{"gene":"AP1AR","run_date":"2026-06-09T22:02:43","timeline":{"discoveries":[{"year":2005,"finding":"The peripheral membrane protein 2c18/gamma-BAR (AP1AR) directly interacts with the gamma 'ear' domain of the AP-1 adaptor protein complex both in vitro and in vivo, colocalizes with gamma1-adaptin at the trans-Golgi network (TGN) and on vesicular profiles, and is required for membrane association of AP-1: overexpression increases membrane-bound gamma1-adaptin and inhibits its brefeldin A-induced release, while knockdown reduces steady-state gamma1-adaptin on membranes. Perturbation of 2c18 levels increases secretion of the lysosomal hydrolase cathepsin D, indicating a role in AP-1-dependent TGN-to-endosome trafficking.","method":"In vitro binding assay, co-immunoprecipitation, ultrastructural colocalization, brefeldin A release assay, siRNA knockdown, cathepsin D secretion assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal in vitro and in vivo binding, multiple orthogonal functional assays (overexpression, knockdown, BFA resistance, cargo secretion), ultrastructural localization","pmids":["15775984"],"is_preprint":false},{"year":2009,"finding":"Gadkin/gamma-BAR (AP1AR) is S-palmitoylated, and this modification is required for its recruitment to TGN/endosomal membranes but not for binding to AP-1. A novel subtype of AP-1-binding motif within Gadkin specifically associates with the gamma1-adaptin ear domain; mutational inactivation of this motif (alone or combined with three conventional AP-1gamma binding peptides) causes Gadkin to mislocalize to the plasma membrane and abrogates its ability to render AP-1 brefeldin A-resistant.","method":"S-palmitoylation assay, NMR (solution structure of intrinsically disordered protein), mutagenesis, localization imaging, brefeldin A resistance assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — mutagenesis of binding motif combined with palmitoylation assay, NMR characterization, functional BFA-resistance readout, single lab but multiple orthogonal methods","pmids":["19965873"],"is_preprint":false}],"current_model":"AP1AR (gamma-BAR/Gadkin) is an S-palmitoylated peripheral membrane protein that is recruited to the trans-Golgi network/endosomal membranes via palmitoylation, where it directly engages the gamma1-adaptin ear domain of the AP-1 clathrin adaptor complex through a novel AP-1-binding motif; this interaction stabilizes AP-1 on membranes and is required for AP-1-dependent trafficking of lysosomal hydrolases (e.g., cathepsin D) between the TGN and endosomes."},"narrative":{"mechanistic_narrative":"AP1AR (gamma-BAR/Gadkin) is a peripheral membrane protein that links the AP-1 clathrin adaptor complex to membranes and supports AP-1-dependent trafficking between the trans-Golgi network and endosomes [PMID:15775984]. It directly binds the gamma1-adaptin ear domain of AP-1, colocalizes with gamma1-adaptin at the TGN, and stabilizes AP-1 on membranes: its overexpression increases membrane-bound gamma1-adaptin and renders it resistant to brefeldin A-induced release, while its depletion reduces steady-state membrane AP-1 and increases secretion of the lysosomal hydrolase cathepsin D [PMID:15775984]. AP1AR is S-palmitoylated, and this lipid modification is required for its recruitment to TGN/endosomal membranes but not for AP-1 binding; the AP-1 interaction itself is mediated by a distinct subtype of gamma1-adaptin ear-binding motif, whose mutation mislocalizes AP1AR to the plasma membrane and abolishes its ability to confer brefeldin A resistance on AP-1 [PMID:19965873]. Beyond these membrane-recruitment and AP-1-stabilizing functions, no further mechanistic detail has been characterized in the available corpus.","teleology":[{"year":2005,"claim":"Established that AP1AR is a direct AP-1 interactor that controls membrane association of the adaptor and thereby AP-1-dependent cargo trafficking, defining its core cellular role.","evidence":"In vitro binding and co-immunoprecipitation with the gamma ear domain, ultrastructural colocalization at the TGN, brefeldin A release assay, siRNA knockdown, and cathepsin D secretion readout","pmids":["15775984"],"confidence":"High","gaps":["Did not define the molecular motif within AP1AR responsible for AP-1 binding","Did not establish how AP1AR itself is recruited to membranes","Range of