{"gene":"UBE2G2","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":1998,"finding":"UBE2G2 was identified as the human homologue of yeast Ubc7p, confirmed to be ubiquitously expressed, and mapped to chromosome 21q22.3. It encodes a 165-amino-acid protein with significant similarity to other UBC family members involved in proteasome-dependent degradation.","method":"cDNA cloning, sequence analysis, chromosomal mapping","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — identification and characterization by cloning and expression analysis; no in vitro enzymatic or structural validation in this paper alone, but replicated across the field","pmids":["9693041"],"is_preprint":false},{"year":2005,"finding":"Recombinant His-tagged UBE2G2 expressed in E. coli adopts the typical alpha/beta secondary structure of class I E2 enzymes and is enzymatically active, capable of binding ubiquitin molecules when exposed to HeLa cell extract in an in vitro ubiquitin-binding assay.","method":"Recombinant protein expression, nickel-affinity purification, circular dichroism, in vitro ubiquitin-binding assay","journal":"Protein expression and purification","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct biochemical activity assay with recombinant protein, single lab, single study","pmids":["16214370"],"is_preprint":false},{"year":2006,"finding":"Crystal structure of human UBE2G2 solved at 2.56 Å resolution; the structure comprises an antiparallel beta-sheet with four strands, five alpha-helices, and two 3(10)-helices. Structural comparison with yeast Ubc7 and UbcH7 suggested that two loop regions of UBE2G2 interact with RING domains, with an extra loop potentially conferring binding specificity.","method":"X-ray crystallography","journal":"Acta crystallographica. Section F","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure at 2.56 Å with structural comparisons; foundational structural data replicated and referenced by multiple subsequent studies","pmids":["16582478"],"is_preprint":false},{"year":2009,"finding":"gp78 forms oligomers via a hydrophobic segment in its cytosolic domain; a gp78 oligomer can simultaneously associate with multiple Ube2g2 molecules via a novel Ube2g2 surface distinct from the predicted RING binding site. This heterooligomeric assembly brings multiple Ube2g2 molecules into proximity, enabling transfer of ubiquitin moieties between neighboring Ube2g2s to form Lys-48-linked active site-linked polyubiquitin chains on the Ube2g2 catalytic cysteine prior to substrate transfer.","method":"Biochemical oligomerization assays, site-directed mutagenesis, in vitro ubiquitination assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution, mutagenesis, multiple orthogonal methods establishing mechanism of polyubiquitin chain preassembly","pmids":["19223579"],"is_preprint":false},{"year":2010,"finding":"Solution NMR structure of Ube2g2 revealed that two catalytically important loops flanking the active site cysteine (residues 95-107 and 130-135) are highly dynamic. 15N spin relaxation and residual dipolar coupling analysis showed these loops require binding partners (E3, acceptor ubiquitin, or thiolester-linked donor ubiquitin) to adopt a catalytically relevant conformation. His94 was identified as a potential general base activated by carboxylate side-chains of Asp98 or Asp99.","method":"NMR spectroscopy, 15N spin relaxation, residual dipolar coupling analysis","journal":"Proteins","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR solution structure with backbone dynamics analysis and functional validation by mutagenesis rationale; single lab but rigorous multi-method study","pmids":["20014027"],"is_preprint":false},{"year":2010,"finding":"AUP1 localizes to lipid droplets in a monotopic fashion with both termini facing the cytosol, and binds Ube2g2 via its C-terminal G2BR domain. Deletion or mutation of the G2BR domain abolishes Ube2g2 binding without affecting AUP1's LD localization. The AUP1-Ube2g2 complex at lipid droplets provides a direct molecular link between lipid droplets and the cellular ubiquitination machinery.","method":"Co-immunoprecipitation, domain deletion/mutation analysis, fluorescence microscopy, subcellular fractionation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding confirmed by domain mutagenesis and localization studies; replicated and extended by subsequent studies","pmids":["21127063"],"is_preprint":false},{"year":2010,"finding":"Ube2g2 binds ubiquitin with ~90 μM affinity in two orientations rotated 180°. It binds Lys-48-linked and Lys-63-linked diubiquitin primarily through the distal ubiquitin subunit (containing the free Lys-48 or Lys-63). For Lys-48-linked diubiquitin, there is ~3-fold preference for the distal subunit, attributed to partial steric occlusion of the proximal subunit's Lys-48, suggesting Lys-48-linked chains are designed to position the terminal ubiquitin's reactive Lys-48 for chain elongation.","method":"NMR chemical shift perturbation, paramagnetic relaxation enhancement, RosettaDock computational modeling","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — NMR-based binding characterization with two orthogonal methods (CSP and PRE), single lab","pmids":["21098018"],"is_preprint":false},{"year":2014,"finding":"Ube2g2 in complex with E3 ligase gp78 mediates polyubiquitylation of HERP, targeting it for proteasomal degradation during ER stress recovery. The polyubiquitylation of HERP in vitro depends on a physical interaction between the CUE domain of gp78 and the ubiquitin-like (UBL) domain of HERP, and this interaction is essential for HERP degradation in vivo.","method":"In vitro ubiquitylation assay, co-immunoprecipitation, domain mapping, cell-based degradation assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vitro ubiquitylation reconstitution plus in vivo validation with domain-level mapping; multiple methods in single study","pmids":["24496447"],"is_preprint":false},{"year":2017,"finding":"NMR conformational dynamics analysis showed that the G2BR domain of gp78 increases the affinity between the RING domain and Ube2g2 by 50-fold via allostery. Binding of G2BR and RING to two distant regions of Ube2g2 sequentially progresses toward ubiquitin transfer through redistribution of ground and excited conformational state populations. The RING domain binding triggers departure of G2BR in an allosteric fashion.","method":"NMR