Here, we describe basic properties of the Arabidopsis thaliana REP (AthREP), first REP outside yeasts or metazoans to be characterized. Deletions in the human CHM locus, encoding one of the two REPs known in humans, result in a retinal. Prenylation, membrane delivery, and recycling of all 60 members of the Rab GTPase family are regulated by two related molecules, Rab escort protein (REP) and GDP dissociation inhibitor (GDI). EMBO J. Stay up-to-date with the latest product news and receive updates from our global community of athletes and partners. 1542T>A, STOP; and two deletions. The Rab escort protein (REP) is an accessory protein of the Rab geranylgeranyl transferase (RGT) complex and it is obligatory for Rab prenylation. Article CAS Google ScholarPosttranslational geranylgeranylation of Rab GTPases is catalyzed by Rab geranylgeranyltransferase (RabGGTase), which consists of a catalytic α/β heterodimer and an accessory Rab escort protein (REP). Upon completion of. Instead, Rab proteins are bound by the Rab escort protein (REP) over a more conserved region of the Rab protein and then presented to the Rab geranylgeranyltransferase. - PMC. Crossref; PubMed; Scopus (202) Google Scholar, 20. To date, the majority of reported mutations in the CHM gene cause a complete loss of REP-1 function. REP 1 publication. In mammalian cells, more than 60 Rabs have been identified [1] . Rab27 has been found to preferentially depend on REP-1 for prenylation, which could be the underlying cause of choroideremia. Seabral Marino ZerialSome Rab escort protein function is necessary for growth in all eukaryotic cells, for it provides a basis for prenylation and targeting of Rabs, without which vesicle transport would be severely impaired. Victoria BC. In this review, the role of Rab3. This modification is preceded by the formation of a trimeric protein complex with the Rab escort protein (REP) and the Rab geranylgeranyltransferase (RabGGTase). We developed a. 2001. CHM Like Rab Escort Protein 2 3 5. The prenylated protein can be solubilized in the cytosol by the GDP dissociation inhibitor (GDI), which shields the hydrophobic geranylgeranyl groups. The role of REP-1 in the Rab cycle (A) Newly synthesized Rab proteins are transported by Rab escort proteins (REPs) to geranylgeranyl transferases. 13, 5262–5273 [PMC free article] [Google Scholar] Ali B. Here we report pathogenic mutations: a novel missense mutation, L550P; a truncation c. REP binds preferentially to Rab proteins that are in the GDP state, but the specific structural. Rab GTPases need to be geranylgeranyled on either one or two cysteine residues in their C-terminus to. Rab PROTEINS EXPRESSION: NEWLY SYNTHESIZED VERSUS. a Rab escort protein and eector of the TOR pathway that plays a role in nutrient signaling. 3: GDI-like N domain [51931] (2 proteins) Similar to FAD-linked reductases in both domains but does not bind FAD Protein Rab escort protein 1 [89546] (1 species)Enables Rab geranylgeranyltransferase activity. In addition to GAPs and GEFs, Rab GDP dissociation inhibitors (GDIs) and Rab escort proteins (REPs) also functions in the adjustment of the Rab GTPases activity (Stenmark, 2009; Müller and Goody, 2018). Shows evidence that REP-1 can chaperone a Rab GTPase to its cognate membrane in a similar manner to GDI. After GG transfer, REP remains associated with diGG-Rab, which leads to insertion of the Rab into a specific membrane. Membrane localization is mediated by geranylgeranylation of two C-terminal cysteine residues by Rab geranylgeranyl transferase (GGTase) with assistance of Rab escort protein (REP) (2, 3). automatic annotation. (C) GTPase activating proteins (GAPs) promote efficient GTP hydrolysis resulting in an inactive state. GFP-tagged. The structure of RGGT. Rab escort protein (REP) presents Rabs to geranylgeranyltransferase which adds isoprenoid moieties to one or two cysteine resides. Acts upstream of or within several processes, including detection of mechanical stimulus involved in sensory perception of sound; iridophore differentiation; and sensory organ development. , Seabra M. 7,9 The double prenylation observed in most Rab proteins proceeds without intermediate release of the mono-prenylated Rab protein. , 2005). Rabs specifically associate with target membranes via the attachment of (usually) two geranylgeranyl groups in a reaction involving Rab escort protein and Rab geranylgeranyl transferase. AAAARAB GERANYLGERANYLTRANSFERASE ALPHA SUBUNITRAB GERANYLGERANYLTRANSFERASE BETA SUBUNITRab Escort Protein 1CHLORIDE IONFARNESYLZINC ION. Under-prenylation of certain Rabs, as a result of