Affinage

RABGGTA

Geranylgeranyl transferase type-2 subunit alpha · UniProt Q92696

Round 2 corrected
Length
567 aa
Mass
65.1 kDa
Annotated
2026-04-28
50 papers in source corpus 13 papers cited in narrative 13 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RABGGTA encodes the alpha subunit of Rab geranylgeranyltransferase (RabGGTase/GGTase-II), a heterodimeric prenyltransferase that, together with its beta subunit (RABGGTB) and the accessory REP proteins, doubly geranylgeranylates C-terminal cysteine motifs on Rab GTPases to enable their membrane association and function (PMID:7991565, PMID:8505342). The 2.7 Å crystal structure of the RabGGTase–REP-1 ternary complex reveals that helices 8, 10, and 12 of the RABGGTA alpha subunit form the REP-1 binding interface, and that phosphoisoprenoid binding allosterically regulates this interaction (PMID:12620235). Hypomorphic loss of RABGGTA in the gunmetal mouse causes thrombocytopenia through defective Rab27 prenylation (PMID:10737774), while tissue-specific knockdown in liver and skeletal muscle impairs glucose metabolism via under-prenylation of RAB14 (disrupting mTORC2/AKT signaling) and RAB8A (blocking GLUT4 translocation), respectively (PMID:34995578, PMID:35961942). RABGGTA is also essential for neuronal survival in vivo (PMID:40847019).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1991 High

    Establishing that mammalian prenyltransferases share a common alpha-subunit architecture placed RABGGTA within a defined enzyme family distinct from farnesyltransferase and GGTase-I.

    Evidence Biochemical purification, gel filtration, and immunoblotting of bovine brain extracts

    PMID:2018975

    Open questions at the time
    • RABGGTA-specific sequence unknown at this point
    • RabGGTase not yet separated as a distinct enzyme from GGTase-I
  2. 1993 High

    Cloning the alpha and beta subunits and reconstituting REP-dependent RabGGTase activity in cells defined the minimal catalytic machinery for Rab prenylation and revealed evolutionary conservation to yeast (MAD2/BET2).

    Evidence cDNA cloning from rat, heterologous co-expression in HEK293, in vitro enzymatic assay

    PMID:8505342

    Open questions at the time
    • Structural basis of REP–RabGGTase interaction unknown
    • Substrate specificity for different Rab C-terminal motifs not resolved
  3. 1994 High

    Demonstrating that RabGGTase doubly geranylgeranylates diverse C-terminal cysteine motifs (XXCC, XCXC, CCXX) established the enzyme's unique capacity among prenyltransferases for dual lipid modification.

    Evidence In vitro prenylation with recombinant enzyme; HPLC and electrospray mass spectrometry of prenylated peptides

    PMID:7991565

    Open questions at the time
    • Mechanism of sequential vs. simultaneous dual prenylation unclear
    • No structural explanation for how the active site accommodates diverse motifs
  4. 2000 High

    Positional cloning of the gunmetal mouse mutation provided the first in vivo genetic evidence that RABGGTA-dependent Rab prenylation is essential for platelet biogenesis and hemostasis, with Rab27 identified as a critical downstream substrate.

    Evidence Positional cloning, RT-PCR, Western blot, RabGGTase activity and Rab27 membrane fractionation in gunmetal platelets

    PMID:10737774

    Open questions at the time
    • Whether other Rabs besides Rab27 contribute to the platelet phenotype
    • No human RABGGTA mutations linked to bleeding disorders at this time
  5. 2003 High

    Solving the crystal structure of the RabGGTase–REP-1 ternary complex revealed the alpha-subunit helices forming the REP-1 interface and an allosteric mechanism by which isoprenoid binding regulates REP recruitment.

    Evidence X-ray crystallography at 2.7 Å resolution with binding affinity measurements

    PMID:12620235

    Open questions at the time
    • No structure of the complete quaternary complex with a Rab substrate bound
    • Structural basis of dual prenylation mechanism unresolved
  6. 2011 High

    Functional characterization of a choroideremia-associated REP1 missense variant confirmed that the REP1–RabGGTase interaction is essential for retinal cell survival, reinforcing the physiological importance of the RABGGTA-containing complex in tissue-specific Rab prenylation.

