Affinage

ARFGAP2

ADP-ribosylation factor GTPase-activating protein 2 · UniProt Q8N6H7

Length
521 aa
Mass
56.7 kDa
Annotated
2026-06-09
31 papers in source corpus 16 papers cited in narrative 16 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ARFGAP2 is a coatomer-dependent ArfGAP that regulates COPI vesicle formation and Golgi-to-ER retrograde transport (human orthologue of yeast Glo3) (PMID:17760859, PMID:19015319). Unlike ArfGAP1, it does not bind membranes directly but is recruited to the Golgi through interaction with coatomer, which in turn stimulates its catalytic GTP hydrolysis on Arf1 (PMID:19015319, PMID:19109418). Recruitment is mediated by a hydrophobic pocket on the gamma1-COP appendage domain within the CM4 (adaptin-like tetrameric) coatomer subcomplex; CM4 brings ARFGAP2 to the membrane while the cage-like CM3 subcomplex is additionally required to stimulate Arf1 GTP hydrolysis, so the full heptameric coatomer is needed for catalysis (PMID:14690497, PMID:22375848). Functionally, ARFGAP2 acts redundantly with ARFGAP3 as a structural component of the COPI coat lattice: combined depletion increases GTP-bound Arf1, prevents proper coat lattice assembly, and causes Golgi unstacking and a block in retrograde transport (PMID:19299515, PMID:20858901). Beyond its housekeeping COPI role, ARFGAP2 is required for STING-mediated proton efflux from the Golgi and for non-transcriptional Golgi trafficking of cytokine cargos, and its deletion attenuates STING-driven cytokine secretion and autoinflammatory pathology in SAVI mice (PMID:39947179).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2004 High

    Establishing how an ArfGAP is physically docked at the Golgi, the gamma-COP appendage domain was shown to bind ARFGAP2 through a single site on its platform subdomain, defining a coatomer-based recruitment interface.

    Evidence Crystal structure of the gamma-COP appendage domain with protein-protein interaction binding assays

    PMID:14690497

    Open questions at the time
    • Did not resolve whether appendage binding alone is sufficient for Golgi recruitment in cells
    • No measurement of effect on GAP catalysis
  2. 2007 High

    Identifying ARFGAP2/3 as human Glo3 orthologues placed them in the COPI pathway, showing Golgi/coatomer colocalization, coatomer binding outside the zinc finger, and a dominant-negative block of retrograde transport.

    Evidence Immunofluorescence, in vitro COPI vesicle generation, truncation pulldown, dominant-negative retrograde transport assay

    PMID:17760859

    Open questions at the time
    • Catalytic activity not reconstituted
    • Functional redundancy with ARFGAP3 not addressed
  3. 2008 High

    Resolving how ARFGAP2/3 act without membrane binding, in vitro reconstitution showed they are recruited by coatomer rather than lipid, and that coatomer stimulates their Arf1 GAP activity to levels comparable to ArfGAP1.

    Evidence In vitro GAP activity assays with recombinant proteins, membrane binding and coatomer-dependent recruitment assays; domain mapping of the central basic coatomer-binding stretch

    PMID:19015319 PMID:19109418

    Open questions at the time
    • Did not identify which coatomer subcomplex mediates stimulation
    • In vivo relevance of domain mutants not fully tested
  4. 2009 Medium

    Defining the minimal functional unit, yeast Glo3 genetics showed the GAP domain plus the BoCCS region — which contacts coatomer, SNAREs, and cargo — is necessary and sufficient, linking ArfGAP function to cargo and SNARE engagement.

    Evidence Yeast genetic epistasis, domain truncation/mutation, dominant-negative growth and genetic suppression assays

    PMID:19602196

    Open questions at the time
    • Mapped in yeast; mammalian BoCCS equivalent not directly tested
    • Direct SNARE/cargo binding affinities not quantified
  5. 2009 High

    Demonstrating the cellular consequence of losing ArfGAP activity, triple knockdown of ArfGAP1/2/3 raised GTP-Arf levels, trapped cis-Golgi proteins in the ERGIC, and blocked retrograde transport, establishing overlapping roles in COPI function.

