docking, while others are enzymes or cytoskeleton-associated proteins. Two-hybrid screening for protein interactions and affinity chromatography have revealed that the endosomal GTPase Rab5a has several different effectors, and this is probably true for other Rabs as well [22,23,24]. This means that a Rab GTPase may be capable of regulating several molecular events at a restricted membrane location. For example, although initial studies showed that Rab5a regulates endocytic vesicle tethering and fusion, more recent evidence suggests that it also controls vesicle formation at the plasma membrane and microtubule-dependent motility of endocytic structures [25,26,27]. Even though effectors for many Rab GTPases have been identified, the identification and functional characterization of Rab effectors is still in an early phase. The introduction of an efficient affinity-chromatography protocol promises to speed up the identification of new effectors .
Gene knock-out studies in yeast have shown that some Rab GTPases are essential, whereas others are dispensable . The only mammalian Rab knockout so far, that of the neuronally expressed Rab3a, resulted only in minor phenotypic changes in mice . Several genetic diseases have been found to involve Rab GTPases or their interacting proteins, however [30,31].
Griscelli syndrome is an autosomal recessive disorder that causes partial albinism. There are two variants of this disease, one that is associated primarily with immunological defects and one associated with neurological dysfunctions. The syndrome with immunological defects is caused by missense mutations in the gene encoding Rab27a . This GTPase regulates the movement of melanosomes to the cell periphery of melanocytes, and it also regulates the secretion of lytic granules in cytotoxic T lymphocytes [33,34]. The lack of Rab27a thus causes pigment anomalies and dysfunctional T lymphocytes, in agreement with the defects observed in the patients. The Griscelli syndrome with neurological symptoms is caused by mutations in the gene encoding the motor protein myosin Va , a putative Rab27a effector that drives the peripheral distribution of melanosomes along actin filaments . As myosin Va does not participate in the exocytosis of lytic granules, the inactivation of this protein does not lead to immunological symptoms.
Choroideremia is an X-linked disease that involves the degeneration of the retinal pigment epithelium and the adjacent choroid and retinal photoreceptor cell layers, leading to blindness. The gene mutated in choroideremia is one of the two REP isoforms, REP-1 . Although the other isoform, REP-2, seems to be sufficient for the geranylgeranylation of all Rab GTPases in all tissues except for the retinal pigment epithelium, REP-1 is essential for the efficient geranylgeranylation of Rab27a in this tissue. Thus, a lack of REP-1 leads to a lack of functional Rab27a specifically in the retinal pigment epithelium . The degeneration of this epithelium and its adjacent layers may be due to deficient melanosome transport and consequently a lack of protection against harmful light exposure.
A subgroup of patients with X-linked nonspecific mental retardation have mutations in the gene for one of the GDI isoforms, GDI-α . This isoform is particularly abundant in the brain, and dysfunctional membrane recycling of one or more Rab GTPases in brain synapses, leading to aberrant neurotransmission, is likely to underly the symptoms in this disease.
The Rab GTPases are a large family of proteins with a variety of regulatory functions in membrane traffic. The central role of these proteins has become clear during the past decade, as part of the progress in understanding in detail the mechanistic principles of transport vesicle formation, movement, and fusion. Sequencing of the human genome has allowed us to realize the diversity of the Rab gene family, though the functions of a majority of the gene products are unknown. The availability of complete genomic sequences, as well as important advances in molecular and cell biological methods, promise to bring a significant progress in our understanding of Rab function in the near future.
At the molecular level, the identification of novel GAPs, GEFs and effectors will yield information about the regulation of Rab GTPases and the molecular complexes they control. Crosstalk with regulatory mechanisms involving other members of the Ras GTPase superfamily is already becoming apparent. A key question concerns the targeting of the Rab GTPases. Which 'receptor' molecules determine their specific intracellular distributions? A combination of biochemical and genetic approaches will hopefully illuminate this issue.
At the level of the membrane, several aspects of Rab GTPase function remain to be clarified. Are Rab GTPases confined to restricted membrane domains  and, if so, how is this determined? Furthermore, how do Rab GTPases and their effectors regulate membrane budding, motility and fusion? With respect to membrane fusion, the role of Rab effectors as membrane tethers is already being revealed, and it seems realistic to expect that Rab-dependent membrane fusion may be reconstituted in vitro from purified components in the near future.
