Affinage

RGP1

RAB6A-GEF complex partner protein 2 · UniProt Q92546

Round 2 corrected
Length
391 aa
Mass
42.5 kDa
Annotated
2026-04-28
77 papers in source corpus 8 papers cited in narrative 8 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RGP1 is an obligate subunit of the Ric1–Rgp1 heterodimeric guanine nucleotide exchange factor (GEF) complex that activates Rab6 (Ypt6 in yeast) on Golgi membranes, thereby controlling retrograde endosome-to-Golgi vesicle trafficking (PMID:10990452, PMID:23091056). CryoEM structural analysis shows that Rgp1 contributes an arrestin fold that engages the hypervariable C-terminal domain of Rab6, while Ric1 provides the catalytic RabGEF helical domain that drives GDP-to-GTP exchange; mutagenesis of the GEF interface abolishes nucleotide exchange activity (PMID:39632878). Loss of Rgp1 destabilizes Rab6, blocks mannose-6-phosphate receptor retrograde transport, impairs phospholipid flippase recycling, delays STING Golgi exit, and in zebrafish disrupts collagen II secretion in chondrocytes leading to craniofacial cartilage defects (PMID:23091056, PMID:22177957, PMID:39657680, PMID:36843607).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2000 High

    The fundamental question of which factor activates Ypt6 was resolved by showing that Rgp1p and Ric1p form a tight complex that directly catalyzes GDP-to-GTP exchange on Ypt6p, and that deletion of either gene blocks Snc1p recycling from endosomes to the Golgi—establishing the Ric1–Rgp1 heterodimer as the dedicated Ypt6 GEF controlling retrograde trafficking.

    Evidence Co-purification, in vitro nucleotide exchange assay, genetic epistasis with YPT6 overexpression, and SNARE localization in S. cerevisiae deletion mutants

    PMID:10990452

    Open questions at the time
    • No structural information on how the two subunits contribute to catalysis
    • Mammalian ortholog activity not yet demonstrated
    • Mechanism of Golgi membrane recruitment unknown
  2. 2008 Low

    A high-copy suppressor screen identified MYR1 as a genetic interactor that suppresses ypt6Δ and ric1Δ temperature sensitivity, expanding the genetic network around the Ric1/Rgp1 pathway but without revealing a direct physical link to Rgp1.

    Evidence High-copy suppressor screen, immunofluorescence, and membrane fractionation in yeast

    PMID:18327588

    Open questions at the time
    • No direct biochemical interaction between Myr1 and Rgp1 demonstrated
    • Functional relevance of Myr1 to the GEF complex mechanism remains unclear
    • Not independently confirmed
  3. 2011 Medium

    The scope of Rgp1-dependent trafficking was broadened beyond SNAREs to include phospholipid flippase recycling, demonstrating that loss of Rgp1 mislocalized the aminophospholipid flippase Dnf2p and sensitized cells to PE-targeting agents.

    Evidence Deletion mutant sensitivity screen and fluorescence microscopy of EGFP-Dnf2p in S. cerevisiae

    PMID:22177957

    Open questions at the time
    • Direct mechanistic link between Rab6/Ypt6 activation and flippase sorting not dissected
    • Mammalian relevance of this lipid asymmetry phenotype not tested
  4. 2012 High

    The mammalian Ric1–Rgp1 complex was confirmed as a Rab6A GEF, and a Rab cascade mechanism was uncovered in which Rab33B-GTP on medial Golgi recruits Ric1, enabling sequential Rab activation from medial to trans-Golgi.

    Evidence Co-immunoprecipitation, in vitro nucleotide exchange assay, siRNA knockdown with M6PR retrograde trafficking readout, Rab33B-GTP pull-down in human cells

    PMID:23091056

    Open questions at the time
    • Structural basis for Rab33B binding to Ric1 C-terminus unresolved
    • Whether Rgp1 contacts Rab33B or only Rab6 not determined
    • In vivo validation of the Rab cascade model in animal tissues lacking
  5. 2014 Medium

    Functional cross-talk between the Ypt1 and Ypt6/Rgp1 pathways was demonstrated: Ypt1 overexpression suppressed both vesicle trafficking and autophagy defects in rgp1Δ cells, revealing that Rgp1-dependent Rab activation intersects with autophagic flux.