spectroscopy, conformational dynamics analysis, binding affinity measurements","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR-based conformational dynamics with quantified binding affinities; mechanistically establishes allosteric activation; single lab with multiple orthogonal NMR approaches","pmids":["28434917"],"is_preprint":false},{"year":2017,"finding":"gp78 RING domain binding to Ube2g2 increases the population of the closed (catalytically active) conformation of Ube2g2~Ub conjugates from ~60% to ~82%. Mutations in the hydrophobic patch of the thiolester-linked ubiquitin that abolish closed conformation also abolish catalytic activity. Organization of the active site into a catalytically viable conformation is the rate-limiting step for a single ubiquitin ligation event.","method":"NMR spectroscopy, single-turnover diubiquitin formation assays, site-directed mutagenesis","journal":"ACS omega","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR with single-turnover activity assays and mutagenesis establishing conformational control of catalysis; single lab with multiple orthogonal methods","pmids":["28884161"],"is_preprint":false},{"year":2021,"finding":"The 27-amino acid G2BR domain of AUP1 binds with high specificity and low nanomolar affinity to the backside of UBE2G2. Crystal/structural analysis of the AUP1 G2BR-UBE2G2 complex revealed an interface with salt bridges, hydrogen bonds, and hydrophobic interactions. G2BRAUP1 allosterically activates UBE2G2-mediated ubiquitination in vitro. In cells, AUP1 G2BR binding prevents rapid degradation of UBE2G2, recruits UBE2G2 to the ER membrane, and is required for UBE2G2 activation at the ER membrane for ERAD.","method":"Co-immunoprecipitation, structural analysis, in vitro ubiquitination assay, cell-based ERAD assays, site-directed mutagenesis, fluorescence microscopy","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — structural determination with mutagenesis plus in vitro reconstitution plus multiple in vivo cell-based phenotypic assays; multiple orthogonal methods","pmids":["34879065"],"is_preprint":false},{"year":2024,"finding":"UBE2G2 directly binds to LGALS3BP and forms a complex with E3 ubiquitin ligase TRIM38, facilitating ubiquitination-mediated degradation of LGALS3BP at the K104 residue. This suppresses PI3K/AKT signaling and inhibits vasculogenic mimicry and metastasis in uveal melanoma.","method":"Co-immunoprecipitation, ubiquitination assays, site-directed mutagenesis (K104 site identification), knockdown/overexpression with phenotypic readouts","journal":"Acta pharmaceutica Sinica. B","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, in vitro ubiquitination, and mutagenesis of ubiquitination site; single lab with multiple complementary methods","pmids":["39807310"],"is_preprint":false},{"year":2024,"finding":"UBE2G2 is required for ERAD-mediated degradation of proinsulin and is involved in the generation of the proinsulin B-chain autoantigen PPIB10-18. Screening of E2 ubiquitin conjugating enzymes identified UBE2G2 as specifically involved in this process.","method":"Gene knockdown screening of E2 enzymes, cell-based ERAD and antigen presentation assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic knockdown with specific cellular phenotype (antigen presentation) readout; single lab, single method","pmids":["38787820"],"is_preprint":false},{"year":2025,"finding":"AUP1 forms a complex with UBE2G2 that interacts with STING, retaining STING in the ER membrane and preventing its translocation to the Golgi and subsequent signaling. Deficiency of either AUP1 or UBE2G2 causes spontaneous STING activation and enhanced type I interferon expression, demonstrating that the AUP1-UBE2G2 complex is a negative regulator of STING-dependent innate immune signaling.","method":"Co-immunoprecipitation, genetic knockdown/knockout, cell-based STING signaling assays, in vitro and in vivo viral infection models","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of complex with STING plus genetic loss-of-function with defined signaling phenotype; single lab with multiple complementary approaches","pmids":["40237449"],"is_preprint":false},{"year":2025,"finding":"A nanobody binding to the backside region of Ube2G2 does not affect ubiquitin loading but differentially inhibits E3-mediated ubiquitination, with order of inhibition HRD1 > CHIP >> TRC8. Occupation of the backside site on Ube2G2 thus differentially affects its interactions with different E3 ligases. G2BR of gp78 enhances Ube2G2 activity when present in cis but its deletion results in similar inhibition as the nanobody.","method":"Nanobody binding assay, in vitro ubiquitination assays with multiple E3 ligases","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro biochemical reconstitution with multiple E3s and specific tool (nanobody); single lab with multiple E3 comparisons","pmids":["40234692"],"is_preprint":false},{"year":2025,"finding":"The m6A reader YTHDF3 directly binds UBE2G2 mRNA in an m6A-dependent manner (confirmed by RIP-qPCR and MeRIP-qPCR), and controls UBE2G2 mRNA stability. Reduced UBE2G2 expression impairs ubiquitination of ACSL4, resulting in ACSL4 stabilization, lipid peroxidation, and ferroptosis.","method":"RIP-qPCR, MeRIP-qPCR, gene overexpression/knockdown, in vitro ubiquitination assay","journal":"Ecotoxicology and environmental safety","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal RNA-binding confirmation methods plus functional ubiquitination assay; single lab","pmids":["41125048"],"is_preprint":false},{"year":2026,"finding":"Inactive (catalytically dead) UBE2G2 induces cell elongation independent of matrix properties, reduces actin stress fibers with dominant cortical ventral fibers aligned along the long axis, redistributes vinculin to ventral stress fibers, and impairs lamellipodia formation. Sequestration of wild-type UBE2G2 by AUP1 to the membrane fraction mimics the elongated phenotype, demonstrating that the cytosolic pool of UBE2G2 is responsible for regulating cell shape and motility.","method":"Inactive mutant expression, live-cell imaging, actin/vinculin immunostaining, wound healing assay, AUP1-mediated membrane sequestration","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — inactive mutant with multiple phenotypic readouts (morphology, actin, focal adhesions, migration) plus mechanistic dissection via AUP1 sequestration; single lab","pmids":["41989348"],"is_preprint":false}],"current_model":"UBE2G2 (human Ubc7/yeast Ubc7p ortholog) is an E2 ubiquitin-conjugating enzyme that assembles Lys-48-linked polyubiquitin chains—via active site-linked polyubiquitin chain intermediates—and transfers them to substrates for proteasomal degradation, functioning primarily in ERAD through partnerships with E3 ligases gp78 (AMFR), HRD1, and TRC8; the E3 gp78 allosterically activates UBE2G2 through dual contacts (G2BR and RING domains), the G2BR domain of AUP1 recruits and stabilizes UBE2G2 at the ER membrane while also allosterically activating it, and the AUP1-UBE2G2 complex additionally retains STING at the ER to suppress innate immune signaling; beyond ERAD, UBE2G2 ubiquitinates substrates including HERP, LGALS3BP (with TRIM38), and ACSL4, and its cytosolic pool regulates cell shape and motility through actin cytoskeleton organization."