loss of function mutations in REP-1, could affect vesicular trafficking, exocytosis. The crystal structures of the REP-1 protein in complex with monoprenylated or C-terminally truncated Rab7 proteins revealed that Rab7. Part of Rab-protein geranylgeRab escort protein-1 (REP1) is linked to choroideremia (CHM), an X-linked degenerative disorder caused by mutations of the gene encoding REP1 (CHM). Mis-regulation of. J. e. Rab escort protein-1 is a multifunctional protein that accompanies newly prenylated rab proteins to their target membranes EMBO J. Rab proteins are hydrophilic, thus, in order for membrane binding they must possess one, or two, C20 geranyl–geranyl lipid groups at their carboxy terminus. Name. , Lamoreux L. Steele-Mortimer, O. The crystal structure of isoprenoid-bound RabGGTase complexed to REP-1 has been solved to 2. After GG transfer, REP remains associated with diGG-Rab, which leads to insertion of the Rab into a specific membrane. 2002. 1994; 13: 5262-5273. While REP–Rab interactions have been studied by biochemical, structural, and genetic methods in animals and yeast, data on the plant RGT complex are still limited. Rab proteins play a critical role in intracellular vesicle trafficking and require post-translational modification by adding lipids at the C-terminus for proper functions. Alexandrov K, Horiuchi H, Steele-Mortimer O, Seabra M, Zerial M: Rab escort protein-1 is a multifunctional protein that accompanies newly prenylated rab proteins to their target membranes. The Rab geranylgeranyl transferase that catalyzes the Rab isoprenylation is a multisubunit enzyme consisting of a Rab escort protein (REP) and a catalytic heterodimer (Leung et al. CHML is an NRF2 target gene that regulates mTOR function. Ras-related protein Rab-3A is a protein that in humans is encoded by the RAB3A gene. Rab escort proteins (REPs) deliver newly synthesized and prenylated Rab to its destination membrane by binding the hydrophobic, insoluble prenyl groups and carrying Rab through the cytoplasm. In 22 patients, small mutations have been. Geranyl-geranyl groups are transferred to Rab proteins by geranyl-geranyl transferase 2 (GGTase2). REP binds to unprenylated Rab, presents it to Rab. , Wasmeier C. More than 30 different Rab proteins have been identified, and many of these have been localized to discrete subcellular. Advertisement. Ordered locus names. REP binds preferentially to Rab proteins that are in the GDP state, but the specific structural domains involved in this interaction have not been. Here, we studied the role of REP in the geranylgeranylation reaction. REP1 acts in the prenylation of Rab GTPases, regulators of intracellular protein trafficking. When a Rab protein is biosynthesized, it is first recognized by Rab escort proteins (REPs) in the cytosol and then recruited to the Rab geranylgeranyl transferase (RabGGTase) complex, by which it undergoes geranylgeranylation modification [2,3] (Figure 1 A). Functions of other effectors of Rab proteins, e. The lipid prenyl groups can then insert into the membrane, anchoring Rab at the cytoplasmic face of a vesicle or the plasma membrane. CHM/REP1 deficiency in inherited. More than 50 Rabs have been described in mammalian cells (1), each. Next, the rab:REP complex is specifically recognized by a rab geranylgeranyl. Rab escort protein. 1992) and was later found in all eukaryotes (reviewed in Gutkowska and Swiezewska 2012 ). , Lin H. Rab GTPases are post-translationally geranylgeranylated on their C-terminal cysteines by Rab geranylgeranyl transferase (RabGGTase) and this modification is essential for their biological activity. Affected males experience progressive atrophy of the choroid, retinal pigment epithelium and retina leading to eventual blindness. rab proteins geranylgeranyltransferase component A 2, CHM like Rab escort protein 2, choroideraemia-like protein, choroideremia-like (Rab escort protein 2), choroideremia-like protein. Lipid anchors are common post-translational modifications for proteins engaged in signaling and vesicular transport in eukaryotic cells. J Cell Physiol, 2000 Dec. The structure of RabGGT reveals an unusual architecture of four distinct domains, each with. CHML. Rabs are monomeric GTPases, which function as regulators of intracellular vesicular transport and organelle dynamics (10, 11). MAPK pathways. Abstract. All newly synthesized Rabs (preferentially in their GDP-bound forms) are recognized by REP (Rab escort protein) and presented to RabGGT (Rab geranylgeranyl transferase), which geranylgeranylates the Rab on one or two C-terminal Cys residues. A Rab