{"gene":"COG3","run_date":"2026-04-28T17:28:53","timeline":{"discoveries":[{"year":1999,"finding":"Sec34p (yeast COG3 ortholog) forms an ~750 kDa protein complex with Sec35p in yeast cytosol, is required in vitro for vesicle tethering to the Golgi, and its temperature-sensitive phenotype is suppressed by the Rab GTPase Ypt1p and the SNARE-associated protein Sly1-20p, placing Sec34p in the ER-to-Golgi vesicle tethering pathway.","method":"Genetic suppressor analysis, two-hybrid interaction, cytosol fractionation, in vitro vesicle tethering assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro tethering assay combined with genetic epistasis and biochemical fractionation, replicated across multiple approaches in same study","pmids":["10562277"],"is_preprint":false},{"year":1999,"finding":"Sec34p (yeast COG3 ortholog) physically associates with Sec35p to form a ~480 kDa multiprotein complex; overexpression of SEC34 specifically suppresses the sec35-1 mutation, confirming a functional partnership in ER-to-Golgi vesicular traffic.","method":"Co-precipitation, high-copy suppressor screen, gel filtration","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 — reciprocal biochemical interaction confirmed by multiple approaches, replicated independently from PMID:10562277","pmids":["10512869"],"is_preprint":false},{"year":2001,"finding":"Human Sec34p (COG3) is a peripheral membrane protein that localizes to cis/medial Golgi cisternae, migrates as part of an ~300 kDa complex in cytosol, and its Golgi association is sensitive to Brefeldin A, consistent with a role in tethering intra-Golgi transport vesicles.","method":"Immunofluorescence microscopy, glycerol velocity gradient fractionation, GFP live imaging, BFA treatment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — direct localization experiment with multiple orthogonal methods in human cells","pmids":["11292827"],"is_preprint":false},{"year":2001,"finding":"Dor1p and seven associated proteins in yeast (including Sec34p/COG3 and Sec35p) constitute the Sec34/35 complex; several subunits show distant homology to exocyst and Vps52/53/54 complex components, defining a conserved family of tethering complexes involved in multiple membrane traffic steps.","method":"Affinity purification, sequence homology analysis, co-purification","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 — complex characterized by affinity purification and sequence analysis, establishing COG3 as part of a conserved tethering family","pmids":["11703943"],"is_preprint":false},{"year":2002,"finding":"Human COG complex (comprising COG3/Sec34 along with COG1–8) is required for normal Golgi morphology; EM of ldlB and ldlC mutants showed Golgi morphology defects, and deep-etch EM of purified COG revealed an ~37-nm two-domain structure.","method":"EM of mutant CHO cells, deep-etch EM of purified complex, biochemical subunit identification","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 — structural EM of purified complex combined with loss-of-function morphology analysis","pmids":["11980916"],"is_preprint":false},{"year":2002,"finding":"The yeast Sec34/35 complex (containing COG3 ortholog Sec34p) interacts genetically and physically with the Rab protein Ypt1p, intra-Golgi SNARE molecules, and COPI vesicle coat proteins, supporting its role as a tether connecting cis-Golgi membranes with COPI-coated retrograde intra-Golgi vesicles.","method":"Genetic interaction analysis, co-immunoprecipitation, two-hybrid","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — multiple physical and genetic interactions identified with orthogonal methods","pmids":["12011112"],"is_preprint":false},{"year":2002,"finding":"Mammalian COG3 (Sec34) directly interacts with COG1 (ldlBp) and COG2 (ldlCp) in vitro and co-immunoprecipitates with GTC-90 and ldlBp from rat liver cytosol; anti-Sec34 antibodies inhibit ER-to-Golgi transport in a semi-intact cell assay in a dose-dependent manner.","method":"Co-immunoprecipitation from rat liver cytosol, in vitro binding assay, semi-intact cell ER-to-Golgi transport assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro transport inhibition combined with direct binding and co-IP","pmids":["11929878"],"is_preprint":false},{"year":2004,"finding":"A COG3 temperature-sensitive allele (cog3-202) in yeast causes mislocalization of Golgi mannosyltransferases Och1p and Mnn1p without accumulating them in retrograde vesicles, consistent with COG3 playing a role in sorting Och1p into retrograde vesicles for intra-Golgi recycling rather than in vesicle fusion.","method":"Temperature-sensitive allele analysis, density gradient fractionation, genetic comparison with sed5(ts) and sft1(ts) strains","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — epistatic comparison of multiple ts mutants with biochemical fractionation","pmids":["15229219"],"is_preprint":false},{"year":2005,"finding":"C. elegans COGC-3 (COG3 ortholog) is required for the glycosylation and gonadal basement membrane localization of the ADAM protease MIG-17; cogc-3 mutants display misdirected distal tip cell migration phenocopying mig-17 mutants, and COGC-3 requires MIG-17 activity for its effect on organ morphogenesis.","method":"Genetic loss-of-function analysis, RNAi of all 8 COG subunits, epistasis, MIG-17 glycosylation and localization assay","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with