Rab escort protein-1 is a multifunctional protein that accompanies newly prenylated rab proteins to their target membranes.

Alexandrov, Kirill; Horiuchi, Hisanori; Steele‐Mortimer, Olivia; Seabra, Miguel C.

doi:10.1002/j.1460-2075.1994.tb06860.x

Cited by 217 publications

(193 citation statements)

References 46 publications

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“…GGTase I can transfer the geranylgeranylated protein directly to RhoGDI. Such a model is supported by the homology between RhoGDI and the Rab escort protein that serves such a function for geranylgeranyltransferase type II (Andres et al, 1993;Alexandrov et al, 1994). However, for Rho proteins that do not bind RhoGDI, such as RhoB, GGTase I as a cytosolic chaperone remains an attractive hypothesis.…”

Section: Discussionmentioning

confidence: 99%

PostprenylationCAAXProcessing Is Required for Proper Localization of Ras but Not Rho GTPases

Michaelson

Ali

Chiu

et al. 2005

MBoC

154

141

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The CAAX motif at the C terminus of most monomeric GTPases is required for membrane targeting because it signals for a series of three posttranslational modifications that include isoprenylation, endoproteolytic release of the C-terminal-AAX amino acids, and carboxyl methylation of the newly exposed isoprenylcysteine. The individual contributions of these modifications to protein trafficking and function are unknown. To address this issue, we performed a series of experiments with mouse embryonic fibroblasts (MEFs) lacking Rce1 (responsible for removal of the -AAX sequence) or Icmt (responsible for carboxyl methylation of the isoprenylcysteine). In MEFs lacking Rce1 or Icmt, farnesylated Ras proteins were mislocalized. In contrast, the intracellular localizations of geranylgeranylated Rho GTPases were not perturbed. Consistent with the latter finding, RhoGDI binding and actin remodeling were normal in Rce1-and Icmtdeficient cells. Swapping geranylgeranylation for farnesylation on Ras proteins or vice versa on Rho proteins reversed the differential sensitivities to Rce1 and Icmt deficiency. These results suggest that postprenylation CAAX processing is required for proper localization of farnesylated Ras but not geranygeranylated Rho proteins.

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Section: Discussionmentioning

confidence: 99%

PostprenylationCAAXProcessing Is Required for Proper Localization of Ras but Not Rho GTPases

Michaelson

Ali

Chiu

et al. 2005

MBoC

154

141

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“…Alexandrow et al reported that REP-1 is associated with the GDPbound form of the rab proteins [33]. After accompanying the rab-GDP complex to the target membrane the REP-protein is released and the GDP is exchanged to GTP.…”

Section: Discussionmentioning

confidence: 99%

Nucleotide induced conformation determines posttranslational isoprenylation of the ras related rab6 protein in insect cells

1995

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Small GTP binding proteins of the rablYPT family art, essential regulators of vectorial transport in the eukaryotic cell. Members of the rab/YPT1 family are found on the cytoplasmic surface of distinct intracellular membrane compartments. Membrane attachment is facilitated by a C-terminal geranylgeranyl moiety. In this report we investigated posttranslational modification and membrane binding of the rab6 protein, a member of the rab/YPT family located on the Golgi apparatus. A set of point mutations, which simulate the GDP or GTP bound conformation, was introduced into the rab6 cDNA. The mutated cDNAs were expressed in insect cells and the ability of the protein products to undergo geranylgeranyl modification and membrane association was assessed by Triton X-114 partition and cell fractionation. We report here that the modification of rab6 in insect cells depends on protein conformation. Only the GDP bound form, but not the GTP bound form is isoprenylated and subsequently membrane bound.