    Evidence siRNA triple knockdown, ARF-GTP measurement, Golgi marker immunofluorescence, retrograde transport assay, electron microscopy

    PMID:19299515

    Open questions at the time
    • Could not isolate ARFGAP2-specific contribution due to redundancy
    • Individual single-knockdown phenotypes not resolved here
  6. 2010 High

    Distinguishing ARFGAP2/3 from ArfGAP1 functionally, live imaging and EM showed ARFGAP2/3 track coatomer dynamics and are required for COPI coat lattice assembly and Golgi cisternal integrity, casting them as structural coat components.

    Evidence Live-cell imaging, siRNA knockdown, electron microscopy of coat lattice

    PMID:20858901

    Open questions at the time
    • Structural basis of lattice incorporation not resolved
    • Did not separate ARFGAP2 from ARFGAP3 contributions
  7. 2012 High

    Dissecting the recruitment-versus-catalysis problem, recombinant subcomplex reconstitution showed CM4 (via the gamma1-COP appendage hydrophobic pocket) recruits ARFGAP2 while CM3 is required to stimulate Arf1 GTP hydrolysis, so both halves of coatomer are needed.

    Evidence Recombinant coatomer subcomplex reconstitution, in vitro GAP activity and membrane recruitment assays

    PMID:22375848

    Open questions at the time
    • Atomic structure of the ARFGAP2-coatomer-Arf1 catalytic assembly not determined
    • How CM3 stimulates catalysis mechanistically unresolved
  8. 2015 Medium

    Probing upstream regulation, GIV/Girdin was found to interact with ArfGAP2/3 at the Golgi and to impose finiteness on Arf1 GTP cycling via Galphai, linking heterotrimeric G-protein signaling to ArfGAP-controlled secretion.

    Evidence Co-immunoprecipitation, Arf1-GTP measurement, secretory transport assay

    PMID:25865347

    Open questions at the time
    • Co-IP does not establish direct ARFGAP2 contact versus ARFGAP3
    • Limited mechanistic detail specific to ARFGAP2
  9. 2019 Medium

    Adding a post-translational regulatory layer, the yeast Snf1/AMPK complex was shown to phosphorylate the non-catalytic region of Glo3 required for Arf1 hydrolysis and COPI coat stability, linking metabolic signaling to ArfGAP activity.

    Evidence Genetic dissection, kinase phosphorylation assay, COPI coat stability assay in yeast

    PMID:31331965

    Open questions at the time
    • Phosphosite conservation/function in mammalian ARFGAP2 not tested
    • Effect on catalytic rate not quantified
  10. 2025 High

    Extending ARFGAP2 beyond housekeeping trafficking, conditional knockout mice revealed it is required for STING-mediated Golgi proton efflux and trafficking of cytokine cargos, and that its loss reduces autoinflammatory pathology in SAVI.

    Evidence Hematopoietic/endothelial conditional KO mice, proton efflux assays, Golgi trafficking assays, cytokine secretion, in vivo SAVI disease model

    PMID:39947179

    Open questions at the time
    • Whether this role requires ARFGAP2 GAP catalysis is not resolved
    • Molecular link between ARFGAP2 and the STING proton channel undefined
    • Cell-type specificity of the requirement not fully mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ARFGAP2's COPI catalytic role mechanistically connects to its requirement for STING-driven proton efflux and cytokine trafficking remains unresolved.
  • No structure of the ARFGAP2-coatomer-Arf1 catalytic complex
  • STING-pathway function not yet tied to GAP activity or coatomer dependence
  • ARFGAP2-specific (versus ARFGAP3) contributions in mammals remain blurred by redundancy

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0005198 structural molecule activity 1
Localization
GO:0005794 Golgi apparatus 3 GO:0031410 cytoplasmic vesicle 2 GO:0005829 cytosol 1
Pathway
R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-168256 Immune System 1
Partners
ARF1ARFGAP3COPAGIV/GIRDINSECRETAGOGIN
Complex memberships
COPI coat / coatomer