},"narrative":{"mechanistic_narrative":"UBE2G2 is a class I E2 ubiquitin-conjugating enzyme that builds Lys-48-linked polyubiquitin chains for proteasomal degradation, functioning centrally in ER-associated degradation (ERAD) through cooperation with RING E3 ligases [PMID:9693041, PMID:16582478, PMID:19223579]. A defining mechanistic feature is that UBE2G2 preassembles Lys-48-linked polyubiquitin chains on its own catalytic cysteine as active site-linked intermediates prior to substrate transfer; the E3 gp78 oligomerizes and engages multiple UBE2G2 molecules through a surface distinct from the RING-binding site, juxtaposing them so ubiquitin moieties are transferred between neighboring UBE2G2s to elongate the chain [PMID:19223579]. Catalysis is governed by conformational dynamics: two dynamic loops flanking the active-site cysteine require binding partners to adopt a catalytically competent state, and E3 engagement shifts the UBE2G2~ubiquitin conjugate into a closed, active conformation that is the rate-limiting step of ligation [PMID:20014027, PMID:28884161]. gp78 activates UBE2G2 allosterically through dual contacts, with its G2BR domain increasing RING affinity ~50-fold, after which RING binding triggers G2BR release [PMID:28434917]. The G2BR domain of AUP1 binds the backside of UBE2G2 with nanomolar affinity to stabilize the enzyme, recruit it to the ER membrane, and allosterically activate it for ERAD [PMID:21127063, PMID:34879065]; backside occupancy differentially tunes UBE2G2 activity across distinct E3 ligases [PMID:40234692]. Through these partnerships UBE2G2 ubiquitinates ERAD and other substrates including HERP, proinsulin, LGALS3BP (with TRIM38), and ACSL4 [PMID:24496447, PMID:39807310, PMID:38787820, PMID:41125048]. Beyond degradation, the AUP1-UBE2G2 complex retains STING at the ER to suppress type I interferon signaling [PMID:40237449], and the cytosolic pool of UBE2G2 regulates cell shape, actin organization, and motility [PMID:41989348].","teleology":[{"year":1998,"claim":"Establishing UBE2G2 as the human ortholog of yeast Ubc7p placed it within the ubiquitin-conjugating enzyme family linked to proteasomal degradation, defining the gene to study.","evidence":"cDNA cloning, sequence analysis, and chromosomal mapping","pmids":["9693041"],"confidence":"Medium","gaps":["No enzymatic activity demonstrated directly","No substrates or E3 partners identified"]},{"year":2006,"claim":"Solving the crystal structure confirmed UBE2G2 as a class I E2 fold and identified loop regions for RING engagement, providing a structural framework for E3 interactions.","evidence":"X-ray crystallography at 2.56 Å with comparison to Ubc7 and UbcH7","pmids":["16582478"],"confidence":"High","gaps":["Static structure does not capture catalytic dynamics","No bound E3 or ubiquitin in the structure"]},{"year":2009,"claim":"Resolving how gp78 oligomers engage multiple UBE2G2 molecules explained how Lys-48 chains are preassembled on the catalytic cysteine before substrate transfer, a non-canonical chain-building mechanism.","evidence":"Biochemical oligomerization assays, mutagenesis, and in vitro ubiquitination reconstitution","pmids":["19223579"],"confidence":"High","gaps":["Stoichiometry and dynamics of chain elongation in vivo unresolved","Whether other E3s use the same juxtaposition mechanism unknown"]},{"year":2010,"claim":"NMR dynamics and ubiquitin-binding studies showed that active-site loops and ubiquitin recognition require partner binding to reach a catalytic conformation and revealed Lys-48 chain positioning preferences, defining the conformational logic of catalysis.","evidence":"NMR spin relaxation, residual dipolar coupling, chemical shift perturbation, and computational docking","pmids":["20014027","21098018"],"confidence":"High","gaps":["Direct functional validation of His94 as general base limited to mutagenesis rationale","Ubiquitin binding measured in isolation, not in full E2-E3 context"]},{"year":2010,"claim":"Identifying AUP1 as a G2BR-domain partner that binds UBE2G2 at lipid droplets connected the ubiquitination machinery to a membrane compartment via a defined recruitment domain.","evidence":"Co-immunoprecipitation, domain mutagenesis, fluorescence microscopy, and fractionation","pmids":["21127063"],"confidence":"High","gaps":["Functional consequence of lipid-droplet localization for substrates not defined here","Whether G2BR also activates UBE2G2 not addressed in this study"]},{"year":2014,"claim":"Demonstrating gp78-UBE2G2 polyubiquitylation of HERP via gp78 CUE–HERP UBL contacts identified a specific ERAD substrate and mapped the recruitment interface, linking the enzyme to ER stress recovery.","evidence":"In vitro ubiquitylation, co-IP, domain mapping, and cell-based degradation assays","pmids":["24496447"],"confidence":"High","gaps":["Generalizability of CUE-UBL substrate recruitment to other substrates unclear","Chain topology on HERP not directly characterized"]},{"year":2017,"claim":"Quantifying gp78 G2BR/RING allostery and the conformational shift to the closed active state established how E3 binding accelerates catalysis and identified active-site organization as rate-limiting.","evidence":"NMR conformational dynamics, binding affinity measurements, and single-turnover diubiquitin assays","pmids":["28434917","28884161"],"confidence":"High","gaps":["Sequence of allosteric events inferred from NMR populations, not real-time kinetics","How allostery integrates with multi-E2 chain assembly