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“…Original studies suggested that the prenylation reaction catalyzed by farnesyl transferase or GGTase I proceeds via a random sequential mechanism by which the enzyme can bind the protein and lipid substrates independently [8,9]. However, recent studies with human and yeast farnesyl transferase supported an ordered addition of substrates [10,11].In contrast with other known prenyl transferases, RabGGTase does not recognize its substrate directly but exerts its function in concert with another protein termed REP (Rab escort protein) [12,13]. Two known mammalian proteins, Eur.…”

mentioning

confidence: 99%

“…In contrast with other known prenyl transferases, RabGGTase does not recognize its substrate directly but exerts its function in concert with another protein termed REP (Rab escort protein) [12,13]. Two known mammalian proteins, REP-1 and REP-2, share 75% amino acid sequence identity and functionally overlap [14].…”

mentioning

confidence: 99%

“…However, the exact sequence of events as well as the kinetic mechanism of the prenylation reaction remains largely unexplored. After prenylation, the Rab protein remains bound to REP which accompanies it to the corresponding membrane [12,22]. The Rab protein is released on to the membrane, presumably through interaction with a membrane receptor/REP-displacing factor which might be shared by REP and GDP-dissociation inhibitors [23].…”

mentioning

confidence: 99%

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Characterization of the ternary complex between Rab7, REP‐1 and Rab geranylgeranyl transferase

Alexandrov

Simón²,

Yurchenko³

et al. 1999

European Journal of Biochemistry

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Geranylgeranylation is a post-translational modification of Rab GTPases that enables them to associate reversibly with intracellular membranes. Geranylgeranylation of Rab proteins is critical for their activity in controlling intracellular membrane transport. According to the currently accepted model for their action, newly synthesized Rab proteins are recruited by Rab escort protein (REP) and are presented to the Rab geranylgeranyl transferase (RabGGTase) which covalentely modifies the Rab protein with two geranylgeranyl moieties. After prenylation, the Rab protein remains in complex with REP and is delivered to the target membrane by the latter. In this work, we show that RabGGTase can form a stable complex with Rab7±REP in the absence of its lipid substrate geranylgeranyl pyrophosphate. In order to characterize this interaction, we developed three fluorescence assays reporting on the interaction of RabGGTase with the Rab7±REP complex. For this interaction we determined a K d value of about 120 nm.Association of RabGGTase with the Rab7±REP complex occurs with a rate constant of < 10 8 m 21´s21 . We demonstrate that the state of the nucleotide bound to Rab7 does not influence the affinity of RabGGTase for the Rab7±REP-1 complex. Finally, we address the issue of substrate specificity of RabGGTase. Titration experiments demonstrate that, in contrast with farnesyl transferase, RabGGTase does not recognize a defined C-terminal sequence motif. Experiments using Rab7 mutants in which the last 16 amino acids were either mutated or truncated revealed that the distal part of the C-terminus makes only a limited contribution to the binding affinity between RabGGTase and the Rab7±REP-1 complex. This demonstrates the functional dissimilarity between RabGGTase and geranylgeranyl transferase I and farnesyl transferase, which interact specifically with the C-terminus of their substrates. Based on these experiments, we propose that RabGGTase recognizes the overall structure arising from the association of Rab and REP and then`scans' the flexible C-terminus to position the proximal cysteines into the active site.Keywords: geranylgeranylation; prenyltransferase; Rab7; Rab geranylgeranyl transferase; REP.Rab proteins are members of the Ras superfamily of small GTP-binding proteins. Many of them were shown to be implicated in control of intracellular vesicular traffic [1,2]. For their function Rab proteins require modification by geranylgeranyl isoprenoids. This allows them to associate reversibly with a membrane in a tightly controlled fashion [3,4]. Covalent attachment of geranylgeranyl groups to two C-terminal cysteines is catalyzed by Rab geranylgeranyl transferase (RabGGTase).Mammalian RabGGTase (GGTase II) is a heterodimer composed of tightly associated a and b subunits of 60 and 38 kDa, respectively [5,6], and belongs to the family of protein prenyl transferases together with farnesyl transferase and geranylgeranyl transferase I (GGTase I) [7]. Substrates of farnesyl transferase include members of the Ras family, lamin b and...

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Rab escort protein-1 is a multifunctional protein that accompanies newly prenylated rab proteins to their target membranes.

Cited by 217 publications

References 46 publications

PostprenylationCAAXProcessing Is Required for Proper Localization of Ras but Not Rho GTPases

PostprenylationCAAXProcessing Is Required for Proper Localization of Ras but Not Rho GTPases

Nucleotide induced conformation determines posttranslational isoprenylation of the ras related rab6 protein in insect cells

Characterization of the ternary complex between Rab7, REP‐1 and Rab geranylgeranyl transferase

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