Affinage

RABGGTB

Geranylgeranyl transferase type-2 subunit beta · UniProt P53611

Round 2 corrected
Length
331 aa
Mass
36.9 kDa
Annotated
2026-04-28
47 papers in source corpus 12 papers cited in narrative 12 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RABGGTB is the catalytic beta subunit of two distinct protein geranylgeranyltransferase complexes: the canonical Rab geranylgeranyltransferase (RabGGTase, paired with RABGGTA and REP escort proteins) that doubly geranylgeranylates Rab GTPases to direct their membrane targeting and vesicular trafficking, and GGTase-III (paired with PTAR1) that geranylgeranylates non-Rab substrates including FBXL2 and the Golgi SNARE Ykt6 (PMID:8505342, PMID:31209342, PMID:32128853). Within RabGGTase, RABGGTB catalyzes attachment of two geranylgeranyl groups to C-terminal di-cysteine motifs (CC, CXC, CCXX) of Rab proteins such as Rab1A, Rab5A, Rab6, and Rab27a; this double prenylation is essential for correct organellar targeting and function, as mono-prenylated Rabs are mistargeted and non-functional (PMID:7991565, PMID:12802062). In the GGTase-III complex, a crystal-structure-defined multivalent interface between PTAR1 and the FBXL2 LRR domain determines substrate specificity, while GGTase-III-dependent double prenylation of Ykt6 is required for Golgi SNARE complex assembly and intra-Golgi trafficking (PMID:31209342, PMID:32128853). RABGGTB-mediated Rab7 geranylgeranylation also promotes autophagosome–lysosome fusion, and overexpression of RABGGTB in SOD1-G93A ALS mouse models delayed disease onset and reduced protein aggregation (PMID:38042502, PMID:36967828).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 1993 High

    Identification of RABGGTB as the catalytic beta subunit of RabGGTase resolved the molecular identity of the enzyme that prenylates Rab GTPases, establishing that it functions as a heterodimer with an alpha subunit and requires the REP escort protein for activity.

    Evidence cDNA cloning and heterologous co-expression in 293 cells with reconstituted enzymatic activity; complemented by biochemical fractionation in choroideremia patient lymphoblasts showing separable Component A (REP) and Component B (alpha/beta) activities

    PMID:8380507 PMID:8505342

    Open questions at the time
    • Structural basis for how RABGGTB engages REP and lipid substrate was unknown
    • Whether RABGGTB participates in complexes beyond RabGGTase was not considered
  2. 1994 High

    Demonstration that RabGGTase doubly geranylgeranylates Rab C-terminal di-cysteine motifs (CC, CXC, CCXX) and that substrate recognition depends on the hypervariable C-terminal region established the catalytic product and substrate-selection rules for the RABGGTB-containing enzyme.

    Evidence In vitro prenylation with HPLC/mass spectrometry of Rab1A, Rab3A, Rab5A tryptic peptides; Rab6 deletion/substitution mutagenesis coupled to prenylation and GDI-extraction assays

    PMID:7991565 PMID:8175798

    Open questions at the time
    • Atomic-level mechanism of double prenylation was unresolved
    • In vivo functional consequences of mono- versus di-prenylation were unknown
  3. 2003 High

    The crystal structure of isoprenoid-bound RabGGTase–REP-1 revealed the allosteric communication between the lipid-binding site and the REP interface, and cell-biological experiments showed that double geranylgeranylation is required for correct Rab targeting to organelles in vivo.

    Evidence X-ray crystallography at 2.7 Å with binding assays; EGFP-Rab mutant localization in HeLa cells, inhibitor treatment, and Rab27a rescue in knockout mice

    PMID:12620235 PMID:12802062

    Open questions at the time
    • Whether RABGGTB could function with alternative alpha subunits was not explored
    • Structural basis for Rab substrate recognition within the active site remained incomplete
  4. 2019 High

    Discovery that RABGGTB pairs with the orphan alpha subunit PTAR1 to form a second prenyltransferase (GGTase-III) that geranylgeranylates the non-Rab substrate FBXL2 fundamentally expanded the functional repertoire of RABGGTB beyond Rab biology.