biochemical glycosylation readout across all 8 subunits in C. elegans","pmids":["16354716"],"is_preprint":false},{"year":2006,"finding":"Acute siRNA knockdown of COG3 in mammalian cells causes accumulation of COG complex-dependent (CCD) vesicles containing medial-Golgi glycosylation enzymes, resulting in defective glycosylation of CD44 and Lamp2; in vitro reconstitution showed COG complex-dependent docking of isolated CCD vesicles, supporting their identity as functional retrograde trafficking intermediates.","method":"siRNA knockdown, vesicle accumulation assay, in vitro vesicle docking reconstitution, lectin/antibody staining of glycoproteins","journal":"Traffic (Copenhagen, Denmark)","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro reconstitution combined with KD cellular phenotype across multiple readouts","pmids":["16420527"],"is_preprint":false},{"year":2007,"finding":"Epistasis analysis shows that COG3 and ZW10/RINT-1 act in separate Golgi trafficking pathways both regulated upstream by Rab6; co-depletion of ZW10 with COG3 did not alter vesicle formation caused by COG3 knockdown, and dominant-negative Rab6 suppressed COG3 KD-induced Golgi fragmentation, whereas dominant-negative Bicaudal-D (Rab6-dynein linker) suppressed ZW10 but not COG3 KD effects.","method":"siRNA epistasis, dominant-negative expression, fluorescence microscopy","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 — systematic epistatic siRNA analysis with multiple genetic combinations","pmids":["17699596"],"is_preprint":false},{"year":2010,"finding":"Golgin-84 interacts with the COG complex through its subunit COG7, and CCD vesicles accumulating in COG3 knockdown cells carry golgin-84; COG3 depletion also reduces the golgin-84/CASP interaction, indicating that golgin-84 on COPI vesicles engages COG before SNARE assembly in intra-Golgi retrograde tethering.","method":"Co-immunoprecipitation, siRNA knockdown, vesicle content analysis, immunofluorescence","journal":"Traffic (Copenhagen, Denmark)","confidence":"High","confidence_rationale":"Tier 2 — physical interaction mapped to specific COG subunit, vesicle cargo analysis in KD cells","pmids":["20874812"],"is_preprint":false},{"year":2011,"finding":"COG3 knockdown in HeLa cells causes mislocalization of multiple Golgi glycosyltransferases (MAN2A1, MGAT1, B4GALT1, ST6GAL1) and blocks Brefeldin A– and Sar1-DN–induced retrograde redistribution of Golgi residents to the ER, with lobe B subunits (COG6, COG8) found on glycosyltransferase-carrying trafficking intermediates.","method":"siRNA knockdown, immunofluorescence, BFA/Sar1-DN redistribution assays, MALDI-TOF glycan analysis","journal":"Glycobiology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (imaging, glycan mass spec, retrograde trafficking assay)","pmids":["21421995"],"is_preprint":false},{"year":2013,"finding":"COG3 (Cog3), a subunit of the Golgi-associated COG complex, contains an Ac/N-degron (N-terminal acetylation degradation signal) that is repressed by direct ligands Cog2 and Cog3 themselves; when the total level of Cog1 increases in the cell, its Ac/N-degron is exposed and Cog1 is destabilized, providing a mechanism for regulating COG complex subunit stoichiometry.","method":"Subunit decoy technique, pulse-chase protein stability assay, genetic manipulation of subunit levels in yeast","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 — novel post-translational regulatory mechanism demonstrated with multiple genetic and biochemical approaches","pmids":["23603116"],"is_preprint":false},{"year":2019,"finding":"Epistatic siRNA screen identified that co-depletion of Rab6A, Rab6A', Rab27A, Rab39A, KIFC3, and KIF25 suppressed COG3 depletion-induced Golgi fragmentation, while no Rabs or Kifs selectively suppressed only COG3-depletion effects, placing COG3 in a Rab6/minus-end kinesin-regulated Golgi organization pathway.","method":"Systematic siRNA epistasis screen (19 Rabs, 44 Kifs), fluorescence microscopy scoring, EM validation","journal":"Frontiers in cell and developmental biology","confidence":"High","confidence_rationale":"Tier 2 — systematic epistatic screen with EM validation, multiple genetic combinations tested","pmids":["31428608"],"is_preprint":false},{"year":2021,"finding":"COG3 knockout in HEK293T cells particularly reduces the ability to polymerize glycosaminoglycan chains on proteoglycans, while all COG subunit KOs reduce GAG modification, indicating COG3 has a specific role in GAG chain elongation within the Golgi.","method":"CRISPR KO of individual COG subunits, biochemical analysis of proteoglycan GAG chains","journal":"Traffic (Copenhagen, Denmark)","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with specific biochemical readout, single study","pmids":["34053170"],"is_preprint":false},{"year":2021,"finding":"In yeast, Cog3-GFP is recruited to Golgi membranes in an Ypt1-dependent manner; a chimeric Rab (Ypt1-SW1Sec4) with altered GEF specificity changes Cog3-GFP localization, demonstrating that Cog3 is a direct effector of the Rab GTPase Ypt1p.","method":"Fluorescent protein localization, chimeric Rab analysis, live imaging","journal":"Methods in molecular biology","confidence":"Medium","confidence_rationale":"Tier 3 — localization experiment with functional genetic context, single study","pmids":["34453710"],"is_preprint":false},{"year":2024,"finding":"siRNA-mediated