    Evidence Genetic suppression analysis, fluorescence microscopy of Snc1-GFP and GFP-Atg8, Western blot cleavage assay in S. cerevisiae

    PMID:24843892

    Open questions at the time
    • Mechanism by which Ypt1 bypasses Ypt6 loss remains unclear
    • Whether autophagy regulation is a direct or indirect consequence of Rgp1 loss not resolved
  6. 2023 Medium

    In vivo vertebrate function was established: CRISPR-mediated loss of Rgp1 in zebrafish impaired Rab6a+ vesicle dynamics in chondrocytes, blocked collagen II secretion, and caused craniofacial cartilage defects and cell death, linking the GEF complex to ECM cargo secretion through a proposed Rab6a–Rab8a relay.

    Evidence CRISPR zebrafish knockout, live imaging of Rab6a+ vesicles, TEM, immunofluorescence, overexpression epistasis

    PMID:36843607

    Open questions at the time
    • Direct physical interaction between Rgp1 and Rab8a not demonstrated
    • Whether cell death is primary or secondary to secretion failure not distinguished
    • Mammalian in vivo cartilage/bone phenotype not yet reported
  7. 2024 High

    The structural mechanism of Rab6 activation was solved: cryoEM revealed that Rgp1 contributes an arrestin fold engaging the Rab6 hypervariable C-terminal domain, while Ric1 provides the catalytic RabGEF helical domain contacting the nucleotide-binding pocket, and mutagenesis confirmed that specific interface residues are essential for exchange activity.

    Evidence CryoEM structure determination and site-directed mutagenesis validated by in vitro nucleotide exchange assay

    PMID:39632878

    Open questions at the time
    • Role of the arrestin fold beyond tail engagement (e.g., membrane curvature sensing) not explored
    • Whether Rgp1 arrestin fold contacts other Rab substrates or is Rab6-specific untested
    • No structure of the full complex on a membrane
  8. 2024 Medium

    Genome-wide screening extended the functional repertoire of the Ric1–Rgp1 complex to innate immune signaling, showing that loss of the complex delays STING exit from the Golgi and enhances STING-dependent signaling.

    Evidence Genome-wide optical pooled CRISPR screen with subcellular STING imaging in human cells

    PMID:39657680

    Open questions at the time
    • Whether Rgp1 loss affects STING trafficking independently of Ric1 not tested
    • Downstream consequences for type I interferon signaling in vivo not assessed
    • Mechanism linking Rab6 activation to STING Golgi export not dissected

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown how the Ric1–Rgp1 complex is recruited to specific Golgi subdomains in vivo, whether the Rgp1 arrestin fold has functions beyond Rab6 tail engagement (e.g., membrane sensing), and whether RGP1 mutations cause human disease.
  • Membrane recruitment mechanism of the GEF complex unresolved
  • No human genetic disease linked to RGP1 mutations reported
  • Potential non-GEF functions of the Rgp1 arrestin fold unexplored

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3
Localization
GO:0005794 Golgi apparatus 4
Pathway
R-HSA-5653656 Vesicle-mediated transport 5 R-HSA-392499 Metabolism of proteins 2 R-HSA-9612973 Autophagy 1
Partners
RAB33BRAB6ARIC1
Complex memberships
Ric1–Rgp1 GEF complex