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 The appendage domain of gamma-COP binds to ARFGAP2 (mammalian Glo3p orthologue) via a single protein-protein interaction site on its platform subdomain, analogous to the alpha-appendage of AP2. Crystal structure of gamma-COP appendage domain combined with protein-protein interaction binding assays Traffic High 14690497
2007 ARFGAP2 and ARFGAP3 are human orthologues of yeast Glo3p; ARFGAP2 localizes to the Golgi complex and peripheral punctate structures colocalizing with coatomer subunits, is associated with COP-I-coated vesicles generated in vitro, and directly binds coatomer via a region outside its zinc finger domain. Expression of a truncated ARFGAP2 lacking its zinc finger domain (DeltaN-ARFGAP2) inhibits COP-I-dependent Golgi-to-ER transport of cholera toxin in vivo. Immunofluorescence colocalization, in vitro COP-I vesicle generation assay, pulldown binding assay with truncation mutant, dominant-negative inhibition of retrograde transport in vivo Traffic High 17760859
2008 Unlike ArfGAP1, ARFGAP2 and ARFGAP3 do not bind directly to membranes but are recruited to the Golgi via interactions with coatomer. In the presence of coatomer, ARFGAP2 and ARFGAP3 GAP activities are comparable to or higher than ArfGAP1 activity, establishing that coatomer functions to stimulate ARFGAP2/3-catalyzed GTP hydrolysis on Arf1. In vitro GAP activity assays with recombinant proteins, membrane binding assays, coatomer-dependent recruitment assays The Journal of cell biology High 19015319
2008 The Golgi localization and catalytic activity of ARFGAP2/3 depends on coatomer interaction. A central basic stretch in ARFGAP3 interacts directly with coatomer and is essential for ArfGAP3 catalytic activity on Arf1-GTP, while a carboxy-amphipathic motif interacts directly with lipid membranes but plays only a minor role in regulating GAP activity. Reporter fusion Golgi localization assay, in vitro GAP activity assays, direct binding assays between isolated domains and coatomer or lipid membranes Molecular biology of the cell High 19109418
2009 The GAP domain together with the BoCCS (binding of coatomer, cargo, and SNAREs) region of yeast Glo3 (ArfGAP2/3 orthologue) is necessary and sufficient for all vital Glo3 functions. The BoCCS region interacts with coatomer, SNAREs, and cargo. A truncated Glo3 lacking the GAP domain acts as a dominant negative whose phenotype is alleviated by mutating the BoCCS region or the Glo3 regulatory motif (GRM), or by overexpression of ER-Golgi SNAREs. Yeast genetic epistasis, domain truncation/mutation analysis, dominant negative growth assay, genetic suppression Traffic Medium 19602196
2009 Simultaneous knockdown of ArfGAP1, ArfGAP2, and ArfGAP3 in mammalian cells increases GTP-bound ARF levels, causes accumulation of cis-Golgi proteins (ERGIC-53, beta-COP, GM130) in the ER-Golgi intermediate compartment, and blocks Golgi-to-ER retrograde transport, phenocopying beta-COP depletion. ArfGAP1, 2, and 3 thus have overlapping roles in regulating COPI function in Golgi-to-ER retrograde transport. siRNA triple knockdown, ARF-GTP level measurement, immunofluorescence of Golgi markers, Golgi-to-ER retrograde transport assay, electron microscopy The Journal of biological chemistry High 19299515
2010 ARFGAP2 and ARFGAP3 follow the dynamic behavior of coatomer upon stimulation of vesicle budding in living cells more closely than ARFGAP1. Knockdown of both ARFGAP2 and ARFGAP3 prevents proper assembly of the COPI coat lattice and causes Golgi unstacking and cisternal shortening, whereas ARFGAP1 knockdown does not produce these effects, indicating ARFGAP2 and ARFGAP3 are key components of the COPI coat lattice necessary for proper vesicle formation. Live-cell imaging, siRNA knockdown, electron microscopy of COPI coat lattice assembly The Journal of biological chemistry High 20858901