knockdown of COG3 in ovarian cancer cell lines disrupts Golgi morphology, reduces MT1-MMP and YKL40 expression, suppresses SNAP23-mediated angiogenesis, and decreases cell proliferation and migration; COG3 knockdown suppresses tumor growth in a mouse xenograft model.","method":"siRNA knockdown, immunofluorescence (Golgi morphology), RT-PCR, western blot, MTT assay, TUNEL assay, tube-formation angiogenesis assay, in vivo tumor xenograft","journal":"MicroRNA (Shariqah, United Arab Emirates)","confidence":"Medium","confidence_rationale":"Tier 2–3 — multiple cellular assays plus in vivo, but pathway placement is correlative; single study","pmids":["38243930"],"is_preprint":false}],"current_model":"COG3 is a core subunit of the conserved oligomeric Golgi (COG) tethering complex that localizes to cis/medial Golgi membranes and, as part of the eight-subunit COG complex, tethers COPI-coated retrograde intra-Golgi vesicles carrying glycosyltransferases back to earlier Golgi cisternae—acting as an effector of the Rab GTPase Ypt1/Rab1 and cooperating with intra-Golgi SNAREs—thereby maintaining the steady-state localization of Golgi glycosylation enzymes required for normal N-glycosylation, O-glycosylation, and proteoglycan synthesis; its stoichiometry within the complex is regulated through an Ac/N-degron mechanism shielded by direct binding partners COG2 and COG3."},"narrative":{"teleology":[{"year":1999,"claim":"Identification of Sec34p (COG3 ortholog) as a component of an ~750 kDa complex required for vesicle tethering to the Golgi established its fundamental role in ER-to-Golgi and intra-Golgi membrane traffic and placed it functionally downstream of the Rab GTPase Ypt1p.","evidence":"In vitro vesicle tethering assay, genetic suppressor analysis, cytosol fractionation, and co-precipitation in S. cerevisiae","pmids":["10562277","10512869"],"confidence":"High","gaps":["Direct physical interaction between Sec34p and Ypt1p not demonstrated at this stage","Subunit composition of the full complex unknown"]},{"year":2001,"claim":"Characterization of the full eight-subunit COG complex and localization of human COG3 to cis/medial-Golgi membranes defined COG3 as a peripheral Golgi-associated protein within a conserved tethering complex family.","evidence":"Immunofluorescence, BFA sensitivity, glycerol gradient fractionation in human cells; affinity purification and sequence homology in yeast","pmids":["11292827","11703943"],"confidence":"High","gaps":["Structural organization of the eight-subunit complex at atomic resolution unknown","Whether COG3 contacts membranes directly or via other subunits not resolved"]},{"year":2002,"claim":"Demonstration that the COG complex interacts physically with COPI coat, intra-Golgi SNAREs, and Ypt1p, and that anti-COG3 antibodies block ER-to-Golgi transport, established COG3 as a nexus connecting vesicle coat recognition, Rab signaling, and SNARE-mediated fusion.","evidence":"Co-immunoprecipitation, two-hybrid, genetic interaction analysis, semi-intact cell transport assay, and deep-etch EM of purified complex","pmids":["12011112","11929878","11980916"],"confidence":"High","gaps":["Whether COG3 directly binds COPI or SNAREs versus acting through other subunits not distinguished","Mechanism of coupling between tethering and SNARE complex assembly unknown"]},{"year":2004,"claim":"A COG3 temperature-sensitive allele revealed that COG3 acts at the level of sorting glycosyltransferases into retrograde vesicles rather than at the fusion step, refining the mechanistic step at which COG3 operates in intra-Golgi recycling.","evidence":"Temperature-shift analysis with density gradient fractionation in yeast, epistatic comparison with SNARE ts mutants","pmids":["15229219"],"confidence":"High","gaps":["Molecular mechanism by which COG3 influences cargo sorting into vesicles not identified","Single allele study—allele-specific effects not excluded"]},{"year":2006,"claim":"In vitro reconstitution of COG-dependent vesicle docking and identification of CCD vesicles carrying Golgi enzymes upon COG3 knockdown proved that COG3 is required for tethering of retrograde intra-Golgi transport intermediates, with direct consequences for glycoprotein processing.","evidence":"siRNA knockdown in HeLa, in vitro vesicle docking reconstitution, lectin staining and glycoprotein analysis","pmids":["16420527"],"confidence":"High","gaps":["Identity of all cargo on CCD vesicles incomplete","Whether tethering defect is solely due to COG3 loss or reflects destabilization of other COG subunits not fully resolved"]},{"year":2010,"claim":"The discovery that golgin-84 on COPI vesicles engages COG (via COG7) before SNARE assembly, and that COG3 depletion disrupts the golgin-84/CASP interaction, established a temporal order: golgin-84–COG tethering precedes SNARE-mediated fusion in retrograde Golgi traffic.","evidence":"Co-immunoprecipitation, siRNA knockdown, vesicle content analysis in HeLa cells","pmids":["20874812"],"confidence":"High","gaps":["Whether golgin-84 engages COG3 directly or exclusively through COG7 not resolved","Structural basis of golgin-84–COG interaction unknown"]},{"year":2013,"claim":"Identification of an Ac/N-degron on COG subunits (including Cog1) that is shielded by COG2 and COG3 binding revealed a quality-control mechanism ensuring proper COG complex stoichiometry, explaining how orphan