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 Rgp1p and Ric1p form a tight complex that binds Ypt6p in a nucleotide-dependent manner and stimulates guanine nucleotide exchange on Ypt6p in vitro. Deletion of RGP1 or RIC1 blocks recycling of the exocytic SNARE Snc1p from early endosomes to the Golgi, and this defect is rescued by overexpression of YPT6, placing Ric1p-Rgp1p as the GEF that activates Ypt6p on Golgi membranes. Genetic screen, co-purification, in vitro nucleotide exchange assay, fluorescence microscopy of SNARE trafficking, epistasis with YPT6 overexpression The EMBO journal High 10990452
2012 Human Ric1 and Rgp1 form a complex that acts as a GEF for Rab6A, preferentially binding its GDP-bound form; both subunits are required for nucleotide exchange activity. Loss of either Ric1 or Rgp1 destabilizes Rab6 protein and blocks Rab6-dependent retrograde transport of mannose-6-phosphate receptors to the Golgi. Additionally, the C-terminus of Ric1 binds Rab33B-GTP (a medial Golgi Rab), establishing a Rab cascade linking medial and trans Golgi. Co-immunoprecipitation, in vitro nucleotide exchange assay, siRNA knockdown with retrograde trafficking readout (M6PR localization), pull-down of Rab33B-GTP by Ric1 The Journal of biological chemistry High 23091056
2011 In yeast, deletion of RGP1 (along with RIC1, YPT6, or GARP subunits) causes hypersensitivity to the PE-binding peptide Ro09-0198 and leads to aberrant intracellular localization of the aminophospholipid flippase Dnf2p, demonstrating that the Ric1/Rgp1 GEF complex and its target Ypt6 are required for recycling of plasma membrane flippases to maintain phospholipid asymmetry. Deletion mutant screen for Ro09-0198 hypersensitivity, fluorescence microscopy of EGFP-Dnf2p localization Biochemical and biophysical research communications Medium 22177957
2014 Overexpression of Ypt1 suppresses both vesicle trafficking defects (restoration of Snc1 plasma membrane delivery) and autophagic defects (increased GFP-Atg8 vacuolar sorting) in yeast rgp1∆, ric1∆, and ypt6 mutants under nutrient-rich and starvation conditions respectively, revealing a functional connection between Ypt1 and Ypt6/Rgp1 pathways in both exocytic and autophagic trafficking. However, Ypt1 overexpression does not restore Ypt6 intracellular localization in rgp1∆ cells. Genetic suppression analysis, fluorescence microscopy of Snc1-GFP and GFP-Atg8, Western blot GFP-Atg8 cleavage assay Cell biology international Medium 24843892
2008 MYR1, encoding a coiled-coil/GYF domain protein, was identified as a high-copy suppressor of ypt6∆ temperature sensitivity and also suppresses ric1∆ temperature sensitivity, genetically linking Myr1 to the Ric1/Rgp1-Ypt6 pathway. Myr1 associates with membranes and large Triton X-100-insoluble structures, and its overexpression affects nuclear envelope morphology. High-copy suppressor genetic screen, immunofluorescence microscopy, membrane fractionation Current genetics Low 18327588
2023 CRISPR-induced loss of Rgp1 in zebrafish causes craniofacial cartilage defects. In live rgp1 mutant chondrocytes, Rab6a+ vesicular compartment movements are altered, consistent with a conserved GEF mechanism. TEM and immunofluorescence show impaired collagen II secretion. Overexpression experiments reveal Rab8a participates in post-Golgi collagen II trafficking. Loss of Rgp1 triggers an Arf4b-mediated stress response followed by nuclear DNA fragmentation and chondrocyte death, proposing an Rgp1-Rab6a-Rab8a pathway for ECM cargo secretion. CRISPR zebrafish loss-of-function, live imaging of Rab6a+ vesicles, transmission electron microscopy, immunofluorescence, overexpression epistasis Frontiers in endocrinology Medium 36843607
2024 CryoEM structure of the Ric1-Rgp1-Rab6 complex reveals the mechanistic basis for Rab6 activation. Ric1-Rgp1 contacts the nucleotide-binding domain of Rab6 via a previously uncharacterized helical domain (designated RabGEF domain), and mutagenesis of residues within this domain abolishes Rab6 nucleotide exchange. Unexpectedly, the complex employs an arrestin fold (contributed by Rgp1) to interact with the Rab6 hypervariable C-terminal domain, suggesting a common mechanism by which Rab GEFs engage the unstructured tails of their substrates. CryoEM structure determination, site-directed mutagenesis of GEF interface residues validated by nucleotide exchange assay Nature communications High 39632878
2024 Genome-wide optical pooled screening for STING trafficking regulators identified that loss of the GARP/RIC1-RGP1 complex increases STING signaling by delaying STING exit from the Golgi, placing Rgp1 (as part of the Ric1-Rgp1 GEF complex) as a regulator of STING Golgi trafficking. Genome-wide optical pooled CRISPR screen, subcellular imaging of STING localization in millions of cells, sgRNA perturbation Cell systems Medium 39657680

