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.