subunits are selectively degraded.","evidence":"Subunit decoy technique, pulse-chase stability assays, genetic manipulation in yeast","pmids":["23603116"],"confidence":"High","gaps":["Ubiquitin ligase responsible for Ac/N-degron-mediated degradation of COG subunits not identified","Whether this regulatory mechanism operates identically in mammalian cells unknown"]},{"year":2019,"claim":"A systematic epistatic siRNA screen placed COG3 within a Rab6/minus-end kinesin-regulated Golgi organization pathway, identifying Rab6A, Rab27A, Rab39A, KIFC3, and KIF25 as upstream regulators whose depletion suppresses COG3 loss-induced Golgi fragmentation.","evidence":"Combinatorial siRNA screen (19 Rabs × 44 kinesins), fluorescence microscopy, EM validation in HeLa cells","pmids":["31428608"],"confidence":"High","gaps":["Direct physical interaction between COG3 and Rab6 not shown","Mechanism by which minus-end kinesins contribute to COG3-dependent Golgi organization uncharacterized"]},{"year":2021,"claim":"COG3 was shown to be a direct Ypt1/Rab1 effector recruited to Golgi membranes in a Ypt1-dependent manner, and COG3 knockout was found to specifically impair glycosaminoglycan chain elongation on proteoglycans, revealing a subunit-specific role in GAG biosynthesis.","evidence":"Chimeric Rab localization assay in yeast; CRISPR KO of individual COG subunits with GAG chain biochemical analysis in HEK293T","pmids":["34453710","34053170"],"confidence":"Medium","gaps":["Structural basis for Ypt1–COG3 effector interaction not resolved","Whether COG3's specific GAG elongation phenotype reflects a direct interaction with GAG biosynthetic enzymes or indirect tethering effects is unknown","GAG elongation phenotype from single study"]},{"year":null,"claim":"The atomic-resolution structure of COG3 within the assembled COG complex, the precise mechanism by which COG3 bridges vesicle coat recognition and SNARE complex assembly, and the identity of the E3 ligase mediating Ac/N-degron-dependent COG subunit turnover remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure of COG3 in the context of the full octameric COG complex","Mechanism coupling COG3-mediated tethering to SNARE priming/zippering not defined","Pathways controlling COG3 expression and degradation in mammalian cells largely unexplored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,5,11]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[2,4,7,12,16]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[9,11]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,5,6,9,11]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[9,12,15]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[4,14]}],"complexes":["COG complex"],"partners":["COG1","COG2","COG7","YPT1","RAB6A","GOLGA5"],"other_free_text":[]},"mechanistic_narrative":"COG3 is a core subunit of the conserved oligomeric Golgi (COG) complex, an eight-subunit vesicle tethering machine that maintains Golgi glycosylation enzyme homeostasis by mediating the capture and docking of COPI-coated retrograde intra-Golgi transport vesicles at cis/medial-Golgi cisternae [PMID:10562277, PMID:12011112, PMID:16420527]. COG3 functions as an effector of the Rab GTPase Ypt1/Rab1, which directs its recruitment to Golgi membranes, and cooperates with intra-Golgi SNAREs and the vesicle tether golgin-84 to complete vesicle docking prior to fusion [PMID:10562277, PMID:34453710, PMID:20874812]. Loss of COG3 causes mislocalization of medial- and trans-Golgi glycosyltransferases, defective N-glycosylation, O-glycosylation, and glycosaminoglycan chain elongation on proteoglycans, and Golgi fragmentation that is suppressed by Rab6 pathway perturbation [PMID:21421995, PMID:34053170, PMID:31428608]. COG3 subunit stoichiometry within the complex is controlled by an Ac/N-degron whose exposure is shielded by direct binding partners COG1 and COG2 [PMID:23603116]."},"prefetch_data":{"uniprot":{"accession":"Q96JB2","full_name":"Conserved oligomeric Golgi complex subunit 3","aliases":["Component of oligomeric Golgi complex 3","Vesicle-docking protein SEC34 homolog","p94"],"length_aa":828,"mass_kda":94.1,"function":"Involved in ER-Golgi transport (PubMed:11929878). Also involved in retrograde (Golgi to ER) transport (PubMed:37711075)","subcellular_location":"Golgi apparatus, Golgi stack membrane","url":"https://www.uniprot.org/uniprotkb/Q96JB2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/COG3","classification":"Common Essential","n_dependent_lines":1076,"n_total_lines":1208,"dependency_fraction":0.890728476821192},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PMVK","stoichiometry":0.2},{"gene":"PSMA6","stoichiometry":0.2},{"gene":"RAB1B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/COG3","total_profiled":1310},"omim":[{"mim_id":"620546","title":"CONGENITAL DISORDER OF GLYCOSYLATION, TYPE IIbb; CDG2BB","url":"https://www.omim.org/entry/620546"},{"mim_id":"617395","title":"CONGENITAL DISORDER OF GLYCOSYLATION, TYPE IIq; CDG2Q","url":"https://www.omim.org/entry/617395"},{"mim_id":"606979","title":"COMPONENT OF OLIGOMERIC GOLGI COMPLEX 8; COG8","url":"https://www.omim.org/entry/606979"},{"mim_id":"606978","title":"COMPONENT OF OLIGOMERIC GOLGI COMPLEX 7; COG7","url":"https://www.omim.org/entry/606978"},{"mim_id":"606977","title":"COMPONENT OF OLIGOMERIC GOLGI COMPLEX 6; COG6","url":"https://www.omim.org/entry/606977"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Golgi