unresolved"]},{"year":2021,"claim":"Structural and functional dissection of the AUP1 G2BR–UBE2G2 interface showed that AUP1 binding stabilizes UBE2G2, recruits it to the ER, and allosterically activates it for ERAD, defining AUP1 as a key activating partner.","evidence":"Structural analysis, co-IP, in vitro ubiquitination, cell-based ERAD assays, and mutagenesis","pmids":["34879065"],"confidence":"High","gaps":["Substrate range stabilized by AUP1-bound UBE2G2 not enumerated","Interplay between AUP1 and gp78 backside binding not resolved"]},{"year":2024,"claim":"Identifying UBE2G2 in degradation of proinsulin and in LGALS3BP ubiquitination (with TRIM38) extended its substrate repertoire beyond canonical ERAD into antigen generation and tumor signaling control.","evidence":"E2 knockdown screening, ERAD/antigen presentation assays, co-IP, and site-directed ubiquitination mapping (K104)","pmids":["38787820","39807310"],"confidence":"Medium","gaps":["Single-lab studies for each substrate","Direct E3 pairing for proinsulin ERAD not defined"]},{"year":2025,"claim":"Discovery that the AUP1-UBE2G2 complex retains STING at the ER, and that backside occupancy differentially tunes activity across HRD1/CHIP/TRC8, expanded UBE2G2 into innate immune regulation and revealed E3-selective control via its backside surface.","evidence":"Co-IP, genetic loss-of-function, STING signaling and viral infection models; nanobody and multi-E3 in vitro ubiquitination","pmids":["40237449","40234692"],"confidence":"Medium","gaps":["Whether STING retention requires catalytic activity not fully resolved","Backside-driven E3 selectivity tested in vitro only"]},{"year":2025,"claim":"Linking m6A-dependent YTHDF3 control of UBE2G2 mRNA stability to ACSL4 ubiquitination connected enzyme abundance to lipid peroxidation and ferroptosis, a degradation-dependent cell-fate axis.","evidence":"RIP-qPCR, MeRIP-qPCR, expression manipulation, and in vitro ubiquitination","pmids":["41125048"],"confidence":"Medium","gaps":["E3 ligase for ACSL4 ubiquitination not identified","Single-lab correlative axis"]},{"year":2026,"claim":"Showing that catalytically dead UBE2G2 and AUP1-mediated sequestration alter actin organization and motility established a cytosolic, cell-shape-regulating role distinct from membrane ERAD.","evidence":"Inactive mutant expression, live-cell imaging, actin/vinculin staining, wound healing, and membrane sequestration","pmids":["41989348"],"confidence":"Medium","gaps":["Cytoskeletal substrates of UBE2G2 not identified","Mechanism linking ubiquitination to actin remodeling unknown"]},{"year":null,"claim":"How UBE2G2 substrate selection is partitioned across its multiple E3 partners and how its non-ERAD functions (STING retention, cytoskeletal regulation) mechanistically couple to chain assembly remain open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying rule for E3/substrate selectivity","Cytoskeletal and immune roles lack defined substrate or chain-type assignment"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3,7,9,11]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[1,3,9]},{"term_id":"GO:0031386","term_label":"protein tag activity","supporting_discovery_ids":[3,6]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[10,13]},{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[5]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[16]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3,7,10]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[7,13]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[13]}],"complexes":["AUP1-UBE2G2 complex","gp78-UBE2G2 complex"],"partners":["AMFR","AUP1","HRD1","TRC8","HERP","LGALS3BP","TRIM38","STING"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P60604","full_name":"Ubiquitin-conjugating enzyme E2 G2","aliases":["E2 ubiquitin-conjugating enzyme G2","Ubiquitin carrier protein G2","Ubiquitin-protein ligase G2"],"length_aa":165,"mass_kda":18.6,"function":"Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins (PubMed:20061386). In vitro catalyzes 'Lys-48'-linked polyubiquitination (PubMed:20061386). Involved in endoplasmic reticulum-associated degradation (ERAD) (PubMed:22607976). Required for sterol-induced ubiquitination of 3-hydroxy-3-methylglutaryl coenzyme A reductase and its subsequent proteasomal degradation (PubMed:23223569)","subcellular_location":"Endoplasmic reticulum; Lipid droplet","url":"https://www.uniprot.org/uniprotkb/P60604/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/UBE2G2","classification":"Not Classified","n_dependent_lines":296,"n_total_lines":1208,"dependency_fraction":0.24503311258278146},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2},{"gene":"CCDC47","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/UBE2G2","total_profiled":1310},"omim":[{"mim_id":"613297","title":"MEMBRANE-ASSOCIATED RING-CH FINGER PROTEIN 6; MARCHF6","url":"https://www.omim.org/entry/613297"},{"mim_id":"611176","title":"JNK/MAPK8-ASSOCIATED MEMBRANE PROTEIN; JKAMP","url":"https://www.omim.org/entry/611176"},{"mim_id":"603124","title":"UBIQUITIN-CONJUGATING ENZYME E2 G2; UBE2G2","url":"https://www.omim.org/entry/603124"},{"mim_id":"602677","title":"RING FINGER PROTEIN 5; RNF5","url":"https://www.omim.org/entry/602677"},{"mim_id":"602434","title":"ANCIENT UBIQUITOUS PROTEIN 1; AUP1","url":"https://www.omim.org/entry/602434"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/UBE2G2"},"hgnc":{"alias_symbol":["UBC7"],"prev_symbol":[]},"alphafold":{"accession":"P60604","domains":[{"cath_id":"3.10.110.10","chopping":"1-165","consensus_level":"medium","plddt":94.3413,"start":1,"end":165}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P60604","model_url":"https://alphafold.ebi.ac.uk/files/AF-P60604-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P60604-F1-predicted_aligned_error_v6.png","plddt_mean":94.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=UBE2G2","jax_strain_url":"https://www.jax.org/strain/search?query=UBE2G2"},"sequence":{"accession":"P60604","fasta_url":"https://rest.uniprot.org/uniprotkb/P60604.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P60604/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P60604"}},"corpus_meta":[{"pmid":"21127063","id":"PMC_21127063","title":"Ancient ubiquitous protein 1 (AUP1) localizes to lipid droplets and binds the E2 ubiquitin conjugase G2 (Ube2g2) via its G2 binding region.