Finally, comprehending the ways in which the regulatory actions of Rabs intertwine with cell-signaling cascades and developmental processes is an enormous task for cell biologists. Here, the natural mutant models provided by human genetic diseases that have defects in Rabs or their auxiliary proteins, as well as the novel genome-wide approaches for gene expression analysis, will be instrumental.
Touchot N, Chardin P, Tavitian A: Four additional members of the ras gene superfamily isolated by an oligonucleotide strategy: molecular cloning of YPT-related cDNAs from a rat brain library. Proc Natl Acad Sci USA. 1987, 84: 8210-8214. Describes the identification of the first mammalian Rab GTPases, and the term 'Rab' is introduced.
Stenmark H, Parton RG, Steele-Mortimer O, Lütcke A, Gruenberg J, Zerial M: Inhibition of rab5 GTPase activity stimulates membrane fusion in endocytosis. EMBO J. 1994, 13: 1287-1296. Shows that a GTPase-deficient mutant of Rab5 stimulates endocytic membrane fusion, whereas a GDP-bound mutant has the opposite effect. Identifies the GTP-bound form as the 'active' one.
Zerial M, McBride H: Rab proteins as membrane organizers. Nat Rev Mol Cell Biol. 2001, 2: 107-117. 10.1038/35052055. An excellent review of the functions of Rab GTPases in membrane traffic.
Bock JB, Matern HT, Peden AA, Scheller RH: A genomic perspective on membrane compartment organization. Nature. 2001, 409: 839-841. 10.1038/35057024. Using information from expressed sequence tags and the recently published genome sequences, this paper describes a bioinformatic analysis of several protein families involved in membrane traffic, including Rab GTPases.
Pereira-Leal JB, Seabra MC: The mammalian Rab family of small GTPases: definition of family and subfamily sequence motifs suggests a mechanism for functional specificity in the Ras superfamily. J Mol Biol. 2000, 301: 1077-1087. 10.1006/jmbi.2000.4010. This outstanding report contains extensive sequence comparisons within the Rab family and analysis of the results along with the information available from crystallography studies. The authors define sequence motifs that can be used to identify proteins belonging to the Rab family, and further, to specify subfamilies. A model is presented in which an effector, upon binding to a Rab, recognizes both Rab family-specific (switch) motifs to discriminate between the nucleotide-bound states, and simultaneously subfamily-specific regions that confer specificity on the interaction.
Moore I, Schell J, Palme K: Subclass-specific sequence motifs identified in Rab GTPases. Trends Biochem Sci. 1995, 20: 10-12. 10.1016/S0968-0004(00)88939-2. This sequence comparison describes the first subclass-specific sequence motifs within the Rab GTPase family. The authors suggest that these may be involved in determining functional specificity.
Chavrier P, Gorvel JP, Stelzer E, Simons K, Gruenberg J, Zerial M: Hypervariable C-terminal domain of rab proteins acts as a targeting signal. Nature. 1991, 353: 769-772. 10.1038/353769a0. Hybrids between Rab2, Rab5 and Rab7 were found to localize to the intracellular membranes determined by the carboxyl termini of the Rab GTPases.
Echard A, Opdam FJ, de Leeuw HJ, Jollivet F, Savelkoul P, Hendriks W, Voorberg J, Goud B, Fransen JA: Alternative splicing of the human Rab6A gene generates two close but functionally different isoforms. Mol Biol Cell. 2000, 11: 3819-3833. Describes the alternative splicing of the Rab6a transcript and the resulting expression of two forms (Rab6a and Rab6a') that differ by three amino acids flanking one of the GTP-binding regions. The two splice forms have different abilities to bind effectors and to regulate intra-Golgi traffic.
Dumas JJ, Zhu ZY, Connolly JL, Lambright DG: Structural basis of activation and GTP hydrolysis in Rab proteins. Structure Fold Des. 1999, 7: 413-423. 10.1016/S0969-2126(99)80054-9. Reports the first high-resolution structure of a Rab GTPase, that of Rab3a complexed with the GTP analog GppNHp. The analysis reveals structural determinants that stabilize the active conformation and regulate the GTPase activity of Rab proteins.
Ostermeier C, Brunger AT: Structural basis of Rab effector specificity: crystal structure of the small G protein Rab3A complexed with the effector domain of Rabphilin-3A. Cell. 1999, 96: 363-374. This important study reports the structure of Rab3a bound to the effector domain of rabphilin-3A, an interacting partner suggested to mediate the regulatory action of the Rab on downstream targets. The work sheds light on the specific determinants of interaction between a Rab in the active conformation and its effectors.