apparatus","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/COG3"},"hgnc":{"alias_symbol":["SEC34"],"prev_symbol":[]},"alphafold":{"accession":"Q96JB2","domains":[{"cath_id":"-","chopping":"222-477","consensus_level":"medium","plddt":90.4278,"start":222,"end":477},{"cath_id":"-","chopping":"478-497_552-629","consensus_level":"medium","plddt":86.9727,"start":478,"end":629},{"cath_id":"1.20.5","chopping":"127-195","consensus_level":"medium","plddt":92.6223,"start":127,"end":195},{"cath_id":"1.20.58","chopping":"698-825","consensus_level":"high","plddt":84.6315,"start":698,"end":825}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96JB2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96JB2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96JB2-F1-predicted_aligned_error_v6.png","plddt_mean":78.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=COG3","jax_strain_url":"https://www.jax.org/strain/search?query=COG3"},"sequence":{"accession":"Q96JB2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96JB2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96JB2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96JB2"}},"corpus_meta":[{"pmid":"19812674","id":"PMC_19812674","title":"Mutational 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overexpression of SEC34 specifically suppresses the sec35-1 mutation, confirming a functional partnership in ER-to-Golgi vesicular traffic.\",\n      \"method\": \"Co-precipitation, high-copy suppressor screen, gel filtration\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal biochemical interaction confirmed by multiple approaches, replicated independently from PMID:10562277\",\n      \"pmids\": [\"10512869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Human Sec34p (COG3) is a peripheral membrane protein that localizes to cis/medial Golgi cisternae, migrates as part of an ~300 kDa complex in cytosol, and its Golgi association is sensitive to Brefeldin A, consistent with a role in tethering intra-Golgi transport vesicles.\",\n      \"method\": \"Immunofluorescence microscopy, glycerol velocity gradient fractionation, GFP live imaging, BFA treatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment with multiple orthogonal methods in human cells\",\n      \"pmids\": [\"11292827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Dor1p and seven associated proteins in yeast (including Sec34p/COG3 and Sec35p) constitute the Sec34/35 complex; several subunits show distant homology to exocyst and Vps52/53/54 complex components, defining a conserved family of tethering complexes involved in multiple membrane traffic steps.\",\n      \"method\": \"Affinity purification, sequence homology analysis, co-purification\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — complex characterized by affinity purification and sequence analysis, establishing COG3 as part of a conserved tethering family\",\n      \"pmids\": [\"11703943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Human COG complex (comprising COG3/Sec34 along with COG1–8) is required for normal Golgi morphology; EM of ldlB and ldlC mutants showed Golgi morphology defects, and deep-etch EM of purified COG revealed an ~37-nm two-domain structure.\",\n      \"method\": \"EM of mutant CHO cells, deep-etch EM of purified complex, biochemical subunit identification\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — structural EM of purified complex combined with loss-of-function morphology analysis\",\n      \"pmids\": [\"11980916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The yeast Sec34/35 complex (containing COG3 ortholog Sec34p) interacts genetically and physically with the Rab protein Ypt1p, intra-Golgi SNARE molecules, and COPI vesicle coat proteins, supporting its role as a tether connecting cis-Golgi membranes with COPI-coated retrograde intra-Golgi vesicles.\",\n      \"method\": \"Genetic interaction analysis, co-immunoprecipitation, two-hybrid\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple physical and genetic interactions identified with orthogonal methods\",\n      \"pmids\": [\"12011112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Mammalian COG3 (Sec34) directly interacts with COG1 (ldlBp) and COG2 (ldlCp) in vitro and co-immunoprecipitates with GTC-90 and ldlBp from rat liver cytosol; anti-Sec34 antibodies inhibit ER-to-Golgi transport in a semi-intact cell assay in a dose-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation from rat liver cytosol, in vitro binding assay, semi-intact cell ER-to-Golgi transport assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro transport inhibition combined with direct binding and co-IP\",\n      \"pmids\": [\"11929878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"A COG3 temperature-sensitive allele (cog3-202) in yeast causes mislocalization of Golgi mannosyltransferases Och1p and Mnn1p without accumulating them in retrograde vesicles, consistent with COG3 playing a role in sorting Och1p into retrograde vesicles for intra-Golgi recycling rather than in vesicle fusion.