cargoes beyond cathepsin D not mapped"]},{"year":2009,"claim":"Separated the membrane-targeting and AP-1-binding determinants of AP1AR, showing palmitoylation drives membrane recruitment while a novel ear-binding motif mediates the AP-1 interaction.","evidence":"S-palmitoylation assay, NMR solution characterization of the intrinsically disordered protein, motif mutagenesis, localization imaging, and brefeldin A resistance assay","pmids":["19965873"],"confidence":"High","gaps":["Palmitoylation enzyme(s) and depalmitoylation regulation not identified","Structural basis of the novel ear-binding motif not resolved at atomic detail","Physiological consequences of mislocalization in cells not fully traced to cargo phenotypes"]},{"year":null,"claim":"How AP1AR-mediated AP-1 stabilization is regulated and integrated with the broader vesicle-formation machinery remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["Upstream signals controlling AP1AR palmitoylation cycling unknown","Full set of trafficking cargoes dependent on AP1AR not defined","Whether AP1AR engages additional adaptors or vesicle components is unexplored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,1]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0]}],"complexes":[],"partners":["AP1G1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q63HQ0","full_name":"AP-1 complex-associated regulatory protein","aliases":["2c18","Adaptor-related protein complex 1-associated regulatory protein","Gamma-1-adaptin brefeldin A resistance protein","GBAR","Gamma-BAR","Gamma-A1-adaptin and kinesin interactor","Gadkin"],"length_aa":302,"mass_kda":34.3,"function":"Necessary for adaptor protein complex 1 (AP-1)-dependent transport between the trans-Golgi network and endosomes. Regulates the membrane association of AP1G1/gamma1-adaptin, one of the subunits of the AP-1 adaptor complex. The direct interaction with AP1G1/gamma1-adaptin attenuates the release of the AP-1 complex from membranes. Regulates endosomal membrane traffic via association with AP-1 and KIF5B thus linking kinesin-based plus-end-directed microtubular transport to AP-1-dependent membrane traffic. May act as effector of AP-1 in calcium-induced endo-lysosome secretion. Inhibits Arp2/3 complex function; negatively regulates cell spreading, size and motility via intracellular sequestration of the Arp2/3 complex","subcellular_location":"Golgi apparatus, trans-Golgi network; Late endosome; Early endosome","url":"https://www.uniprot.org/uniprotkb/Q63HQ0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/AP1AR","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CLTA","stoichiometry":0.2},{"gene":"CLTB","stoichiometry":0.2},{"gene":"STX7","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/AP1AR","total_profiled":1310},"omim":[{"mim_id":"610851","title":"ADAPTOR-RELATED PROTEIN COMPLEX 1-ASSOCIATED REGULATORY PROTEIN; AP1AR","url":"https://www.omim.org/entry/610851"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Golgi apparatus","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/AP1AR"},"hgnc":{"alias_symbol":["PRO0971","2C18","gamma-BAR"],"prev_symbol":["C4orf16"]},"alphafold":{"accession":"Q63HQ0","domains":[{"cath_id":"1.20.5","chopping":"65-137","consensus_level":"medium","plddt":92.8847,"start":65,"end":137}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q63HQ0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q63HQ0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q63HQ0-F1-predicted_aligned_error_v6.png","plddt_mean":64.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=AP1AR","jax_strain_url":"https://www.jax.org/strain/search?query=AP1AR"},"sequence":{"accession":"Q63HQ0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q63HQ0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q63HQ0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q63HQ0"}},"corpus_meta":[{"pmid":"9154796","id":"PMC_9154796","title":"Exon skipping and circular RNA formation in transcripts of the human cytochrome P-450 2C18 gene in epidermis and of the rat androgen binding protein gene in testis.","date":"1997","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/9154796","citation_count":158,"is_preprint":false},{"pmid":"11708911","id":"PMC_11708911","title":"Analysis of selective regions in the active sites of human cytochromes P450, 2C8, 