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21127063","citation_count":105,"is_preprint":false},{"pmid":"19223579","id":"PMC_19223579","title":"Mechanistic insights into active site-associated polyubiquitination by the ubiquitin-conjugating enzyme Ube2g2.","date":"2009","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/19223579","citation_count":83,"is_preprint":false},{"pmid":"24496447","id":"PMC_24496447","title":"Ube2g2-gp78-mediated HERP polyubiquitylation is involved in ER stress recovery.","date":"2014","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/24496447","citation_count":37,"is_preprint":false},{"pmid":"20014027","id":"PMC_20014027","title":"Solution structure and dynamics of human ubiquitin conjugating enzyme Ube2g2.","date":"2010","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/20014027","citation_count":29,"is_preprint":false},{"pmid":"28434917","id":"PMC_28434917","title":"Conformational Dynamics and Allostery in E2:E3 Interactions Drive Ubiquitination: gp78 and Ube2g2.","date":"2017","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/28434917","citation_count":26,"is_preprint":false},{"pmid":"9693041","id":"PMC_9693041","title":"Identification, expression, and chromosomal localization of ubiquitin conjugating enzyme 7 (UBE2G2), a human homologue of the Saccharomyces cerevisiae ubc7 gene.","date":"1998","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9693041","citation_count":26,"is_preprint":false},{"pmid":"16582478","id":"PMC_16582478","title":"Structure of human ubiquitin-conjugating enzyme E2 G2 (UBE2G2/UBC7).","date":"2006","source":"Acta crystallographica. 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It encodes a 165-amino-acid protein with significant similarity to other UBC family members involved in proteasome-dependent degradation.\",\n      \"method\": \"cDNA cloning, sequence analysis, chromosomal mapping\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — identification and characterization by cloning and expression analysis; no in vitro enzymatic or structural validation in this paper alone, but replicated across the field\",\n      \"pmids\": [\"9693041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Recombinant His-tagged UBE2G2 expressed in E. coli adopts the typical alpha/beta secondary structure of class I E2 enzymes and is enzymatically active, capable of binding ubiquitin molecules when exposed to HeLa cell extract in an in vitro ubiquitin-binding assay.\",\n      \"method\": \"Recombinant protein expression, nickel-affinity purification, circular dichroism, in vitro ubiquitin-binding assay\",\n      \"journal\": \"Protein expression and purification\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct biochemical activity assay with recombinant protein, single lab, single study\",\n      \"pmids\": [\"16214370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Crystal structure of human UBE2G2 solved at 2.56 Å resolution; the structure comprises an antiparallel beta-sheet with four strands, five alpha-helices, and two 3(10)-helices. Structural comparison with yeast Ubc7 and UbcH7 suggested that two loop regions of UBE2G2 interact with RING domains, with an extra loop potentially conferring binding specificity.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"Acta crystallographica. Section F\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure at 2.56 Å with structural comparisons; foundational structural data replicated and referenced by multiple subsequent studies\",\n      \"pmids\": [\"16582478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"gp78 forms oligomers via a hydrophobic segment in its cytosolic domain; a gp78 oligomer can simultaneously associate with multiple Ube2g2 molecules via a novel Ube2g2 surface distinct from the predicted RING binding site. This heterooligomeric assembly brings multiple Ube2g2 molecules into proximity, enabling transfer of ubiquitin moieties between neighboring Ube2g2s to form Lys-48-linked active site-linked polyubiquitin chains on the Ube2g2 catalytic cysteine prior to substrate transfer.\",\n      \"method\": \"Biochemical oligomerization assays, site-directed mutagenesis, in vitro ubiquitination assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution, mutagenesis, multiple orthogonal methods establishing mechanism of polyubiquitin chain preassembly\",\n      \"pmids\": [\"19223579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Solution NMR structure of Ube2g2 revealed that two catalytically important loops flanking the active site cysteine (residues 95-107 and 130-135) are highly dynamic. 15N spin relaxation and residual dipolar coupling analysis showed these loops require binding partners (E3, acceptor ubiquitin, or thiolester-linked donor ubiquitin) to adopt a catalytically relevant conformation. His94 was identified as a potential general base activated by carboxylate side-chains of Asp98 or Asp99.\",\n      \"method\": \"NMR spectroscopy, 15N spin relaxation, residual dipolar coupling analysis\",\n      \"journal\": \"Proteins\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR solution structure with backbone dynamics analysis and functional validation by mutagenesis rationale; single lab but rigorous multi-method study\",\n      \"pmids\": [\"20014027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"AUP1 localizes to lipid droplets in a monotopic fashion with both termini facing the cytosol, and binds Ube2g2 via its C-terminal G2BR domain. Deletion or mutation of the G2BR domain abolishes Ube2g2 binding without affecting AUP1's LD localization. The AUP1-Ube2g2 complex at lipid droplets provides a direct molecular link between lipid droplets and the cellular ubiquitination machinery.\",\n      \"method\": \"Co-immunoprecipitation, domain deletion/mutation analysis, fluorescence microscopy, subcellular fractionation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding confirmed by domain mutagenesis and localization studies; replicated and extended by subsequent studies\",\n      \"pmids\": [\"21127063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Ube2g2 binds ubiquitin with ~90 μM affinity in two orientations rotated 180°. It binds Lys-48-linked and Lys-63-linked diubiquitin primarily through the distal ubiquitin subunit (containing the free Lys-48 or Lys-63). For Lys-48-linked diubiquitin, there is ~3-fold preference for the distal subunit, attributed to partial steric occlusion of the proximal subunit's Lys-48, suggesting Lys-48-linked chains are designed to position the terminal ubiquitin's reactive Lys-48 for chain elongation.