\",\n      \"method\": \"Temperature-sensitive allele analysis, density gradient fractionation, genetic comparison with sed5(ts) and sft1(ts) strains\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistatic comparison of multiple ts mutants with biochemical fractionation\",\n      \"pmids\": [\"15229219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"C. elegans COGC-3 (COG3 ortholog) is required for the glycosylation and gonadal basement membrane localization of the ADAM protease MIG-17; cogc-3 mutants display misdirected distal tip cell migration phenocopying mig-17 mutants, and COGC-3 requires MIG-17 activity for its effect on organ morphogenesis.\",\n      \"method\": \"Genetic loss-of-function analysis, RNAi of all 8 COG subunits, epistasis, MIG-17 glycosylation and localization assay\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with biochemical glycosylation readout across all 8 subunits in C. elegans\",\n      \"pmids\": [\"16354716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Acute siRNA knockdown of COG3 in mammalian cells causes accumulation of COG complex-dependent (CCD) vesicles containing medial-Golgi glycosylation enzymes, resulting in defective glycosylation of CD44 and Lamp2; in vitro reconstitution showed COG complex-dependent docking of isolated CCD vesicles, supporting their identity as functional retrograde trafficking intermediates.\",\n      \"method\": \"siRNA knockdown, vesicle accumulation assay, in vitro vesicle docking reconstitution, lectin/antibody staining of glycoproteins\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro reconstitution combined with KD cellular phenotype across multiple readouts\",\n      \"pmids\": [\"16420527\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Epistasis analysis shows that COG3 and ZW10/RINT-1 act in separate Golgi trafficking pathways both regulated upstream by Rab6; co-depletion of ZW10 with COG3 did not alter vesicle formation caused by COG3 knockdown, and dominant-negative Rab6 suppressed COG3 KD-induced Golgi fragmentation, whereas dominant-negative Bicaudal-D (Rab6-dynein linker) suppressed ZW10 but not COG3 KD effects.\",\n      \"method\": \"siRNA epistasis, dominant-negative expression, fluorescence microscopy\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — systematic epistatic siRNA analysis with multiple genetic combinations\",\n      \"pmids\": [\"17699596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Golgin-84 interacts with the COG complex through its subunit COG7, and CCD vesicles accumulating in COG3 knockdown cells carry golgin-84; COG3 depletion also reduces the golgin-84/CASP interaction, indicating that golgin-84 on COPI vesicles engages COG before SNARE assembly in intra-Golgi retrograde tethering.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, vesicle content analysis, immunofluorescence\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — physical interaction mapped to specific COG subunit, vesicle cargo analysis in KD cells\",\n      \"pmids\": [\"20874812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"COG3 knockdown in HeLa cells causes mislocalization of multiple Golgi glycosyltransferases (MAN2A1, MGAT1, B4GALT1, ST6GAL1) and blocks Brefeldin A– and Sar1-DN–induced retrograde redistribution of Golgi residents to the ER, with lobe B subunits (COG6, COG8) found on glycosyltransferase-carrying trafficking intermediates.\",\n      \"method\": \"siRNA knockdown, immunofluorescence, BFA/Sar1-DN redistribution assays, MALDI-TOF glycan analysis\",\n      \"journal\": \"Glycobiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (imaging, glycan mass spec, retrograde trafficking assay)\",\n      \"pmids\": [\"21421995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"COG3 (Cog3), a subunit of the Golgi-associated COG complex, contains an Ac/N-degron (N-terminal acetylation degradation signal) that is repressed by direct ligands Cog2 and Cog3 themselves; when the total level of Cog1 increases in the cell, its Ac/N-degron is exposed and Cog1 is destabilized, providing a mechanism for regulating COG complex subunit stoichiometry.\",\n      \"method\": \"Subunit decoy technique, pulse-chase protein stability assay, genetic manipulation of subunit levels in yeast\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — novel post-translational regulatory mechanism demonstrated with multiple genetic and biochemical approaches\",\n      \"pmids\": [\"23603116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Epistatic siRNA screen identified that co-depletion of Rab6A, Rab6A', Rab27A, Rab39A, KIFC3, and KIF25 suppressed COG3 depletion-induced Golgi fragmentation, while no Rabs or Kifs selectively suppressed only COG3-depletion effects, placing COG3 in a Rab6/minus-end kinesin-regulated Golgi organization pathway.\",\n      \"method\": \"Systematic siRNA epistasis screen (19 Rabs, 44 Kifs), fluorescence microscopy scoring, EM validation\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — systematic epistatic screen with EM validation, multiple genetic combinations tested\",\n      \"pmids\": [\"31428608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"COG3 knockout in HEK293T cells particularly reduces the ability to polymerize glycosaminoglycan chains on proteoglycans, while all COG subunit KOs reduce GAG modification, indicating COG3 has a specific role in GAG chain elongation within the Golgi.