Chattopadhyay D, Langsley G, Carson M, Recacha R, DeLucas L, Smith C: Structure of the nucleotide-binding domain of Plasmodium falciparum Rab6 in the GDP-bound form. Acta Crystallogr. 2000, D56: 937-944. Reports the crystal structure of P. falciparum Rab6 and its comparison with Rab3a. The work reveals a high degree of conservation of the core fold and also suggests that the switch mechanism is highly similar between the two proteins.
Esters H, Alexandrov K, Constantinescu A-T, Goody RS, Scheidig AJ: High-resolution crystal structure of S. cerevisiae Ypt51(ΔC15)-GppNHp, a small GTP-binding protein involved in the regulation of endocytosis. J Mol Biol. 2000, 298: 111-121. 10.1006/jmbi.2000.3645. A report of the first crystal structure of a yeast Rab GTPase, that of Ypt51p, a regulator of endocytic events, including comparisons with other closely related Rab proteins to pinpoint determinants for specific effector binding and for fine tuning the intrinsic rate of GTP hydrolysis.
Milburn MV, Tong L, DeVos AM, Brünger A, Yamaizumi Z, Nishimura S, Kim S-H: Molecular switch for signal transduction: structural differences between active and inactive forms of protooncogenic ras proteins. Science. 1990, 247: 939-945. This paper and  are the initial reports on the nucleotide-induced conformational changes in small GTPases, introducing the switch concept.
Stroupe C, Brunger AT: Crystal structures of a Rab protein in its inactive and active conformations. J Mol Biol. 2000, 304: 585-598. 10.1006/jmbi.2000.4236. This important study reports the first crystal structures of a Rab GTPase, the S. cerevisiae Sec4p, in both GDP- and GTP-bound conformations. The analysis allows precise identification of the switch regions and provides detailed information on the mechanisms regulating the Rab GTPase cycle.
Schlichting I, Almo SC, Rapp G, Wilson K, Petratos K, Lentfer A, Wittinghofer A, Kabsch W, Pai EF, Petsko GA, Goody RS: Time-resolved X-ray crystallographic study of the conformational change in Ha-Ras p21 protein on GTP hydrolysis. Nature. 1990, 345: 309-315. 10.1038/345309a0. This paper and  are the initial reports on the nucleotide induced conformational changes in small GTPases, introducing the switch concept.
Anant JS, Desnoyers L, Machius M, Demeler B, Hansen JC, Westover KD, Deisenhofer J, Seabra MC: Mechanism of Rab geranylgeranylation: formation of the catalytic ternary complex. Biochemistry. 1998, 37: 12559-12568. 10.1021/bi980881a. Characterizes the ternary complex formed between a Rab GTPase, REP and the geranylgeranyl transferase. The REP-Rab complex is the substrate for the geranylgeranyl transferase.
Alexandrov K, Horiuchi H, Steele-Mortimer O, Seabra MC, Zerial M: Rab escort protein-1 is a multifunctional protein that accompanies newly prenylated rab proteins to their target membranes. EMBO J. 1994, 13: 5262-5273. Shows evidence that REP-1 can chaperone a Rab GTPase to its cognate membrane in a similar manner to GDI.
Dirac-Svejstrup AB, Sumizawa T, Pfeffer SR: Identification of a GDI displacement factor that releases endosomal Rab GTPases from Rab-GDI. EMBO J. 1997, 16: 465-472. 10.1093/emboj/16.3.465. Describes the characterization and partial purification of a membrane protein that acts as a GDI displacement factor for Rab5, Rab7 and Rab9. This factor is likely to participate in the specific targeting of these Rab GTPases to endosomes.
Ullrich O, Stenmark H, Alexandrov K, Huber LA, Kaibuchi K, Sasaki T, Takai Y, Zerial M: Rab GDP dissociation inhibitor as a general regulator for the membrane association of rab proteins. J Biol Chem. 1993, 268: 18143-18150. Shows that excess GDI can retrieve a number of different Rab GTPases from cellular membranes, indicating that GDI serves as a general regulator of Rab-membrane interactions.