    Evidence Co-immunoprecipitation, reconstituted in vitro prenylation, subcellular fractionation, and X-ray crystallography of the GGTase-III–FBXL2–SKP1 ternary complex with mutagenesis

    PMID:31209342

    Open questions at the time
    • Full substrate scope of GGTase-III was unknown
    • Physiological contexts where GGTase-III versus RabGGTase activity is limiting were uncharacterized
  5. 2020 High

    Identification of Ykt6 as a second GGTase-III substrate and demonstration that GGTase-III-dependent double prenylation of Ykt6 is required for Golgi SNARE complex assembly established RABGGTB's role in Golgi organization through a non-Rab pathway.

    Evidence Biotinylated geranylgeranyl labeling, in vitro prenylation, X-ray crystallography of GGTase-III–Ykt6, gene-knockout cell lines with Golgi trafficking assays

    PMID:32128853

    Open questions at the time
    • Whether additional SNARE or Golgi-resident proteins are GGTase-III substrates is unknown
    • Relative contribution of RabGGTase versus GGTase-III to overall RABGGTB function in vivo is unresolved
  6. 2023 Medium

    Placing RABGGTB-mediated Rab7 prenylation upstream of autophagosome–lysosome fusion linked RABGGTB to autophagic flux, and in vivo overexpression in SOD1-G93A ALS mice was neuroprotective, extending survival and reducing protein aggregation.

    Evidence Lentiviral overexpression in ALS cell models with autophagy flux assays; AAV9-mediated spinal cord delivery in SOD1-G93A mice with behavioral, survival, and histological readouts

    PMID:36967828 PMID:38042502

    Open questions at the time
    • Whether the neuroprotective effect is solely Rab7-dependent or also involves GGTase-III substrates is untested
    • Findings are from single-laboratory studies and have not been independently replicated
    • Therapeutic relevance to human ALS is unestablished
  7. 2025 Medium

    Knockdown of the GGTase-III alpha subunit PTAR1 in pancreatic beta cells severely impaired glucose-stimulated insulin secretion, implicating the RABGGTB-containing GGTase-III complex in regulated exocytosis beyond the nervous system.

    Evidence siRNA knockdown of PTAR1 in INS-1 832/13 cells and primary islets with ELISA-based insulin secretion assays

    PMID:40598917

    Open questions at the time
    • RABGGTB itself was not directly knocked down; the effect is inferred indirectly through the alpha subunit
    • Identity of the GGTase-III substrate(s) responsible for the secretion defect is not established
    • Independent replication is needed

Open questions

Synthesis pass · forward-looking unresolved questions
  • The complete substrate repertoire of GGTase-III, the structural basis for how RABGGTB partitions between RabGGTase and GGTase-III in the same cell, and the in vivo consequences of selectively disrupting one complex versus the other remain open questions.
  • No systematic substrate screen for GGTase-III has been reported
  • No structural or kinetic model explains competitive assembly of RABGGTB with RABGGTA versus PTAR1
  • Conditional knockout studies distinguishing RabGGTase from GGTase-III functions in specific tissues are lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 4
Localization
GO:0005829 cytosol 2 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-5653656 Vesicle-mediated transport 2 R-HSA-9612973 Autophagy 1
Partners
CHMCHMLCHODLFBXL2PTAR1RABGGTAYKT6
Complex memberships
GGTase-III (PTAR1–RABGGTB)RabGGTase (RABGGTA–RABGGTB)