\",\n      \"method\": \"NMR chemical shift perturbation, paramagnetic relaxation enhancement, RosettaDock computational modeling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — NMR-based binding characterization with two orthogonal methods (CSP and PRE), single lab\",\n      \"pmids\": [\"21098018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Ube2g2 in complex with E3 ligase gp78 mediates polyubiquitylation of HERP, targeting it for proteasomal degradation during ER stress recovery. The polyubiquitylation of HERP in vitro depends on a physical interaction between the CUE domain of gp78 and the ubiquitin-like (UBL) domain of HERP, and this interaction is essential for HERP degradation in vivo.\",\n      \"method\": \"In vitro ubiquitylation assay, co-immunoprecipitation, domain mapping, cell-based degradation assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro ubiquitylation reconstitution plus in vivo validation with domain-level mapping; multiple methods in single study\",\n      \"pmids\": [\"24496447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NMR conformational dynamics analysis showed that the G2BR domain of gp78 increases the affinity between the RING domain and Ube2g2 by 50-fold via allostery. Binding of G2BR and RING to two distant regions of Ube2g2 sequentially progresses toward ubiquitin transfer through redistribution of ground and excited conformational state populations. The RING domain binding triggers departure of G2BR in an allosteric fashion.\",\n      \"method\": \"NMR spectroscopy, conformational dynamics analysis, binding affinity measurements\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR-based conformational dynamics with quantified binding affinities; mechanistically establishes allosteric activation; single lab with multiple orthogonal NMR approaches\",\n      \"pmids\": [\"28434917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"gp78 RING domain binding to Ube2g2 increases the population of the closed (catalytically active) conformation of Ube2g2~Ub conjugates from ~60% to ~82%. Mutations in the hydrophobic patch of the thiolester-linked ubiquitin that abolish closed conformation also abolish catalytic activity. Organization of the active site into a catalytically viable conformation is the rate-limiting step for a single ubiquitin ligation event.\",\n      \"method\": \"NMR spectroscopy, single-turnover diubiquitin formation assays, site-directed mutagenesis\",\n      \"journal\": \"ACS omega\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR with single-turnover activity assays and mutagenesis establishing conformational control of catalysis; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"28884161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The 27-amino acid G2BR domain of AUP1 binds with high specificity and low nanomolar affinity to the backside of UBE2G2. Crystal/structural analysis of the AUP1 G2BR-UBE2G2 complex revealed an interface with salt bridges, hydrogen bonds, and hydrophobic interactions. G2BRAUP1 allosterically activates UBE2G2-mediated ubiquitination in vitro. In cells, AUP1 G2BR binding prevents rapid degradation of UBE2G2, recruits UBE2G2 to the ER membrane, and is required for UBE2G2 activation at the ER membrane for ERAD.\",\n      \"method\": \"Co-immunoprecipitation, structural analysis, in vitro ubiquitination assay, cell-based ERAD assays, site-directed mutagenesis, fluorescence microscopy\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structural determination with mutagenesis plus in vitro reconstitution plus multiple in vivo cell-based phenotypic assays; multiple orthogonal methods\",\n      \"pmids\": [\"34879065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"UBE2G2 directly binds to LGALS3BP and forms a complex with E3 ubiquitin ligase TRIM38, facilitating ubiquitination-mediated degradation of LGALS3BP at the K104 residue. This suppresses PI3K/AKT signaling and inhibits vasculogenic mimicry and metastasis in uveal melanoma.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, site-directed mutagenesis (K104 site identification), knockdown/overexpression with phenotypic readouts\",\n      \"journal\": \"Acta pharmaceutica Sinica. B\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, in vitro ubiquitination, and mutagenesis of ubiquitination site; single lab with multiple complementary methods\",\n      \"pmids\": [\"39807310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"UBE2G2 is required for ERAD-mediated degradation of proinsulin and is involved in the generation of the proinsulin B-chain autoantigen PPIB10-18. Screening of E2 ubiquitin conjugating enzymes identified UBE2G2 as specifically involved in this process.\",\n      \"method\": \"Gene knockdown screening of E2 enzymes, cell-based ERAD and antigen presentation assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic knockdown with specific cellular phenotype (antigen presentation) readout; single lab, single method\",\n      \"pmids\": [\"38787820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AUP1 forms a complex with UBE2G2 that interacts with STING, retaining STING in the ER membrane and preventing its translocation to the Golgi and subsequent signaling. Deficiency of either AUP1 or UBE2G2 causes spontaneous STING activation and enhanced type I interferon expression, demonstrating that the AUP1-UBE2G2 complex is a negative regulator of STING-dependent innate immune signaling.\",\n      \"method\": \"Co-immunoprecipitation, genetic knockdown/knockout, cell-based STING signaling assays, in vitro and in vivo viral infection models\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of complex with STING plus genetic loss-of-function with defined signaling phenotype; single lab with multiple complementary approaches\",\n      \"pmids\": [\"40237449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A nanobody binding to the backside region of Ube2G2 does not affect ubiquitin loading but differentially inhibits E3-mediated ubiquitination, with order of inhibition HRD1 > CHIP >> TRC8. Occupation of the backside site on Ube2G2 thus differentially affects its interactions with different E3 ligases. G2BR of gp78 enhances Ube2G2 activity when present in cis but its deletion results in similar inhibition as the nanobody.