    Evidence In vitro transcription/translation, functional prenylation assay with REP1 p.H507R mutant

    PMID:21905166

    Open questions at the time
    • Mutation is in REP1, not RABGGTA itself; direct RABGGTA variants in human retinal disease unknown
    • Specific Rab substrates mediating retinal pathology not fully identified
  7. 2016 Medium

    Showing that RABGGTA knockdown phenocopies nitrogen-containing bisphosphonate cytotoxicity in cancer cells—and cannot be rescued by GGPP alone—established RabGGTase as the critical prenyltransferase target mediating bisphosphonate-induced autophagic cell death.

    Evidence siRNA knockdown, cell viability, GGPP rescue experiments, autophagy/apoptosis markers in glioblastoma and breast cancer lines

    PMID:27462771

    Open questions at the time
    • Single-lab study without in vivo validation
    • Specific Rab substrates whose under-prenylation triggers autophagy not identified
    • Whether GGTase-I inhibition contributes in parallel not fully excluded
  8. 2022 High

    Tissue-specific RABGGTA knockdown in liver and skeletal muscle revealed organ-specific metabolic roles: hepatic loss disrupts RAB14-dependent mTORC2/AKT insulin signaling, while skeletal muscle loss impairs RAB8A-dependent GLUT4 translocation, demonstrating substrate-specific physiological consequences of Rab prenylation deficiency.

    Evidence AAV8 (liver) and AAV9 (muscle) in vivo knockdown, siRNA screening, AKT phosphorylation, mTORC2 assembly, GLUT4 translocation assays, GGPP/GGOH rescue

    PMID:34995578 PMID:35961942

    Open questions at the time
    • Contribution of other under-prenylated Rabs beyond RAB14/RAB8A in these tissues not excluded
    • Human genetic validation of RABGGTA in metabolic disease absent
    • Whether chronic RABGGTA deficiency leads to compensatory prenylation by other enzymes unknown
  9. 2025 Medium

    An in vivo CRISPR screen in mouse brain identified RABGGTA as essential for neuronal survival, extending the gene's known physiological roles beyond hematopoiesis and metabolism to the nervous system.

    Evidence AAV-based pooled CRISPR screen (CrAAVe-seq) with targeted sgRNA validation in mouse neurons

    PMID:40847019

    Open questions at the time
    • Specific Rab substrates and downstream pathways mediating neuronal death not identified
    • Single study without independent replication
    • Whether partial vs. complete loss of RABGGTA is tolerated in neurons unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • No human Mendelian disease has been directly attributed to RABGGTA mutations, and the structural basis for dual prenylation within the active site—including how the second geranylgeranyl group is added—remains unresolved.
  • No human loss-of-function mutations in RABGGTA reported
  • No structure of the full quaternary complex (RabGGTase–REP–Rab substrate) during catalysis
  • Relative contributions of RABGGTA to prenylation of different Rab family members in vivo not systematically determined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 6
Localization
GO:0005829 cytosol 2
Pathway
R-HSA-392499 Metabolism of proteins 6 GO:0005886 plasma membrane 2 R-HSA-162582 Signal Transduction 2 R-HSA-382551 Transport of small molecules 2 R-HSA-109582 Hemostasis 1
Partners
CHMCHMLRAB14RAB27ARAB8ARABGGTB
Complex memberships
RabGGTase (Rab geranylgeranyltransferase / GGTase-II)