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 RABGGTB encodes the beta subunit of the catalytic Component B (a heterodimer of alpha and beta subunits) of Rab geranylgeranyl transferase (RabGGTase). When the rat alpha and beta subunit cDNAs were co-transfected into 293 cells, the expressed protein produced RabGGTase activity stimulated by Component A (REP). The beta subunit (331 aa) is the yeast BET2 ortholog. cDNA cloning, heterologous co-expression in 293 cells, in vitro enzymatic activity assay The Journal of Biological Chemistry High 8505342
1993 Choroideremia (X-linked retinal degeneration) results from deficiency of Component A (REP-1) of RabGGTase, leaving Component B (which contains RABGGTB) intact. Lymphoblasts from choroideremia patients showed markedly deficient Component A activity but normal Component B activity, establishing that the two components are functionally separable and that RABGGTB-containing Component B activity is unaffected. Enzymatic activity assay in patient lymphoblasts, biochemical fractionation Science High 8380507
1994 RabGGTase (containing RABGGTB) catalyzes geranylgeranylation of both adjacent C-terminal cysteines in Rab1A (-XXCC), Rab3A (-XCXC), and Rab5A (-CCXX), as confirmed by HPLC and electrospray mass spectrometry of in vitro prenylated tryptic peptides. In vitro prenylation assay with recombinant enzyme, HPLC, electrospray mass spectrometry Proceedings of the National Academy of Sciences of the USA High 7991565
1994 RabGGTase processing of Rab6 requires the loop3/beta3 region and the hypervariable C-terminal region of Rab6 but not the effector domain, defining sequence requirements for substrate recognition by the RABGGTB-containing enzyme. Rab6 proteins geranylgeranylated on CXC or CC motifs were significantly better substrates for RabGDI extraction than those prenylated on CAAL motifs. In vitro prenylation assay with Rab6 deletion/substitution mutants, membrane extraction assays with RabGDI The Journal of Biological Chemistry High 8175798
2003 The crystal structure of isoprenoid-bound RabGGTase (containing both alpha and RABGGTB subunits) complexed with REP-1 was solved at 2.7 Å. The RabGGTase–REP-1 interface buries ~680 Ų and is formed by helices 8, 10, and 12 of the RabGGTase alpha subunit and helices D and E of REP-1. The affinity of RabGGTase for REP-1 is allosterically regulated by the phosphoisoprenoid substrate via a long-range trans-domain signal transduction mechanism. X-ray crystallography (2.7 Å), biochemical binding assays Molecular Cell High 12620235
2003 Di-geranylgeranyl modification catalyzed by RabGGTase (containing RABGGTB) is essential for correct targeting of Rab5a to endosomes and Rab27a to melanosomes; mono-cysteine Rab mutants are mistargeted to the ER and are non-functional in vivo, demonstrating that the RABGGTB-dependent double prenylation provides targeting information. Transient expression of EGFP-Rab mutants in HeLa cells, CAAX prenyl transferase inhibition, temperature-shift experiments, transgenic rescue assay in Rab27a-null mice Molecular Biology of the Cell High 12802062