Schalk I, Zeng K, Wu SK, Stura EA, Matteson J, Huang MD, Tandon A, Wilson IA, Balch WE: Structure and mutational analysis of Rab GDP-dissociation inhibitor. Nature. 1996, 381: 42-48. 10.1038/381042a0. The crystal structure of GDI-α at 1.8Å resolution. The structure consists of a large multi-sheet domain I and a smaller α-helical domain II. Sequence-conserved regions between GDI and REP are clustered on one side of the structure.
Ullrich O, Horiuchi H, Bucci C, Zerial M: Membrane association of Rab5 mediated by GDP-dissociation inhibitor and accompanied by GDP/GTP exchange. Nature. 1994, 368: 157-160. 10.1038/368157a0. A purified Rab5-GDI complex was used to demonstrate that GDI can deliver Rab GTPases to specific membranes and that membrane association of the Rab GTPase is accompanied by GDI release and nucleotide exchange.
Stenmark H, Vitale G, Ullrich O, Zerial M: Rabaptin-5 is a direct effector of the small GTPase Rab5 in endocytic membrane fusion. Cell. 1995, 83: 423-432. Rabaptin-5, a cytosolic coiled-coil protein, was found to interact specifically with Rab5-GTP and to be recruited to endosomes containing Rab5-GTP. Rabaptin-5 is required for Rab5-dependent endosome fusion.
Simonsen A, Lippé R, Christoforidis S, Gaullier J-M, Brech A, Callaghan J, Toh B-H, Murphy C, Zerial M, Stenmark H: EEA1 links PI(3)K function to Rab5 regulation of endosome fusion. Nature. 1998, 394: 494-498. 10.1038/28879. EEA1 was identified as a Rab5 effector on early endosomes. Its recruitment to endosome membranes and function in endocytic membrane fusion require binding to Rab5-GTP as well as phosphatidylinositol 3-phosphate.
Christoforidis S, McBride HM, Burgoyne RD, Zerial M: The Rab5 effector EEA1 is a core component of endosome docking. Nature. 1999, 397: 621-626. 10.1038/17618. An affinity column with immobilized Rab5-GTP was used to isolate Rab5 effectors from brain cytosol. As many as 22 different proteins are specifically retained on this column, indicating that Rab5 has many effectors. One of these effectors, EEA1, could completely substitute for cytosol in an in vitro endosome fusion assay.
Gorvel JP, Chavrier P, Zerial M, Gruenberg J: rab5 controls early endosome fusion in vitro. Cell. 1991, 64: 915-925. The first demonstration that Rab5 regulates endocytic membrane fusion. In an in vitro assay, a dominant-negative Rab5 mutant, as well as anti-Rab5 antibodies, inhibit homotypic endosome fusion.
McLauchlan H, Newell J, Morrice N, Osborne A, West M, Smythe E: A novel role for Rab5-GDI in ligand sequestration into clathrin-coated pits. Curr Biol. 1998, 8: 34-45. Rab5-GDI was identified as a complex required for the formation of plasma membrane-derived clathrin-coated vesicles in semi-intact cells. This is the first evidence that Rab5 plays a direct role in vesicle formation.
Nielsen E, Severin F, Backer JM, Hyman AA, Zerial M: Rab5 regulates motility of early endosomes on microtubules. Nat Cell Biol. 1999, 1: 376-382. 10.1038/14075. Video microscopy demonstrated that GFP-Rab5-positive structures move along microtubules in vivo. In vitro, Rab5 was found to stimulate the association of endosomes with microtubules and the minus-end-directed transport of endosomes. Rab5-dependent endosome motility depends on the phosphatidylinositol 3-kinase hVPS34.
Lazar T, Götte M, Gallwitz D: Vesicular transport: how many Ypt/Rab-GTPases make a eukaryotic cell?. Trends Biochem Sci. 1997, 22: 468-472. 10.1016/S0968-0004(97)01150-X. This review discusses the functions of yeast Rab GTPases (Ypt proteins) in light of the completed S. cerevisiae genome sequence. Only Ypt proteins that regulate biosynthetic traffic are essential.
Geppert M, Goda Y, Stevens CF, Südhof TC: The small GTP-binding protein Rab3A regulates a late step in synaptic vesicle fusion. Nature. 1997, 387: 810-814. 10.1038/42954. The first (and so far only) knockout of a mammalian Rab GTPase in mice. Rab3a-/- mice are viable and show no striking phenotype, but electrophysiology reveals minor differences in Ca2+-induced synaptic vesicle exocytosis compared to Rab3a+/+ mice.