2011 ARFGAP2 physically interacts with the calcium-binding protein secretagogin with high affinity (equilibrium dissociation constant 100 pM to 10 nM range), as identified by protein array screening and validated by surface plasmon resonance and GST pulldown assays. Protein array screening, surface plasmon resonance, GST pulldown assay Molecular bioSystems Medium 21528130
2012 Within the CM4 (adaptin-like tetrameric) subcomplex of coatomer, ARFGAP2 interacts with a novel hydrophobic pocket on the appendage domain of gamma1-COP. CM4 (but not CM3) is recruited to membranes through Arf1 and subsequently recruits ARFGAP2. Neither CM3 nor CM4 alone stimulates ARFGAP2 activity, but both subcomplexes together are required: CM4 functions in GAP recruitment while the cage-like CM3 subcomplex stimulates ARFGAP2-dependent GTP hydrolysis on Arf1. Recombinant coatomer subcomplex reconstitution, in vitro GAP activity assays, membrane recruitment assays Traffic High 22375848
2015 GIV/Girdin interacts with ArfGAP2/3 at the Golgi as part of a mechanism by which Gαi activation imposes finiteness on Arf1 GTP cycling. Selective inhibition of the GIV-Gαi pathway elevates GTP-bound Arf1 levels and delays protein transport along the secretory pathway. Co-immunoprecipitation, Arf1-GTP level measurement, secretory pathway transport assay Developmental cell Medium 25865347
2015 In yeast, Glo3 (ArfGAP2/3 orthologue) and ergosterol collaborate in transport of a subset of plasma membrane cargoes (tryptophan transporter Tat2, general amino acid permease Gap1, v-SNARE Snc1). In a glo3Δ erg3Δ double mutant, these cargoes accumulate in internal endosomal structures after endocytosis, suggesting a role for ArfGAP2/3 in recycling from endosomes. Yeast double-mutant genetic epistasis, fluorescence microscopy of cargo localization Biology open Medium 25964658
2019 In budding yeast, Glo3 (ArfGAP2/3 orthologue) specifically triggers Arf1 GTP hydrolysis that impinges on COPI coat stability. The Snf1 kinase complex (yeast AMPK homologue) phosphorylates the non-catalytic region of Glo3 that is crucial for this effect, thereby regulating Glo3 function in the COPI vesicle cycle. Genetic dissection, kinase phosphorylation assay, COPI coat stability assay in yeast Journal of cell science Medium 31331965
2001 ARFGAP2 (Zfp289) is a novel zinc finger protein whose mRNA expression is induced by Id-1 in mouse mammary epithelial cells. The protein is predominantly cytoplasmic as determined by GFP fusion localization, and its constitutive expression increases the S-phase index in serum-free culture, indicating a role in proliferation downstream of Id-1. Degenerate PCR cloning from Id-1-transfected cells, GFP fusion subcellular localization, S-phase index measurement by flow cytometry The Journal of biological chemistry Medium 11278321
2025 ArfGAP2 is required for STING-mediated proton efflux from the Golgi and for non-transcriptional Golgi trafficking of protein cargos downstream of STING activation. Deletion of ArfGAP2 in hematopoietic and endothelial cells markedly reduces STING-mediated cytokine and chemokine secretion, immune cell activation, and autoinflammatory pathology in SAVI mice. Conditional knockout mice (hematopoietic/endothelial-specific), proton efflux assays, Golgi trafficking assays, cytokine secretion measurements, in vivo autoinflammatory disease model Cell High 39947179
2018 ArfGAP2 and ArfGAP3 do not play a role in GBF1 recruitment to Golgi membranes, as determined by in vivo experiments examining Arf-GDP-regulated GBF1 recruitment. In vivo GBF1 recruitment assay with ArfGAP2/3 perturbation Journal of cell science Medium 29507113
2021 ArfGAP2 does not act as a GAP for human Arl1; exogenous expression of ArfGAP2 (unlike ArfGAP1) does not cause dissociation of endogenous Arl1 from the TGN. Overexpression assay with TGN localization readout by immunofluorescence FASEB journal Medium 33715220