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1991 The alpha subunit of protein farnesyltransferase is shared with geranylgeranyltransferase I (GGTase-I), establishing that RABGGTA (the alpha subunit of RabGGTase/GGTase-II) is part of a family of prenyltransferases that share a common alpha subunit architecture, and that the two prenyltransferases are separable by ion exchange chromatography despite sharing the alpha subunit. Biochemical purification, gel filtration, ion exchange chromatography, immunoblotting with anti-alpha-subunit antibodies Cell High 2018975
1993 The alpha (567 aa) and beta (331 aa) subunits of rat Rab geranylgeranyltransferase (Component B) were cloned; co-transfection of both cDNAs in HEK293 cells reconstituted RabGGTase activity stimulated by Component A (REP). The yeast homologs are MAD2 (alpha) and BET2 (beta), establishing evolutionary conservation. cDNA cloning, heterologous expression, in vitro enzymatic activity assay The Journal of biological chemistry High 8505342
1993 Deficiency of Rab geranylgeranyltransferase Component A (REP-1, the accessory component that works with the RABGGTA/RABGGTB catalytic heterodimer) causes choroideremia; lymphoblasts from choroideremia patients showed marked deficiency in Component A activity but not Component B activity, and the deficiency was more pronounced for Rab3A than Rab1A, implying the existence of multiple Component A proteins. Enzymatic activity assay in patient-derived lymphoblasts, substrate specificity analysis Science High 8380507
1994 Rab geranylgeranyltransferase (containing RABGGTA) catalyzes geranylgeranylation of both adjacent cysteine residues in Rab1A (-XXCC), Rab3A (-XCXC), and Rab5A (-CCXX) C-terminal motifs, demonstrating that the enzyme doubly prenylates substrates regardless of the precise cysteine arrangement. In vitro prenylation assay with recombinant RabGGTase and REP, HPLC and electrospray mass spectrometry of tryptic peptides Proceedings of the National Academy of Sciences of the United States of America High 7991565
1997 The human RABGGTA gene is located in a tandem head-to-tail arrangement immediately upstream of the TGM1 (transglutaminase 1) gene on chromosome 14q11, with RABGGTA's polyadenylation signal only 2.3 kbp upstream of the TGM1 cap site. Despite this proximity, RT-PCR in human keratinocytes showed that RABGGTA expression is unaffected by calcium concentration, retinoic acid, vitamin D3, or TPA — conditions that strongly regulate TGM1 — establishing that the two genes are not functionally co-regulated in epidermal terminal differentiation. Genomic mapping, RT-PCR under differentiation-inducing conditions Biochemical and biophysical research communications Medium 9196026
2000 The gunmetal (gm) mouse phenotype (thrombocytopenia, prolonged bleeding, reduced platelet granule contents) results from a G→A splice-acceptor mutation in Rabggta that causes exon 1 skipping, eliminating the start codon. This reduces RABGGTA protein and RabGGTase activity ~4-fold in platelets and significantly decreases geranylgeranylation and membrane association of Rab27, establishing that Rab geranylgeranylation is critical for platelet biogenesis and hemostasis. Positional cloning, RT-PCR, Western blot, RabGGTase activity assay, Rab27 prenylation and membrane-fractionation assay in gm platelets Proceedings of the National Academy of Sciences of the United States of America High 10737774
2000 The complete exon/intron structure of the 5'-UTR of human RABGGTA was determined, revealing an exon alpha upstream of the coding sequence with organizational similarity to mouse Rabggta but non-homologous sequence. Promoter features are consistent with a housekeeping gene. Sequencing of the coding region in patients with platelet storage pool deficiencies found no causative mutations, though polymorphisms including a putative cryptic splice mutation in intron 4 were identified. Genomic sequencing, RT-PCR, sequence analysis of patient samples Molecular genetics and metabolism Medium 11136552