Source papers

Stage 0 corpus · 77 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
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
2018 High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies. Molecular cell 580 29395067
2015 A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface. Cell 433 26638075
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2010 Systematic analysis of human protein complexes identifies chromosome segregation proteins. Science (New York, N.Y.) 421 20360068
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2007 Systematic analysis of the protein interaction network for the human transcription machinery reveals the identity of the 7SK capping enzyme. Molecular cell 367 17643375
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2015 ∆F508 CFTR interactome remodelling promotes rescue of cystic fibrosis. Nature 209 26618866
1995 Molecular cloning and structural characterization of the Arg-gingipain proteinase of Porphyromonas gingivalis. Biosynthesis as a proteinase-adhesin polyprotein. The Journal of biological chemistry 173 7836351
2009 Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip. American journal of human genetics 164 19913121
2000 Ric1p and Rgp1p form a complex that catalyses nucleotide exchange on Ypt6p. The EMBO journal 149 10990452
1994 Pathogenesis of periodontitis: a major arginine-specific cysteine proteinase from Porphyromonas gingivalis induces vascular permeability enhancement through activation of the kallikrein/kinin pathway. The Journal of clinical investigation 146 8040277
1997 A reversibly glycosylated polypeptide (RGP1) possibly involved in plant cell wall synthesis: purification, gene cloning, and trans-Golgi localization. Proceedings of the National Academy of Sciences of the United States of America 126 9207152
2022 Human transcription factor protein interaction networks. Nature communications 123 35140242
2017 The human cytoplasmic dynein interactome reveals novel activators of motility. eLife 118 28718761
1997 Molecular cloning and characterization of Porphyromonas gingivalis lysine-specific gingipain. A new member of an emerging family of pathogenic bacterial cysteine proteinases. The Journal of biological chemistry 109 8999833
1998 Haemoglobin receptor protein is intragenically encoded by the cysteine proteinase-encoding genes and the haemagglutinin-encoding gene of Porphyromonas gingivalis. Molecular microbiology 107 9466255
2011 The interconversion of UDP-arabinopyranose and UDP-arabinofuranose is indispensable for plant development in Arabidopsis. The Plant cell 106 21478444
2005 Complex genomic rearrangements lead to novel primate gene function. Genome research 96 15710750
2006 Arabidopsis reversibly glycosylated polypeptides 1 and 2 are essential for pollen development. Plant physiology 95 17071651
1994 Expression of the gene for a small GTP binding protein in transgenic tobacco elevates endogenous cytokinin levels, abnormally induces salicylic acid in response to wounding, and increases resistance to tobacco mosaic virus infection. Proceedings of the National Academy of Sciences of the United States of America 85 11607497
1995 Characterization, genetic analysis, and expression of a protease antigen (PrpRI) of Porphyromonas gingivalis W50. Infection and immunity 81 7591131
1997 Domain-specific rearrangement between the two Arg-gingipain-encoding genes in Porphyromonas gingivalis: possible involvement of nonreciprocal recombination. Microbiology and immunology 69 9130229
1996 Analysis of the prtP gene encoding porphypain, a cysteine proteinase of Porphyromonas gingivalis. Journal of bacteriology 69 8631659
2005 Generation and annotation of the DNA sequences of human chromosomes 2 and 4. Nature 66 15815621