\",\n      \"method\": \"CRISPR KO of individual COG subunits, biochemical analysis of proteoglycan GAG chains\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with specific biochemical readout, single study\",\n      \"pmids\": [\"34053170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In yeast, Cog3-GFP is recruited to Golgi membranes in an Ypt1-dependent manner; a chimeric Rab (Ypt1-SW1Sec4) with altered GEF specificity changes Cog3-GFP localization, demonstrating that Cog3 is a direct effector of the Rab GTPase Ypt1p.\",\n      \"method\": \"Fluorescent protein localization, chimeric Rab analysis, live imaging\",\n      \"journal\": \"Methods in molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — localization experiment with functional genetic context, single study\",\n      \"pmids\": [\"34453710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"siRNA-mediated knockdown of COG3 in ovarian cancer cell lines disrupts Golgi morphology, reduces MT1-MMP and YKL40 expression, suppresses SNAP23-mediated angiogenesis, and decreases cell proliferation and migration; COG3 knockdown suppresses tumor growth in a mouse xenograft model.\",\n      \"method\": \"siRNA knockdown, immunofluorescence (Golgi morphology), RT-PCR, western blot, MTT assay, TUNEL assay, tube-formation angiogenesis assay, in vivo tumor xenograft\",\n      \"journal\": \"MicroRNA (Shariqah, United Arab Emirates)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — multiple cellular assays plus in vivo, but pathway placement is correlative; single study\",\n      \"pmids\": [\"38243930\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"COG3 is a core subunit of the conserved oligomeric Golgi (COG) tethering complex that localizes to cis/medial Golgi membranes and, as part of the eight-subunit COG complex, tethers COPI-coated retrograde intra-Golgi vesicles carrying glycosyltransferases back to earlier Golgi cisternae—acting as an effector of the Rab GTPase Ypt1/Rab1 and cooperating with intra-Golgi SNAREs—thereby maintaining the steady-state localization of Golgi glycosylation enzymes required for normal N-glycosylation, O-glycosylation, and proteoglycan synthesis; its stoichiometry within the complex is regulated through an Ac/N-degron mechanism shielded by direct binding partners COG2 and COG3.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"COG3 is a core subunit of the conserved oligomeric Golgi (COG) complex, an eight-subunit vesicle tethering machine that maintains Golgi glycosylation enzyme homeostasis by mediating the capture and docking of COPI-coated retrograde intra-Golgi transport vesicles at cis/medial-Golgi cisternae [PMID:10562277, PMID:12011112, PMID:16420527]. COG3 functions as an effector of the Rab GTPase Ypt1/Rab1, which directs its recruitment to Golgi membranes, and cooperates with intra-Golgi SNAREs and the vesicle tether golgin-84 to complete vesicle docking prior to fusion [PMID:10562277, PMID:34453710, PMID:20874812]. Loss of COG3 causes mislocalization of medial- and trans-Golgi glycosyltransferases, defective N-glycosylation, O-glycosylation, and glycosaminoglycan chain elongation on proteoglycans, and Golgi fragmentation that is suppressed by Rab6 pathway perturbation [PMID:21421995, PMID:34053170, PMID:31428608]. COG3 subunit stoichiometry within the complex is controlled by an Ac/N-degron whose exposure is shielded by direct binding partners COG1 and COG2 [PMID:23603116].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Identification of Sec34p (COG3 ortholog) as a component of an ~750 kDa complex required for vesicle tethering to the Golgi established its fundamental role in ER-to-Golgi and intra-Golgi membrane traffic and placed it functionally downstream of the Rab GTPase Ypt1p.\",\n      \"evidence\": \"In vitro vesicle tethering assay, genetic suppressor analysis, cytosol fractionation, and co-precipitation in S. cerevisiae\",\n      \"pmids\": [\"10562277\", \"10512869\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct physical interaction between Sec34p and Ypt1p not demonstrated at this stage\", \"Subunit composition of the full complex unknown\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Characterization of the full eight-subunit COG complex and localization of human COG3 to cis/medial-Golgi membranes defined COG3 as a peripheral Golgi-associated protein within a conserved tethering complex family.\",\n      \"evidence\": \"Immunofluorescence, BFA sensitivity, glycerol gradient fractionation in human cells; affinity purification and sequence homology in yeast\",\n      \"pmids\": [\"11292827\", \"11703943\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural organization of the eight-subunit complex at atomic resolution unknown\", \"Whether COG3 contacts membranes directly or via other subunits not resolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstration that the COG complex interacts physically with COPI coat, intra-Golgi SNAREs, and Ypt1p, and that anti-COG3 antibodies block ER-to-Golgi transport, established COG3 as a nexus connecting vesicle coat recognition, Rab signaling, and SNARE-mediated fusion.\",\n      \"evidence\": \"Co-immunoprecipitation, two-hybrid, genetic interaction analysis, semi-intact cell transport assay, and deep-etch EM of purified complex\",\n      \"pmids\": [\"12011112\", \"11929878\", \"11980916\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether COG3 directly binds COPI or SNAREs versus acting through other subunits not distinguished\", \"Mechanism of coupling between tethering and SNARE complex assembly unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"A COG3 temperature-sensitive allele revealed that COG3 acts at the level of sorting glycosyltransferases into retrograde vesicles rather than at the fusion step, refining the mechanistic step at which COG3 operates in intra-Golgi recycling.