2008 The beta-subunit of Rab geranylgeranyl transferase (RABGGTB) interacts with the cytoplasmic domain of chondrolectin (CHODL), identified by a complete Sos Recruitment System (SRS) yeast two-hybrid screen (8 independent isolates) and confirmed by in vitro transcription/translation and co-immunoprecipitation. Yeast two-hybrid (SRS screen), in vitro transcription/translation, co-immunoprecipitation Cellular & Molecular Biology Letters Medium 18161010
2019 RABGGTB (the catalytic beta subunit of RabGGTase) forms a previously unknown prenyltransferase complex with the orphan alpha subunit PTAR1, named GGTase3. This complex specifically geranylgeranylates FBXL2 (a CaaX-motif F-box protein) to enable its membrane localization, where FBXL2 mediates polyubiquitylation of membrane-anchored proteins. Crystal structure of the full-length GGTase3–FBXL2–SKP1 complex reveals that substrate specificity is determined by an extensive multivalent interface between the LRR domain of FBXL2 and PTAR1, not through the CaaX motif alone. Co-IP, in vitro prenylation assay, subcellular fractionation/localization, X-ray crystallography of ternary complex, mutagenesis Nature Structural & Molecular Biology High 31209342
2020 GGTase-III (PTAR1 + RABGGTB) geranylgeranylates the Golgi SNARE Ykt6, converting mono-farnesylated Ykt6 to a doubly prenylated form. In GGTase-III-deficient cells, Ykt6 remained singly prenylated, Golgi SNARE complex assembly was severely impaired, and Golgi apparatus structure and intra-Golgi protein trafficking were disrupted. Crystal structure of GGTase-III in complex with Ykt6 provides structural basis for double prenylation. Biotinylated geranylgeranyl analogue labeling, in vitro prenylation assay, X-ray crystallography, gene knockout cell lines, Golgi trafficking assays The EMBO Journal High 32128853
2023 Overexpression of RABGGTB in NSC34-hSOD1G93A and TDP-43 ALS cell models improved cell proliferation and promoted autophagosome-lysosome fusion by enhancing geranylgeranylation of Rab7, and reduced abnormal SOD1 protein aggregation, placing RABGGTB-mediated Rab7 prenylation upstream of autophagy flux in motor neurons. Lentiviral overexpression, immunofluorescence, cell proliferation assay, autophagy flux analysis in cell lines Brain Research Bulletin Medium 38042502
2023 Intrathecal injection of AAV9-RabGGTB in SOD1G93A mice increased RABGGTB protein in spinal cord motoneurons, delayed disease onset and extended survival, and reduced misfolded SOD1 aggregation and glial overactivation, demonstrating that RABGGTB overexpression is neuroprotective in vivo in an ALS model. AAV-mediated gene overexpression in mice, immunofluorescence, behavioral tests (rotarod, footprint, neurological scoring), survival analysis Frontiers in Aging Neuroscience Medium 36967828
2025 Both subunits of GGTase-III (PTAR1 and RABGGTB) are expressed in human islets, mouse islets, and INS-1 832/13 cells. siRNA-mediated knockdown of PTAR1 (the alpha subunit that partners with RABGGTB) reduced glucose-stimulated insulin secretion by ~60% and KCl-induced insulin secretion by ~69%, and Ykt6 (a GGTase-III substrate) is expressed in these cells, establishing a role for the RABGGTB-containing GGTase-III complex in insulin secretion. siRNA knockdown, ELISA-based insulin secretion assay, Western blotting in INS-1 cells and primary islets Cellular Physiology and Biochemistry Medium 40598917