2C9, 2C18, and 2C19 homology models using GRID/CPCA.","date":"2001","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11708911","citation_count":61,"is_preprint":false},{"pmid":"15775984","id":"PMC_15775984","title":"Gamma-BAR, a novel AP-1-interacting protein involved in post-Golgi trafficking.","date":"2005","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/15775984","citation_count":39,"is_preprint":false},{"pmid":"7116574","id":"PMC_7116574","title":"Effect of diethylstilbestrol on the transformable mouse embryo fibroblast C3H/10T1/2C18 cells. Tumor promotion, cell growth, DNA synthesis, and ornithine decarboxylase.","date":"1982","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/7116574","citation_count":36,"is_preprint":false},{"pmid":"16359177","id":"PMC_16359177","title":"P450 2C18 catalyzes the metabolic bioactivation of phenytoin.","date":"2005","source":"Chemical research in toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/16359177","citation_count":24,"is_preprint":false},{"pmid":"19965873","id":"PMC_19965873","title":"A novel subtype of AP-1-binding motif within the palmitoylated trans-Golgi network/endosomal accessory protein Gadkin/gamma-BAR.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19965873","citation_count":9,"is_preprint":false},{"pmid":"12378636","id":"PMC_12378636","title":"Establishment of a transgenic cell line stably expressing human cytochrome P450 2C18 and identification of a CYP2C18 clone with exon 5 missing.","date":"2002","source":"World journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/12378636","citation_count":7,"is_preprint":false},{"pmid":"39558356","id":"PMC_39558356","title":"Gain of bipolar disorder-related lncRNA AP1AR-DT in mice induces depressive and anxiety-like behaviors by reducing Negr1-mediated excitatory synaptic transmission.","date":"2024","source":"BMC medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39558356","citation_count":5,"is_preprint":false},{"pmid":"38110158","id":"PMC_38110158","title":"Identification of cytochrome P450 2C18 and 2C76 in tree shrews: P450 2C18 effectively oxidizes typical human P450 2C9/2C19 chiral substrates warfarin and omeprazole with less stereoselectivity.","date":"2023","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38110158","citation_count":3,"is_preprint":false},{"pmid":"8191796","id":"PMC_8191796","title":"[Study on endocytosis and nuclear accumulation of epidermal growth factor (EGF) in normal C3H mouse fibroblast cells C3H10 T1/2C18 and 3H-TdR transformed counterpart cells].","date":"1993","source":"Shi yan sheng wu xue bao","url":"https://pubmed.ncbi.nlm.nih.gov/8191796","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7509,"output_tokens":814,"usd":0.017368,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7239,"output_tokens":1538,"usd":0.037323,"stage2_stop_reason":"end_turn"},"total_usd":0.054691,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"The peripheral membrane protein 2c18/gamma-BAR (AP1AR) directly interacts with the gamma 'ear' domain of the AP-1 adaptor protein complex both in vitro and in vivo, colocalizes with gamma1-adaptin at the trans-Golgi network (TGN) and on vesicular profiles, and is required for membrane association of AP-1: overexpression increases membrane-bound gamma1-adaptin and inhibits its brefeldin A-induced release, while knockdown reduces steady-state gamma1-adaptin on membranes. Perturbation of 2c18 levels increases secretion of the lysosomal hydrolase cathepsin D, indicating a role in AP-1-dependent TGN-to-endosome trafficking.\",\n      \"method\": \"In vitro binding assay, co-immunoprecipitation, ultrastructural colocalization, brefeldin A release assay, siRNA knockdown, cathepsin D secretion assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal in vitro and in vivo binding, multiple orthogonal functional assays (overexpression, knockdown, BFA resistance, cargo secretion), ultrastructural localization\",\n      \"pmids\": [\"15775984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Gadkin/gamma-BAR (AP1AR) is S-palmitoylated, and this modification is required for its recruitment to TGN/endosomal membranes but not for binding to AP-1. A novel subtype of AP-1-binding motif within Gadkin specifically associates with the gamma1-adaptin ear domain; mutational inactivation of this motif (alone or combined with three conventional AP-1gamma binding peptides) causes Gadkin to mislocalize to the plasma membrane and abrogates its ability to render AP-1 brefeldin A-resistant.