\",\n      \"evidence\": \"Temperature-shift analysis with density gradient fractionation in yeast, epistatic comparison with SNARE ts mutants\",\n      \"pmids\": [\"15229219\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which COG3 influences cargo sorting into vesicles not identified\", \"Single allele study—allele-specific effects not excluded\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"In vitro reconstitution of COG-dependent vesicle docking and identification of CCD vesicles carrying Golgi enzymes upon COG3 knockdown proved that COG3 is required for tethering of retrograde intra-Golgi transport intermediates, with direct consequences for glycoprotein processing.\",\n      \"evidence\": \"siRNA knockdown in HeLa, in vitro vesicle docking reconstitution, lectin staining and glycoprotein analysis\",\n      \"pmids\": [\"16420527\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of all cargo on CCD vesicles incomplete\", \"Whether tethering defect is solely due to COG3 loss or reflects destabilization of other COG subunits not fully resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"The discovery that golgin-84 on COPI vesicles engages COG (via COG7) before SNARE assembly, and that COG3 depletion disrupts the golgin-84/CASP interaction, established a temporal order: golgin-84–COG tethering precedes SNARE-mediated fusion in retrograde Golgi traffic.\",\n      \"evidence\": \"Co-immunoprecipitation, siRNA knockdown, vesicle content analysis in HeLa cells\",\n      \"pmids\": [\"20874812\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether golgin-84 engages COG3 directly or exclusively through COG7 not resolved\", \"Structural basis of golgin-84–COG interaction unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identification of an Ac/N-degron on COG subunits (including Cog1) that is shielded by COG2 and COG3 binding revealed a quality-control mechanism ensuring proper COG complex stoichiometry, explaining how orphan subunits are selectively degraded.\",\n      \"evidence\": \"Subunit decoy technique, pulse-chase stability assays, genetic manipulation in yeast\",\n      \"pmids\": [\"23603116\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin ligase responsible for Ac/N-degron-mediated degradation of COG subunits not identified\", \"Whether this regulatory mechanism operates identically in mammalian cells unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"A systematic epistatic siRNA screen placed COG3 within a Rab6/minus-end kinesin-regulated Golgi organization pathway, identifying Rab6A, Rab27A, Rab39A, KIFC3, and KIF25 as upstream regulators whose depletion suppresses COG3 loss-induced Golgi fragmentation.\",\n      \"evidence\": \"Combinatorial siRNA screen (19 Rabs × 44 kinesins), fluorescence microscopy, EM validation in HeLa cells\",\n      \"pmids\": [\"31428608\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct physical interaction between COG3 and Rab6 not shown\", \"Mechanism by which minus-end kinesins contribute to COG3-dependent Golgi organization uncharacterized\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"COG3 was shown to be a direct Ypt1/Rab1 effector recruited to Golgi membranes in a Ypt1-dependent manner, and COG3 knockout was found to specifically impair glycosaminoglycan chain elongation on proteoglycans, revealing a subunit-specific role in GAG biosynthesis.\",\n      \"evidence\": \"Chimeric Rab localization assay in yeast; CRISPR KO of individual COG subunits with GAG chain biochemical analysis in HEK293T\",\n      \"pmids\": [\"34453710\", \"34053170\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis for Ypt1–COG3 effector interaction not resolved\", \"Whether COG3's specific GAG elongation phenotype reflects a direct interaction with GAG biosynthetic enzymes or indirect tethering effects is unknown\", \"GAG elongation phenotype from single study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The atomic-resolution structure of COG3 within the assembled COG complex, the precise mechanism by which COG3 bridges vesicle coat recognition and SNARE complex assembly, and the identity of the E3 ligase mediating Ac/N-degron-dependent COG subunit turnover remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of COG3 in the context of the full octameric COG complex\", \"Mechanism coupling COG3-mediated tethering to SNARE priming/zippering not defined\", \"Pathways controlling COG3 expression and degradation in mammalian cells largely unexplored\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 5, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [2, 4, 7, 12, 16]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [9, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 5, 6, 9, 11]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [9, 12, 15]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [4, 14]}\n    ],\n    \"complexes\": [\n      \"COG complex\"\n    ],\n    \"partners\": [\n      \"COG1\",\n      \"COG2\",\n      \"COG7\",\n      \"YPT1\",\n      \"RAB6A\",\n      \"GOLGA5\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}