1993 cDNA structure, expression and nucleic acid-binding properties of three RNA-binding proteins in tobacco: occurrence of tissue-specific alternative splicing. Nucleic acids research 64 8371974
2012 Ric1-Rgp1 complex is a guanine nucleotide exchange factor for the late Golgi Rab6A GTPase and an effector of the medial Golgi Rab33B GTPase. The Journal of biological chemistry 63 23091056
1998 Genetic variation of Porphyromonas gingivalis genes encoding gingipains, cysteine proteinases with arginine or lysine specificity. Biological chemistry 62 9524073
1991 A novel ras-related rgp1 gene encoding a GTP-binding protein has reduced expression in 5-azacytidine-induced dwarf rice. Molecular & general genetics : MGG 54 1715972
2020 Unbiased Identification of trans Regulators of ADAR and A-to-I RNA Editing. Cell reports 52 32433965
2002 Glucosylation activity and complex formation of two classes of reversibly glycosylated polypeptides. Plant physiology 52 12011358
2019 TNF-α inhibits glucocorticoid receptor-induced gene expression by reshaping the GR nuclear cofactor profile. Proceedings of the National Academy of Sciences of the United States of America 48 31182584
2015 Quantitative Proteomics Reveals Dynamic Interactions of the Minichromosome Maintenance Complex (MCM) in the Cellular Response to Etoposide Induced DNA Damage. Molecular & cellular proteomics : MCP 44 25963833
2013 True arrestins and arrestin-fold proteins: a structure-based appraisal. Progress in molecular biology and translational science 42 23764049
2019 MaXLinker: Proteome-wide Cross-link Identifications with High Specificity and Sensitivity. Molecular & cellular proteomics : MCP 39 31839598
2022 In-Depth In Vivo Crosslinking in Minutes by a Compact, Membrane-Permeable, and Alkynyl-Enrichable Crosslinker. Analytical chemistry 38 35575683
1995 Involvement of small GTP-binding proteins in defense signal-transduction pathways of higher plants. Proceedings of the National Academy of Sciences of the United States of America 34 11607540
2020 The Effects of Oral Rehmannia glutinosa Polysaccharide Administration on Immune Responses, Antioxidant Activity and Resistance Against Aeromonas hydrophila in the Common Carp, Cyprinus carpio L. Frontiers in immunology 32 32457762
2018 Global assessment of its network dynamics reveals that the kinase Plk1 inhibits the phosphatase PP6 to promote Aurora A activity. Science signaling 28 29764989
2010 Variation at the NFATC2 locus increases the risk of thiazolidinedione-induced edema in the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) study. Diabetes care 28 20628086
2023 Rehmannia glutinosa Polysaccharides: Optimization of the Decolorization Process and Antioxidant and Anti-Inflammatory Effects in LPS-Stimulated Porcine Intestinal Epithelial Cells. Antioxidants (Basel, Switzerland) 20 37107289
1997 Multiple colonization defects in a cysteine protease mutant of Porphyromonas gingivalis. Journal of periodontal research 20 9085224
1994 Characterization of a cDNA encoding a novel type of RNA-binding protein in tobacco: its expression and nucleic acid-binding properties. Molecular & general genetics : MGG 18 8078461
2011 Involvement of Golgi-associated retrograde protein complex in the recycling of the putative Dnf aminophospholipid flippases in yeast. Biochemical and biophysical research communications 16 22177957
1993 Molecular characterization of rgp2, a gene encoding a small GTP-binding protein from rice. Molecular & general genetics : MGG 16 8455556
2022 Characterization of a novel polysaccharide from red ginseng and its ameliorative effect on oxidative stress injury in myocardial ischemia. Chinese medicine 15 36153627
2015 Cell wall composition and digestibility alterations in Brachypodium distachyon achieved through reduced expression of the UDP-arabinopyranose mutase. Frontiers in plant science 15 26136761