\",\n      \"method\": \"S-palmitoylation assay, NMR (solution structure of intrinsically disordered protein), mutagenesis, localization imaging, brefeldin A resistance assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mutagenesis of binding motif combined with palmitoylation assay, NMR characterization, functional BFA-resistance readout, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"19965873\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"AP1AR (gamma-BAR/Gadkin) is an S-palmitoylated peripheral membrane protein that is recruited to the trans-Golgi network/endosomal membranes via palmitoylation, where it directly engages the gamma1-adaptin ear domain of the AP-1 clathrin adaptor complex through a novel AP-1-binding motif; this interaction stabilizes AP-1 on membranes and is required for AP-1-dependent trafficking of lysosomal hydrolases (e.g., cathepsin D) between the TGN and endosomes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"AP1AR (gamma-BAR/Gadkin) is a peripheral membrane protein that links the AP-1 clathrin adaptor complex to membranes and supports AP-1-dependent trafficking between the trans-Golgi network and endosomes [#0]. It directly binds the gamma1-adaptin ear domain of AP-1, colocalizes with gamma1-adaptin at the TGN, and stabilizes AP-1 on membranes: its overexpression increases membrane-bound gamma1-adaptin and renders it resistant to brefeldin A-induced release, while its depletion reduces steady-state membrane AP-1 and increases secretion of the lysosomal hydrolase cathepsin D [#0]. AP1AR is S-palmitoylated, and this lipid modification is required for its recruitment to TGN/endosomal membranes but not for AP-1 binding; the AP-1 interaction itself is mediated by a distinct subtype of gamma1-adaptin ear-binding motif, whose mutation mislocalizes AP1AR to the plasma membrane and abolishes its ability to confer brefeldin A resistance on AP-1 [#1]. Beyond these membrane-recruitment and AP-1-stabilizing functions, no further mechanistic detail has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established that AP1AR is a direct AP-1 interactor that controls membrane association of the adaptor and thereby AP-1-dependent cargo trafficking, defining its core cellular role.\",\n      \"evidence\": \"In vitro binding and co-immunoprecipitation with the gamma ear domain, ultrastructural colocalization at the TGN, brefeldin A release assay, siRNA knockdown, and cathepsin D secretion readout\",\n      \"pmids\": [\"15775984\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Did not define the molecular motif within AP1AR responsible for AP-1 binding\",\n        \"Did not establish how AP1AR itself is recruited to membranes\",\n        \"Range of cargoes beyond cathepsin D not mapped\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Separated the membrane-targeting and AP-1-binding determinants of AP1AR, showing palmitoylation drives membrane recruitment while a novel ear-binding motif mediates the AP-1 interaction.\",\n      \"evidence\": \"S-palmitoylation assay, NMR solution characterization of the intrinsically disordered protein, motif mutagenesis, localization imaging, and brefeldin A resistance assay\",\n      \"pmids\": [\"19965873\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Palmitoylation enzyme(s) and depalmitoylation regulation not identified\",\n        \"Structural basis of the novel ear-binding motif not resolved at atomic detail\",\n        \"Physiological consequences of mislocalization in cells not fully traced to cargo phenotypes\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How AP1AR-mediated AP-1 stabilization is regulated and integrated with the broader vesicle-formation machinery remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Upstream signals controlling AP1AR palmitoylation cycling unknown\",\n        \"Full set of trafficking cargoes dependent on AP1AR not defined\",\n        \"Whether AP1AR engages additional adaptors or vesicle components is unexplored\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"AP1G1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":3,"faith_pct":100.0}}