\",\n      \"method\": \"Nanobody binding assay, in vitro ubiquitination assays with multiple E3 ligases\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro biochemical reconstitution with multiple E3s and specific tool (nanobody); single lab with multiple E3 comparisons\",\n      \"pmids\": [\"40234692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The m6A reader YTHDF3 directly binds UBE2G2 mRNA in an m6A-dependent manner (confirmed by RIP-qPCR and MeRIP-qPCR), and controls UBE2G2 mRNA stability. Reduced UBE2G2 expression impairs ubiquitination of ACSL4, resulting in ACSL4 stabilization, lipid peroxidation, and ferroptosis.\",\n      \"method\": \"RIP-qPCR, MeRIP-qPCR, gene overexpression/knockdown, in vitro ubiquitination assay\",\n      \"journal\": \"Ecotoxicology and environmental safety\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal RNA-binding confirmation methods plus functional ubiquitination assay; single lab\",\n      \"pmids\": [\"41125048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Inactive (catalytically dead) UBE2G2 induces cell elongation independent of matrix properties, reduces actin stress fibers with dominant cortical ventral fibers aligned along the long axis, redistributes vinculin to ventral stress fibers, and impairs lamellipodia formation. Sequestration of wild-type UBE2G2 by AUP1 to the membrane fraction mimics the elongated phenotype, demonstrating that the cytosolic pool of UBE2G2 is responsible for regulating cell shape and motility.\",\n      \"method\": \"Inactive mutant expression, live-cell imaging, actin/vinculin immunostaining, wound healing assay, AUP1-mediated membrane sequestration\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — inactive mutant with multiple phenotypic readouts (morphology, actin, focal adhesions, migration) plus mechanistic dissection via AUP1 sequestration; single lab\",\n      \"pmids\": [\"41989348\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"UBE2G2 (human Ubc7/yeast Ubc7p ortholog) is an E2 ubiquitin-conjugating enzyme that assembles Lys-48-linked polyubiquitin chains—via active site-linked polyubiquitin chain intermediates—and transfers them to substrates for proteasomal degradation, functioning primarily in ERAD through partnerships with E3 ligases gp78 (AMFR), HRD1, and TRC8; the E3 gp78 allosterically activates UBE2G2 through dual contacts (G2BR and RING domains), the G2BR domain of AUP1 recruits and stabilizes UBE2G2 at the ER membrane while also allosterically activating it, and the AUP1-UBE2G2 complex additionally retains STING at the ER to suppress innate immune signaling; beyond ERAD, UBE2G2 ubiquitinates substrates including HERP, LGALS3BP (with TRIM38), and ACSL4, and its cytosolic pool regulates cell shape and motility through actin cytoskeleton organization.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"UBE2G2 is a class I E2 ubiquitin-conjugating enzyme that builds Lys-48-linked polyubiquitin chains for proteasomal degradation, functioning centrally in ER-associated degradation (ERAD) through cooperation with RING E3 ligases [#0, #2, #3]. A defining mechanistic feature is that UBE2G2 preassembles Lys-48-linked polyubiquitin chains on its own catalytic cysteine as active site-linked intermediates prior to substrate transfer; the E3 gp78 oligomerizes and engages multiple UBE2G2 molecules through a surface distinct from the RING-binding site, juxtaposing them so ubiquitin moieties are transferred between neighboring UBE2G2s to elongate the chain [#3]. Catalysis is governed by conformational dynamics: two dynamic loops flanking the active-site cysteine require binding partners to adopt a catalytically competent state, and E3 engagement shifts the UBE2G2~ubiquitin conjugate into a closed, active conformation that is the rate-limiting step of ligation [#4, #9]. gp78 activates UBE2G2 allosterically through dual contacts, with its G2BR domain increasing RING affinity ~50-fold, after which RING binding triggers G2BR release [#8]. The G2BR domain of AUP1 binds the backside of UBE2G2 with nanomolar affinity to stabilize the enzyme, recruit it to the ER membrane, and allosterically activate it for ERAD [#5, #10]; backside occupancy differentially tunes UBE2G2 activity across distinct E3 ligases [#14]. Through these partnerships UBE2G2 ubiquitinates ERAD and other substrates including HERP, proinsulin, LGALS3BP (with TRIM38), and ACSL4 [#7, #11, #12, #15]. Beyond degradation, the AUP1-UBE2G2 complex retains STING at the ER to suppress type I interferon signaling [#13], and the cytosolic pool of UBE2G2 regulates cell shape, actin organization, and motility [#16].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Establishing UBE2G2 as the human ortholog of yeast Ubc7p placed it within the ubiquitin-conjugating enzyme family linked to proteasomal degradation, defining the gene to study.\",\n      \"evidence\": \"cDNA cloning, sequence analysis, and chromosomal mapping\",\n      \"pmids\": [\"9693041\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No enzymatic activity demonstrated directly\", \"No substrates or E3 partners identified\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Solving the crystal structure confirmed UBE2G2 as a class I E2 fold and identified loop regions for RING engagement, providing a structural framework for E3 interactions.\",\n      \"evidence\": \"X-ray crystallography at 2.56 Å with comparison to Ubc7 and UbcH7\",\n      \"pmids\": [\"16582478\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Static structure does not capture catalytic dynamics\", \"No bound E3 or ubiquitin in the structure\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Resolving how gp78 oligomers engage multiple UBE2G2 molecules explained how Lys-48 chains are preassembled on the catalytic cysteine before substrate transfer, a non-canonical chain-building mechanism.\",\n      \"evidence\": \"Biochemical oligomerization assays, mutagenesis, and in vitro ubiquitination reconstitution\",\n      \"pmids\": [\"19223579\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and dynamics of chain elongation in vivo unresolved\", \"Whether other E3s use the same juxtaposition mechanism unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"NMR dynamics and ubiquitin-binding studies showed that active-site loops and ubiquitin recognition require partner binding to reach a catalytic conformation and revealed Lys-48 chain positioning preferences, defining the conformational logic of catalysis.