1994 Production and analysis of asymmetric hybrid plants between monocotyledon (Oryza sativa L.) and dicotyledon (Daucus carota L.). TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik 15 24177855
2019 Proteomic Analysis Reveals a Role for RSK in p120-catenin Phosphorylation and Melanoma Cell-Cell Adhesion. Molecular & cellular proteomics : MCP 14 31678930
2023 Interactomes of Glycogen Synthase Kinase-3 Isoforms. Journal of proteome research 12 36779422
2022 Proximity labeling of endogenous RICTOR identifies mTOR complex 2 regulation by ADP ribosylation factor ARF1. The Journal of biological chemistry 11 35973513
2024 Structural characterization of Russula griseocarnosa polysaccharide and its improvement on hematopoietic function. International journal of biological macromolecules 9 38395281
2023 C9orf72 protein quality control by UBR5-mediated heterotypic ubiquitin chains. EMBO reports 9 37317656
2000 Overexpression, purification, and refolding of a Porphyromonas gingivalis cysteine protease from Escherichia coli. Protein expression and purification 9 10733878
2014 Ypt1 suppresses defects of vesicle trafficking and autophagy in Ypt6 related mutants. Cell biology international 8 24843892
2024 Interaction network of human early embryonic transcription factors. EMBO reports 7 38297188
2024 DSBSO-Based XL-MS Analysis of Breast Cancer PDX Tissues to Delineate Protein Interaction Network in Clinical Samples. Journal of proteome research 7 38334954
2023 Integrated microbiome-metabolome-genome axis data of Laiwu and Lulai pigs. Scientific data 7 37179393
2024 The endogenous association among MMP2/miR-1248/Circ_0087558/miR-643/ MAP2K6 axis can contribute to brain metastasis in basal-like subtype of breast cancer. Heliyon 6 39027611
2024 Depletion of loss-of-function germline mutations in centenarians reveals longevity genes. Nature communications 6 39424787
2024 Structural basis for Rab6 activation by the Ric1-Rgp1 complex. Nature communications 6 39632878
2022 Bipartite rgp Locus Diversity in Streptococcus thermophilus Corresponds to Backbone and Side Chain Differences of Its Rhamnose-Containing Cell Wall Polysaccharide. Applied and environmental microbiology 6 36350137
2020 Platinum Drug Sensitivity Polymorphisms in Stage III Non-small Cell Lung Cancer With Invasion of Mediastinal Lymph Nodes. Cancer genomics & proteomics 6 32859637
2008 Characterization of MYR1, a dosage suppressor of YPT6 and RIC1 deficient mutants. Current genetics 5 18327588
2024 Classification and functional characterization of regulators of intracellular STING trafficking identified by genome-wide optical pooled screening. Cell systems 4 39657680
2023 Rgp1 contributes to craniofacial cartilage development and Rab8a-mediated collagen II secretion. Frontiers in endocrinology 4 36843607
1990 Molecular analysis of RGP1, a new yeast gene required for proper mitotic growth. Nucleic acids research 4 2179863
2025 Receptor deorphanization in starfish reveals the evolution of relaxin signaling as a regulator of reproduction. BMC biology 3 40001176
2003 Activation of hypersensitive response genes in the absence of pathogens in transgenic tobacco plants expressing a rice small GTPase. Planta 3 12937984
2026 Linking cortical structure and delirium in the elderly: insights from cohort study and shared genetic risk analysis. Journal of translational medicine 0 41680881
2024 Risk model based on genes regulating the response of tumor cells to T-cell-mediated killing in esophageal squamous cell carcinoma. Aging 0 38305770
2024 Classification and functional characterization of regulators of intracellular STING trafficking identified by genome-wide optical pooled screening. bioRxiv : the preprint server for biology 0 38645119
2024 Structural basis for Rab6 activation by the Ric1-Rgp1 complex. bioRxiv : the preprint server for biology 0 38766083