Olkkonen VM, Ikonen E: Genetic defects of intracellular membrane transport. N Engl J Med. 2000, 343: 1095-1104. 10.1056/NEJM200010123431507. Reviews our current knowledge about inherited diseases that are caused by mutations in genes encoding regulators of intracellular membrane traffic.
Deacon SW, Gelfand VI: Of yeast, mice and men: Rab proteins and organelle transport. J Cell Biol. 2001, 152: F21-F24. 10.1083/jcb.152.4.F21. Discusses several recent articles that implicate Rab27a in the intracellular transport of lytic granules and melanosomes.
Menasche G, Pastural E, Feldmann J, Certain S, Ersoy F, Dupuis S, Wulfraat N, Bianchi D, Fischer A, Le Deist F, de Saint Basile G: Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome. Nat Genet. 2000, 25: 173-176. 10.1038/76024. The first demonstration of a Rab gene mutated in genetic disease.
Hume AN, Collinson LM, Rapak A, Gomes AQ, Hopkins CR, Seabra MC: Rab27a regulates the peripheral distribution of melanosomes in melanocytes. J Cell Biol. 2001, 152: 795-808. 10.1083/jcb.152.4.795. Provides evidence for the role of Rab27a in the peripheral distribution of melanosomes in melanocytes, and for myosin Va as a Rab27a effector. Rab27a was found to colocalize with myosin Va on melanosomes in melanoma cells. Dominant-negative Rab27a mutants have a peri-nuclear distribution of melanosomes. Rab27a and myosin Va were found to coimmunoprecipitate.
Stinchcombe JC, Barral DC, Mules EH, Booth S, Hume AN, Machesky LM, Seabra MC, Griffiths GM: Rab27a is required for regulating secretion in cytotoxic T lymphocytes. J Cell Biol. 2001, 152: 825-833. 10.1083/jcb.152.4.825. Shows the importance of Rab27a for the function of cytotoxic T lymphocytes. Lymphocytes from ashen mice with a loss-of-function mutation in the Rab27a gene show reduced polarization and reduced release of cytotoxic granules upon stimulation.
Pastural E, Barrat FJ, Dufourcq-Lagelouse R, Certain S, Sanal O, Jabado N, Seger R, Griscelli C, Fischer A, De Saint-Basile G: Griscelli disease maps to chromosome 15q21 and is associated with mutations in the myosin-Va gene. Nat Genet. 1997, 16: 289-292. Shows that myosin Va is mutated in Griscelli syndrome patients with neurological symptoms.
Seabra MC, Brown MS, Goldstein JL: Retinal degeneration in choroideremia: deficiency of rab geranylgeranyl transferase. Science. 1993, 259: 377-381. Shows that lymphoblasts from choroideremia patients are deficient in an isoform of component A of geranylgeranyl transferase, now known as REP-1.
Seabra MC, Ho YK, Anant JS: Deficient geranylgeranylation of Ram/Rab27 in choroideremia. J Biol Chem. 1995, 270: 24420-24427. 10.1074/jbc.270.41.24420. Identifies Rab27 as a Rab GTPase that is inefficiently geranylgeranylated in choroideremia, in the absence of REP-1. Rab27 is found in the retinal pigment epithelium, which is affected in choroideremia.
D'Adamo P, Menegon A, Lo Nigro C, Grasso M, Gulisano M, Tamanini F, Bienvenu T, Gedeon AK, Oostra B, Wu SK, et al: Mutations in GDI1 are responsible for X-linked non-specific mental retardation. Nat Genet. 1998, 19: 134-139. 10.1038/487. Mutations in the GDI1 gene (encoding GDI-α) were found in two families with X-linked nonspecific mental retardation. One mutation was a null, whereas the other inhibited binding to Rab3a.
Olkkonen VM, Stenmark H: Role of rab GTPases in membrane traffic. Int Rev Cytol. 1997, 176: 1-85. A comprehensive review of the regulation and functions of Rab GTPases.
We are grateful to Tapani Ihalainen for help in preparing Figure 4. This work was supported by the Research Council of Norway (H.S.), the Norwegian Cancer Society (H.S.), the Novo-Nordisk Foundation (H.S.), the Academy of Finland (grants 45817, 49987 and 50641 to V.M.O.), and the Sigrid Juselius Foundation (V.M.O.).