escort protein regulates the MAPK pathway that controls filamentous growth in yeast. The Rab escort protein (REP) is an essential component of the heterotrimeric enzyme Rab geranylgeranyl transferase that modifies the carboxy-terminal cysteines of the Ras-like small G proteins belonging to the Rab/Ypt family. After their synthesis on cytosolic ribosomes, Rab proteins are recognized by the Rab escort protein (REP), of which two isoforms (REP-1 and REP-2) are present in mammalian cells. The CHM gene encodes for Rab escort protein-1 (REP-1). Research suggests that when REP-1 is absent or nonfunctional, REP-2 can perform the protein escort duties of REP-1 in many of the body's tissues. First symptoms, such as night blindness. The REP recognizes and binds to conserved sequences in Rabs and the catalytic complex transfers the geranylgeranyl group. NCBI. Posttranslational geranylgeranylation of Rab GTPases is catalyzed by Rab geranylgeranyltransferase (RabGGTase), which consists of a catalytic α/β heterodimer and an accessory Rab escort protein. Acts upstream of or within blood vessel development. In their active state, Rab proteins perform a myriad of functions, including. REP binds unprenylated Rab and presents it to Rab GGTase. Like other GTPases, Rabs cycle between an inactive (GDP. Rab escort protein 1 ( REP1) also known as rab proteins geranylgeranyltransferase component A 1 is an enzyme that in humans is encoded by the CHM gene. 1LTX: Structure of Rab Escort Protein-1 in complex with Rab geranylgeranyl. The REP recognizes and binds to conserved sequences in Rabs and the catalytic complex transfers the geranylgeranyl group. Gene ID: 102409063, updated on 28-Nov-2023. EMBO J. Following prenylation, REP is postulated to accompany the modified GTPase to its specific target membrane. Normal Function The CHM gene provides instructions for producing the Rab escort protein-1 (REP-1), which is active (expressed) throughout the body. 0, 300 mM NaCl, and 2 mM beta-mercaptoethanol, 1 mM PMSF as described above. Newly synthesized Rab proteins are bound to Rab escort proteins (REP) and presented to the Rab geranylgeranyltransferase (GGTase) type II, which mediates the prenylation of Rab proteins on two carboxy terminal cysteine residues. In addition, four Rab subfamily regions (RabSF) were defined as regions of high conservation within subfami-Rab proteins are geranylgeranylated on one or two C-terminal cysteines by Rab geranylgeranyl transferase (RabGGTase). Rab escort protein 1. AR42J cells are derived from rat pancreatic exocrine tumor cells and develop an acinar cell-like phenotype when treated with dexamethasone (Dex). The coupling of environmental conditions to cell growth and division is integral to cell fitness. Binds unprenylated Rab proteins and presents the substrate peptide to the catalytic component B. Rabs specifically associate with target membranes via the attachment of (usually) two geranylgeranyl groups in a reaction involving Rab escort protein and Rab geranylgeranyl transferase. [Google Scholar] Simons K, Zerial M. Interactions. 2, 3 We have investigated its interaction with the Rab escort protein 1 (REP-1) and Rab geranylgeranyltransferase (Rab GGTase). Rab escort protein-1 (REP1) is linked to choroideremia (CHM), an X-linked degenerative disorder caused by mutations of the gene encoding REP1 (CHM). Posttranslational modification of Rab proteins by geranylgeranyltransferase type II requires that they first bind to Rab escort protein (REP). GGTase2 requires Rab escort protein 1 (REP1) to bind Rab proteins. 7 Å resolution. Under-prenylation of certain Rabs, as a result of loss of function mutations in REP-1, could affect vesicular trafficking, exocytosis and. CHM Like Rab Escort Protein 2 2 3. Newly synthesized RABs are bound to a RAB escort protein, CHM (also known as REP1) or CHML (REP2) (Alexandrov et al, 1994; Shen and Seabra, 1996). Y. Its struc-ture is composed of two subdomains. Rab GTPases participating in the regulation of vesicle trafficking in eukaryotes are geranylgeranylated by the Rab geranylgeranyl transferase (RabGGTase) in complex with the Rab escort protein (REP). So far, efforts to obtain the structure of the whole complex of RGGT αβ heterodimer together. Rab proteins and the road maps for intracellular transport. Here, we studied the role of REP in the geranylgeranylation reaction. Part of Rab-protein geranylgeranyltransferase complex. Rab GTPases participating in the regulation of vesicle trafficking in eukaryotes are geranylgeranylated by the Rab geranylgeranyl transferase (RabGGTase) in complex with the Rab escort protein (REP). Rab proteins as molecular switches. von Bokhoven H, et al. Posttranslational attachment of geranylgeranyl moieties is essential for Rab function. Find. Furthermore, Rab escort protein1 (REP1), which has been shown to be critical for prenylation of Rab G-proteins, is also expressed in these cells. Rab escort protein-1 is a multifunctional protein that accompanies newly prenylated rab proteins to their target membranes. As shown earlier (Pylypenko et al. In addition, four Rab subfamily regions (RabSF) were defined as regions of high conservation within subfami- Rab proteins are geranylgeranylated on one or two C-terminal cysteines by Rab geranylgeranyl transferase (RabGGTase). REP proteins are composed of two conserved domains connected by a 150. Involved in protein geranylgeranylation. Go to Variation Viewer for CHML variants; Summary. The third enzyme, geranylgeranyltransferase 2 (GGT2 or RabGGT) recognizes the complex of Rab GTPase substrate proteins with a specific Rab escort protein (REP) to attach one or two geranylgeranyl anchors to cysteines in a more flexible but also carboxy-terminal motif. Rab escort proteins are required for Rab prenylation, which is an absolute requirement for Rab function (Seabra and Wasmeier, 2004). Y. 1 INTRODUCTION. Van den Hurk et al. In its GDP-bound or “inactive” state, it is subsequently. Fluorescence methods for monitoring interactions of Rab proteins with nucleotides, Rab escort protein, and geranylgeranyltransferase Methods Enzymol . Geranylgeranylation is mediated by Rab geranylgeranyl transferase (GGTase II, also known as RABGGTB) in cooperation with Rab escort protein (REP, for which there are several isoforms) (Leung et al. (a) Rab proteins are intrinsically soluble and require the post-translational covalent attachment of isoprenoid moieties to their C-termini for membrane association. GGTase2 requires Rab escort protein 1 (REP1) to bind Rab proteins. Cells were lysed in 50 mM Tris, pH 8. In addition to mutations in the Rabs themselves, mutations in Rab-related proteins are also associated with (partial) dysfunction of Rab proteins or changes in Rab activity, e. In this review we explore the role of REP1 in the retina and its newly discovered systemic manifestations, and discuss the therapeutic strategies for tackling this. We confirmed that overexpression of MRS6 induces hyperpolarized growth (Fig. CHML is localized. M itogen- a ctivated p rotein k inase (MAPK) pathways. Loss of functional REP1 leads to the accumulation of unprenylated Rab proteins and defective intracellular protein trafficking, the putative cause for photoreceptor, retinal pigment epithelium. 7 A resolution. are relatively abundant cytosolic proteins that bind prenylated Rab-GTPases with high specificity. MRS6 overexpression stimulated 14 filamentous/invasive growth and phosphorylation of the ERK-type fMAPK, Kss1. Rab escort proteins (REP) 1 assist in the geranylgeranylation of the Rab/Ypt type of small G proteins, which is catalyzed by Rab geranylgeranyl transferase (GGTase; reviewed in Ref. , 2006). REP functions as a molecular chaperone that presents Rab proteins to the RabGGTase and after. It helps in vesicle transportation, so mutations in CHM genes result in trafficking defects that affects photo-transduction in rod photoreceptor cells. accompanies newly prenylated rab proteins to their target. Chan D, et al. The reaction is dependent on a Rab-binding protein, termed Rab escort protein (REP). Part of Rab-protein geranylgeranyltransferase complex. As a slowly progressing monogenic retinal degeneration with a clearly identifiable phenotype and a reliable diagnosis, CHM is an ideal candidate for gene therapy. J Biol Chem 272:16972–16977. 37 Whether myocardial Rab proteins are regulated in human cardiac. 88: 2: CHML: CHM Like Rab Escort ProteinThis enzymatic reaction is catalyzed by geranylgeranyltransferase type II (i. Choroideremia patients have loss of function mutations in REP1 and the murine Hermansky–Pudlak syndrome model gunmetal possesses a splice-site mutation in the α. Chm CHM Rab escort protein [ (Norway rat)] Enables small GTPase binding activity. It is involved in calcium-triggered exocytosis in neurons. Mrs6 is a Rab escort protein (REP) that makes a complex with the Rab GTPases Ypt1, Sec4, Ypt6, Vps21 107 – 109. The process by which they gain these lipid moieties is known as isoprenylation. Rab escort protein 1 Curated. Prenylation is mediated by the Rab escort protein (REP), which binds to the Rab and presents it to the Rab geranylgeranyltransferase (GGTase) for double prenylation . At3g06540 Imported.