Source papers

Stage 0 corpus · 47 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
1993 Retinal degeneration in choroideremia: deficiency of rab geranylgeranyl transferase. Science (New York, N.Y.) 297 8380507
2018 An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. Nature communications 201 29568061
2008 Systematic identification of mRNAs recruited to argonaute 2 by specific microRNAs and corresponding changes in transcript abundance. PloS one 148 18461144
1994 Rab geranylgeranyl transferase catalyzes the geranylgeranylation of adjacent cysteines in the small GTPases Rab1A, Rab3A, and Rab5A. Proceedings of the National Academy of Sciences of the United States of America 134 7991565
2003 Membrane targeting of Rab GTPases is influenced by the prenylation motif. Molecular biology of the cell 129 12802062
2016 A Network of Conserved Synthetic Lethal Interactions for Exploration of Precision Cancer Therapy. Molecular cell 113 27453043
2010 Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score. Molecular medicine (Cambridge, Mass.) 108 20379614
2021 Systematically defining selective autophagy receptor-specific cargo using autophagosome content profiling. Molecular cell 105 33545068
2013 Parallel SCF adaptor capture proteomics reveals a role for SCFFBXL17 in NRF2 activation via BACH1 repressor turnover. Molecular cell 100 24035498
2003 Structure of Rab escort protein-1 in complex with Rab geranylgeranyltransferase. Molecular cell 98 12620235
2019 GGTase3 is a newly identified geranylgeranyltransferase targeting a ubiquitin ligase. Nature structural & molecular biology 89 31209342
1993 cDNA cloning and expression of the alpha and beta subunits of rat Rab geranylgeranyl transferase. The Journal of biological chemistry 89 8505342
2017 The STUbL RNF4 regulates protein group SUMOylation by targeting the SUMO conjugation machinery. Nature communications 86 29180619
2017 Assembly of the U5 snRNP component PRPF8 is controlled by the HSP90/R2TP chaperones. The Journal of cell biology 78 28515276
2020 A SNARE geranylgeranyltransferase essential for the organization of the Golgi apparatus. The EMBO journal 69 32128853
2022 Scalable multiplex co-fractionation/mass spectrometry platform for accelerated protein interactome discovery. Nature communications 65 35831314
2010 Genetic variation in 3-hydroxy-3-methylglutaryl CoA reductase modifies the chemopreventive activity of statins for colorectal cancer. Cancer prevention research (Philadelphia, Pa.) 62 20403997
1994 Determination of structural requirements for the interaction of Rab6 with RabGDI and Rab geranylgeranyltransferase. The Journal of biological chemistry 60 8175798
2017 Systematic protein-protein interaction mapping for clinically relevant human GPCRs. Molecular systems biology 58 28298427
2008 Genes associated with the tumour microenvironment are differentially expressed in cured versus primary chemotherapy-refractory diffuse large B-cell lymphoma. British journal of haematology 32 18419622
2021 Expression of Rab Prenylation Pathway Genes and Relation to Disease Progression in Choroideremia. Translational vision science & technology 9 34254989
2018 Assessment of Protein Prenylation Pathway in Multiple Sclerosis Patients. Journal of molecular neuroscience : MN 9 29574663
2023 Protective effects of intrathecal injection of AAV9-RabGGTB-GFP+ in SOD1G93A mice. Frontiers in aging neuroscience 8 36967828
1995 Studies of cloning, chromosomal mapping, and embryonic expression of the mouse Rab geranylgeranyl transferase beta subunit. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 7 7544156
2008 The cytoplasmic domain of chondrolectin interacts with the beta-subunit of Rab geranylgeranyl transferase. Cellular & molecular biology letters 6 18161010
1997 Studies of the mouse Rab geranylgeranyl transferase beta subunit: gene structure, expression and regulation. Gene 6 9031634
2020 ChIP-Seq-Based Approach in Mouse Enteric Precursor Cells Reveals New Potential Genes with a Role in Enteric Nervous System Development and Hirschsprung Disease. International journal of molecular sciences 4 33260622
2025 Exploring genetic and epigenetic markers for predicting or monitoring response to cognitive-behavioral therapy in obsessive-compulsive disorder: A systematic review. Neuroscience and biobehavioral reviews 3 40324706
2023 RABGGTB plays a critical role in ALS pathogenesis. Brain research bulletin 3 38042502
2023 Rab Geranylgeranyltransferase Subunit Beta as a Potential Indicator to Assess the Progression of Amyotrophic Lateral Sclerosis. Brain sciences 2 38002490
2025 Genome-wide DNA methylation profiles in the raphe nuclei of patients with autism spectrum disorder. Psychiatry and clinical neurosciences 1 40272067
2025 Significant upregulation of prenyltransferase-related genes in neuromyelitis optica: Diagnostic potential and clinical correlations. Multiple sclerosis and related disorders 1 40712510
2023 Sex-based Dysregulation of Inflammation-related Genes in Periodontitis. International journal of molecular and cellular medicine 1 38751653
2025 Novel Roles for Geranylgeranyl Transferase-III (GGTase-III) in Insulin Secretion. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 0 40598917
2024 Assessment of Rab geranylgeranyltransferase subunit beta in amyotrophic lateral sclerosis. Frontiers in neurology 0 39224887