Source papers

Stage 0 corpus · 31 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 The autonomic higher order processing nuclei of the lower brain stem are among the early targets of the Alzheimer's disease-related cytoskeletal pathology. Acta neuropathologica 76 11515783
2004 Gamma-COP appendage domain - structure and function. Traffic (Copenhagen, Denmark) 70 14690497
2008 Differential roles of ArfGAP1, ArfGAP2, and ArfGAP3 in COPI trafficking. The Journal of cell biology 61 19015319
2007 Two human ARFGAPs associated with COP-I-coated vesicles. Traffic (Copenhagen, Denmark) 50 17760859
2008 Discrete determinants in ArfGAP2/3 conferring Golgi localization and regulation by the COPI coat. Molecular biology of the cell 40 19109418
2015 Activation of Gαi at the Golgi by GIV/Girdin imposes finiteness in Arf1 signaling. Developmental cell 37 25865347
2011 Identification of a high-affinity network of secretagogin-binding proteins involved in vesicle secretion. Molecular bioSystems 35 21528130
2009 Three homologous ArfGAPs participate in coat protein I-mediated transport. The Journal of biological chemistry 33 19299515
2009 The GAP domain and the SNARE, coatomer and cargo interaction region of the ArfGAP2/3 Glo3 are sufficient for Glo3 function. Traffic (Copenhagen, Denmark) 29 19602196
2001 Anatomic relationships of the human nucleus paragigantocellularis lateralis: a DiI labeling study. Autonomic neuroscience : basic & clinical 28 11474639
2013 ArfGAP3 regulates the transport of cation-independent mannose 6-phosphate receptor in the post-Golgi compartment. Current biology : CB 25 24076238
2001 Molecular cloning and characterization of a zinc finger protein involved in Id-1-stimulated mammary epithelial cell growth. The Journal of biological chemistry 25 11278321
2010 ARFGAP2 and ARFGAP3 are essential for COPI coat assembly on the Golgi membrane of living cells. The Journal of biological chemistry 24 20858901
2013 Selection of new appropriate reference genes for RT-qPCR analysis via transcriptome sequencing of cynomolgus monkeys (Macaca fascicularis). PloS one 22 23613744
2001 Alpha2 receptor binding in the medulla oblongata in the sudden infant death syndrome. Journal of neuropathology and experimental neurology 18 11273002
2025 ArfGAP2 promotes STING proton channel activity, cytokine transit, and autoinflammation. Cell 15 39947179
2019 Dissection of GTPase-activating proteins reveals functional asymmetry in the COPI coat of budding yeast. Journal of cell science 15 31331965
2015 The ArfGAP2/3 Glo3 and ergosterol collaborate in transport of a subset of cargoes. Biology open 10 25964658
2012 Distinct role of subcomplexes of the COPI coat in the regulation of ArfGAP2 activity. Traffic (Copenhagen, Denmark) 10 22375848
1978 Genetic control of immunologic unresponsiveness to adjuvant-free solutions of beta-D-galactosidase. I. Inheritance of the Ir-Z1 and ir-Z2 loci in mice. Journal of immunology (Baltimore, Md. : 1950) 9 96178
2023 MIF Variant rs755622 Is Associated with Severe Crohn's Disease and Better Response to Anti-TNF Adalimumab Therapy. Genes 8 36833379
2021 ArfGAP1 acts as a GTPase-activating protein for human ADP-ribosylation factor-like 1 protein. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 8 33715220
2018 The Arf-GDP-regulated recruitment of GBF1 to Golgi membranes requires domains HDS1 and HDS2 and a Golgi-localized protein receptor. Journal of cell science 8 29507113
2022 ArfGAP3 regulates vesicle transport and glucose uptake in myoblasts. Cellular signalling 7 36476390
2016 Integration of genome-wide association and extant brain expression QTL identifies candidate genes influencing prepulse inhibition in inbred F1 mice. Genes, brain, and behavior 6 26482417
2011 Protein networks involved in vesicle fusion, transport, and storage revealed by array-based proteomics. Methods in molecular biology (Clifton, N.J.) 6 21877276
2023 DeepGenePrior: A deep learning model for prioritizing genes affected by copy number variants. PLoS computational biology 3 37486921
2016 DASAF: An R Package for Deep Sequencing-Based Detection of Fetal Autosomal Abnormalities from Maternal Cell-Free DNA. BioMed research international 3 27437397
2025 Rac1 Suppression by the Focal Adhesion Protein GIT ArfGAP2 and Podocyte Protection. Journal of the American Society of Nephrology : JASN 2 40019803
2024 Label-free quantitative proteomics reveals the mechanisms of Aurora kinase B in renal cell carcinoma. SAGE open medicine 2 38516642
2025 Targets and Potential Mechanism of Chondroitin Sulfate A-selenium Nanoparticle on Kashin-Beck Disease Chondrocytes. Biological trace element research 0 40138104

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