2003 The crystal structure of isoprenoid-bound RabGGTase (RABGGTA/RABGGTB heterodimer) complexed with REP-1 was solved to 2.7 Å. The interface buries ~680 Ų and is formed by helices 8, 10, and 12 of the RABGGTA alpha subunit and helices D and E of REP-1. The affinity of RabGGTase for REP-1 is allosterically regulated by phosphoisoprenoid binding via long-range trans-domain signal transduction. X-ray crystallography (2.7 Å), binding affinity measurements demonstrating allosteric regulation by isoprenoid Molecular cell High 12620235
2011 A missense variant in REP1 (p.H507R) associated with choroideremia was shown by in vitro transcription/translation assay to produce a full-length but functionally impaired protein that cannot properly bind Rab geranylgeranyltransferase (the RABGGTA/RABGGTB complex), thereby preventing REP1-mediated Rab prenylation and establishing that the REP1–RabGGTase interaction is essential for RPE and photoreceptor function. In vitro transcription/translation, functional prenylation assay, structural modeling Human mutation High 21905166
2016 Knockdown of RABGGTA in glioblastoma and breast cancer cell lines phenocopied the anti-proliferative effect of zoledronic acid and could not be rescued by geranylgeranyl diphosphate (GGPP) supplementation alone, demonstrating that RabGGTase activity (and thus Rab protein geranylgeranylation) mediates the anti-cancer cytotoxic mechanism of nitrogen-containing bisphosphonates, with autophagy (not apoptosis) as the predominant cell death pathway. siRNA knockdown of RABGGTA, cell viability assay, GGPP rescue experiment, autophagy/apoptosis markers Oncotarget Medium 27462771
2022 AAV8-mediated liver-specific knockdown of RABGGTA in vivo triggered systemic glucose metabolism disorders. Mechanistically, geranylgeranylation deficiency of RAB14 inhibited AKT (Ser473) phosphorylation and disrupted hepatic insulin signaling, possibly by impeding mTORC2 complex assembly. GGPP supplementation prevented simvastatin-caused disruption of hepatic insulin signaling in vitro, and geranylgeraniol (GGOH) ameliorated simvastatin-induced glucose metabolism disorders in vivo. AAV8-mediated in vivo knockdown, siRNA screening, AKT phosphorylation assay, mTORC2 assembly assay, GGPP/GGOH rescue in vitro and in vivo Metabolism: clinical and experimental High 34995578
2022 AAV9-mediated knockdown of RABGGTA specifically in skeletal muscle impaired glucose disposal in vivo (reduced glucose uptake in gastrocnemius, tibialis anterior, soleus, and EDL muscles) without disrupting insulin signaling (AKT Ser473 phosphorylation was unaffected), contrasting with GGTase-I inhibition which suppressed AKT phosphorylation. Geranylgeranylation deficiency of RAB8A specifically inhibited insulin-stimulated GLUT4 translocation and glucose uptake in skeletal muscle cells, placing RABGGTA upstream of RAB8A-mediated GLUT4 trafficking. AAV9-mediated in vivo knockdown, glucose uptake assay, GLUT4 translocation assay, geranylgeranylation-site RAB8A mutant Journal of cachexia, sarcopenia and muscle High 35961942
2025 An in vivo AAV-based CRISPR pooled screen (CrAAVe-seq) in mouse brains identified RABGGTA as an essential gene for neuronal survival, validated by targeted sgRNA experiments showing that loss of RABGGTA leads to neuronal death in vivo. In vivo pooled CRISPR screen (AAV delivery, Cre-sensitive sgRNA), neuronal survival readout by sgRNA depletion, validation with targeted sgRNAs Nature neuroscience Medium 40847019