\",\n      \"evidence\": \"NMR spin relaxation, residual dipolar coupling, chemical shift perturbation, and computational docking\",\n      \"pmids\": [\"20014027\", \"21098018\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct functional validation of His94 as general base limited to mutagenesis rationale\", \"Ubiquitin binding measured in isolation, not in full E2-E3 context\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identifying AUP1 as a G2BR-domain partner that binds UBE2G2 at lipid droplets connected the ubiquitination machinery to a membrane compartment via a defined recruitment domain.\",\n      \"evidence\": \"Co-immunoprecipitation, domain mutagenesis, fluorescence microscopy, and fractionation\",\n      \"pmids\": [\"21127063\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of lipid-droplet localization for substrates not defined here\", \"Whether G2BR also activates UBE2G2 not addressed in this study\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrating gp78-UBE2G2 polyubiquitylation of HERP via gp78 CUE–HERP UBL contacts identified a specific ERAD substrate and mapped the recruitment interface, linking the enzyme to ER stress recovery.\",\n      \"evidence\": \"In vitro ubiquitylation, co-IP, domain mapping, and cell-based degradation assays\",\n      \"pmids\": [\"24496447\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generalizability of CUE-UBL substrate recruitment to other substrates unclear\", \"Chain topology on HERP not directly characterized\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Quantifying gp78 G2BR/RING allostery and the conformational shift to the closed active state established how E3 binding accelerates catalysis and identified active-site organization as rate-limiting.\",\n      \"evidence\": \"NMR conformational dynamics, binding affinity measurements, and single-turnover diubiquitin assays\",\n      \"pmids\": [\"28434917\", \"28884161\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Sequence of allosteric events inferred from NMR populations, not real-time kinetics\", \"How allostery integrates with multi-E2 chain assembly unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Structural and functional dissection of the AUP1 G2BR–UBE2G2 interface showed that AUP1 binding stabilizes UBE2G2, recruits it to the ER, and allosterically activates it for ERAD, defining AUP1 as a key activating partner.\",\n      \"evidence\": \"Structural analysis, co-IP, in vitro ubiquitination, cell-based ERAD assays, and mutagenesis\",\n      \"pmids\": [\"34879065\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate range stabilized by AUP1-bound UBE2G2 not enumerated\", \"Interplay between AUP1 and gp78 backside binding not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identifying UBE2G2 in degradation of proinsulin and in LGALS3BP ubiquitination (with TRIM38) extended its substrate repertoire beyond canonical ERAD into antigen generation and tumor signaling control.\",\n      \"evidence\": \"E2 knockdown screening, ERAD/antigen presentation assays, co-IP, and site-directed ubiquitination mapping (K104)\",\n      \"pmids\": [\"38787820\", \"39807310\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab studies for each substrate\", \"Direct E3 pairing for proinsulin ERAD not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Discovery that the AUP1-UBE2G2 complex retains STING at the ER, and that backside occupancy differentially tunes activity across HRD1/CHIP/TRC8, expanded UBE2G2 into innate immune regulation and revealed E3-selective control via its backside surface.\",\n      \"evidence\": \"Co-IP, genetic loss-of-function, STING signaling and viral infection models; nanobody and multi-E3 in vitro ubiquitination\",\n      \"pmids\": [\"40237449\", \"40234692\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether STING retention requires catalytic activity not fully resolved\", \"Backside-driven E3 selectivity tested in vitro only\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linking m6A-dependent YTHDF3 control of UBE2G2 mRNA stability to ACSL4 ubiquitination connected enzyme abundance to lipid peroxidation and ferroptosis, a degradation-dependent cell-fate axis.\",\n      \"evidence\": \"RIP-qPCR, MeRIP-qPCR, expression manipulation, and in vitro ubiquitination\",\n      \"pmids\": [\"41125048\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase for ACSL4 ubiquitination not identified\", \"Single-lab correlative axis\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showing that catalytically dead UBE2G2 and AUP1-mediated sequestration alter actin organization and motility established a cytosolic, cell-shape-regulating role distinct from membrane ERAD.\",\n      \"evidence\": \"Inactive mutant expression, live-cell imaging, actin/vinculin staining, wound healing, and membrane sequestration\",\n      \"pmids\": [\"41989348\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cytoskeletal substrates of UBE2G2 not identified\", \"Mechanism linking ubiquitination to actin remodeling unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How UBE2G2 substrate selection is partitioned across its multiple E3 partners and how its non-ERAD functions (STING retention, cytoskeletal regulation) mechanistically couple to chain assembly remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying rule for E3/substrate selectivity\", \"Cytoskeletal and immune roles lack defined substrate or chain-type assignment\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3, 7, 9, 11]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [1, 3, 9]},\n      {\"term_id\": \"GO:0031386\", \"supporting_discovery_ids\": [3, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [10, 13]},\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3, 7, 10]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [7, 13]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"complexes\": [\n      \"AUP1-UBE2G2 complex\",\n      \"gp78-UBE2G2 complex\"\n    ],\n    \"partners\": [\n      \"AMFR\",\n      \"AUP1\",\n      \"HRD1\",\n      \"TRC8\",\n      \"HERP\",\n      \"LGALS3BP\",\n      \"TRIM38\",\n      \"STING\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}