Source papers

Stage 0 corpus · 50 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
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
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
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
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
1991 Protein farnesyltransferase and geranylgeranyltransferase share a common alpha subunit. Cell 371 2018975
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
1993 Retinal degeneration in choroideremia: deficiency of rab geranylgeranyl transferase. Science (New York, N.Y.) 297 8380507
2012 A high-throughput approach for measuring temporal changes in the interactome. Nature methods 273 22863883
2008 Blue eye color in humans may be caused by a perfectly associated founder mutation in a regulatory element located within the HERC2 gene inhibiting OCA2 expression. Human genetics 227 18172690
2017 Optimized fragmentation schemes and data analysis strategies for proteome-wide cross-link identification. Nature communications 221 28524877
2018 An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. Nature communications 201 29568061
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
2000 Rab geranylgeranyl transferase alpha mutation in the gunmetal mouse reduces Rab prenylation and platelet synthesis. Proceedings of the National Academy of Sciences of the United States of America 130 10737774
2020 Receptor-mediated clustering of FIP200 bypasses the role of LC3 lipidation in autophagy. The EMBO journal 100 33226137
2017 Mammalian APE1 controls miRNA processing and its interactome is linked to cancer RNA metabolism. Nature communications 99 28986522
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 92 31209342
1993 cDNA cloning and expression of the alpha and beta subunits of rat Rab geranylgeranyl transferase. The Journal of biological chemistry 89 8505342
2004 Proteins associated with type II bone morphogenetic protein receptor (BMPR-II) and identified by two-dimensional gel electrophoresis and mass spectrometry. Proteomics 77 15188402
2021 Histone deacetylase inhibitors inhibit cervical cancer growth through Parkin acetylation-mediated mitophagy. Acta pharmaceutica Sinica. B 66 35256949
2022 Scalable multiplex co-fractionation/mass spectrometry platform for accelerated protein interactome discovery. Nature communications 65 35831314
2019 Genome-Wide CRISPR-Cas9 Screen Reveals Selective Vulnerability of ATRX-Mutant Cancers to WEE1 Inhibition. Cancer research 64 31551363
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
2011 Comprehensive mutation analysis (20 families) of the choroideremia gene reveals a missense variant that prevents the binding of REP1 with Rab geranylgeranyl transferase. Human mutation 46 21905166
2002 Expressed sequence tag analysis of adult human iris for the NEIBank Project: steroid-response factors and similarities with retinal pigment epithelium. Molecular vision 41 12107412
2016 Gene signatures associated with adaptive humoral immunity following seasonal influenza A/H1N1 vaccination. Genes and immunity 21 27534615
2016 Anti-cancer effects of nitrogen-containing bisphosphonates on human cancer cells. Oncotarget 20 27462771
2017 Mapping the in vitro interactome of cardiac sodium (Na+ )-calcium (Ca2+ ) exchanger 1 (NCX1). Proteomics 15 28755400
2022 Triphenyltin exposure induced abnormal morphological colouration in adult male guppies (Poecilia reticulata). Ecotoxicology and environmental safety 12 35905627
2025 CRISPR screening by AAV episome-sequencing (CrAAVe-seq): a scalable cell-type-specific in vivo platform uncovers neuronal essential genes. Nature neuroscience 10 40847019
2018 Assessment of Protein Prenylation Pathway in Multiple Sclerosis Patients. Journal of molecular neuroscience : MN 9 29574663
2024 Sequential window acquisition of all theoretical mass spectra (SWATH-MS) as an emerging proteomics approach for the discovery of dark-cutting beef biomarkers. Meat science 8 39096797
2020 Proteome alterations associated with the oleic acid and cis-9, trans-11 conjugated linoleic acid content in bovine skeletal muscle. Journal of proteomics 8 32335295
2022 Mevalonate pathway orchestrates insulin signaling via RAB14 geranylgeranylation-mediated phosphorylation of AKT to regulate hepatic glucose metabolism. Metabolism: clinical and experimental 7 34995578
1997 The genes encoding geranylgeranyl transferase alpha-subunit and transglutaminase 1 are very closely linked but not functionally related in terminally differentiating keratinocytes. Biochemical and biophysical research communications 6 9196026
2022 Geranylgeranyl pyrophosphate depletion by statins compromises skeletal muscle insulin sensitivity. Journal of cachexia, sarcopenia and muscle 5 35961942
2013 Genetic characterization and in vivo image analysis of novel zebrafish Danio rerio pigment mutants. Journal of fish biology 5 23639161
2000 5'-UTR structural organization, transcript expression, and mutational analysis of the human Rab geranylgeranyl transferase alpha-subunit (RABGGTA) gene. Molecular genetics and metabolism 5 11136552
2023 Rab Geranylgeranyltransferase Subunit Beta as a Potential Indicator to Assess the Progression of Amyotrophic Lateral Sclerosis. Brain sciences 2 38002490
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
2026 CpG Methylation of Protein Prenyltransferase Genes FNTA, FNTB, PGGT1B and RABGGTA in Cancer Cell Lines. Epigenomes 0 41892366
2026 Machine learning identifies molecular targets of Di (2-ethylhexyl) phthalate in pulmonary arterial hypertension. Frontiers in bioinformatics 0 41938339