{"gene":"VCF2","run_date":"2026-04-28T23:00:23","timeline":{"discoveries":[{"year":2023,"finding":"VCF2 (FAM104 family member) directly binds p97/VCP via a novel alpha-helical motif and associates with p97-UFD1-NPL4 and p97-UBXN2B complexes in cells","method":"Direct binding assay (pulldown), Co-immunoprecipitation, identification of novel alpha-helical binding motif","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, direct binding demonstrated, novel motif characterized, multiple orthogonal methods in single study","pmids":["37713320"],"is_preprint":false},{"year":2023,"finding":"VCF2 localizes to the nucleus and promotes nuclear import of p97/VCP; loss of VCF1/2 results in reduced nuclear p97 levels","method":"Subcellular fractionation, live-cell imaging, loss-of-function (knockout/knockdown) with quantification of nuclear p97 levels","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — direct localization experiment with functional consequence (reduced nuclear p97), loss-of-function phenotype clearly linked to nuclear import mechanism","pmids":["37713320"],"is_preprint":false},{"year":2023,"finding":"Loss of VCF1/2 causes slow growth and hypersensitivity to p97 chemical inhibition in the absence and presence of DNA damage, indicating FAM104 proteins are critical regulators of nuclear p97 functions","method":"Loss-of-function (knockout) with growth assays and chemical inhibitor sensitivity assays under basal and DNA-damage conditions","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with defined cellular phenotype, but pathway placement inferred from chemical inhibitor sensitivity rather than direct epistasis","pmids":["37713320"],"is_preprint":false}],"current_model":"VCF2 (FAM104 family member) is a nuclear cofactor of p97/VCP that directly binds p97 via a novel alpha-helical motif, associates with p97-UFD1-NPL4 and p97-UBXN2B complexes, and promotes the nuclear import of p97, with its loss reducing nuclear p97 levels and causing hypersensitivity to p97 inhibition and DNA damage."},"narrative":{"teleology":[{"year":2023,"claim":"Establishing how VCF2 engages p97/VCP: direct binding through a novel alpha-helical motif and co-complex formation with p97-UFD1-NPL4 and p97-UBXN2B resolved the molecular basis of VCF2-p97 interaction and placed VCF2 within the p97 cofactor network.","evidence":"Direct pulldown binding assays, reciprocal co-immunoprecipitation, and motif characterization in human cells (eLife)","pmids":["37713320"],"confidence":"High","gaps":["No structural model of the VCF2 alpha-helical motif bound to p97","Whether VCF2 and VCF1 bind p97 competitively or cooperatively is unresolved","Stoichiometry of VCF2 within p97-UFD1-NPL4 and p97-UBXN2B complexes is unknown"]},{"year":2023,"claim":"Defining VCF2's cellular function: demonstration that VCF2 promotes nuclear import of p97, with its loss reducing nuclear p97 levels and causing slow growth and hypersensitivity to p97 inhibition and DNA damage, established VCF2 as a gatekeeper of nuclear p97 availability.","evidence":"Subcellular fractionation, live-cell imaging, and knockout/knockdown growth and drug-sensitivity assays in human cells (eLife)","pmids":["37713320"],"confidence":"High","gaps":["Mechanism of nuclear import facilitation (carrier-dependent vs. direct escort) is uncharacterized","Specific nuclear p97 substrates affected by VCF2 loss remain unidentified","Pathway placement relies on inhibitor sensitivity rather than direct epistasis with known p97-dependent nuclear pathways"]},{"year":null,"claim":"The molecular mechanism by which VCF2 promotes p97 nuclear import, the identity of nuclear p97 substrates dependent on VCF2, and the division of labor between VCF1 and VCF2 remain open questions.","evidence":"","pmids":[],"confidence":"Low","gaps":["No import receptor or NLS-dependent mechanism identified for VCF2-mediated p97 nuclear entry","Functional redundancy versus specialization of VCF1 and VCF2 not dissected","In vivo physiological roles (organism-level phenotype) are unexplored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[1]}],"complexes":[],"partners":["VCP","UFD1","NPLOC4","UBXN2B"],"other_free_text":[]},"mechanistic_narrative":"VCF2 is a nuclear cofactor of the AAA-ATPase p97/VCP that directly binds p97 through a novel alpha-helical motif and associates with p97-UFD1-NPL4 and p97-UBXN2B complexes [PMID:37713320]. VCF2 localizes to the nucleus and promotes nuclear import of p97; loss of VCF2 (and its paralog VCF1) reduces nuclear p97 levels, causes slow growth, and confers hypersensitivity to p97 chemical inhibition and DNA damage, establishing VCF2 as a critical regulator of nuclear p97 functions [PMID:37713320]."},"prefetch_data":{"uniprot":{"accession":"Q5XKR9","full_name":"Protein VCF2","aliases":["VCP nuclear cofactor family member 2"],"length_aa":115,"mass_kda":13.1,"function":"","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q5XKR9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/VCF2","classification":"Not Classified","n_dependent_lines":218,"n_total_lines":1208,"dependency_fraction":0.1804635761589404},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/VCF2","total_profiled":1310},"omim":[{"mim_id":"621109","title":"VCP NUCLEAR COFACTOR FAMILY, MEMBER 1; VCF1","url":"https://www.omim.org/entry/621109"},{"mim_id":"601023","title":"VALOSIN-CONTAINING PROTEIN; VCP","url":"https://www.omim.org/entry/601023"},{"mim_id":"301141","title":"VCP NUCLEAR COFACTOR FAMILY, MEMBER 2; VCF2","url":"https://www.omim.org/entry/301141"}],"hpa":{"profiled":true,"resolved_as":"FAM104B","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/FAM104B"},"hgnc":{"alias_symbol":["FLJ20434"],"prev_symbol":["CXorf44","FAM104B"]},"alphafold":{"accession":"Q5XKR9","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5XKR9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5XKR9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5XKR9-F1-predicted_aligned_error_v6.png","plddt_mean":60.53},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=VCF2","jax_strain_url":"https://www.jax.org/strain/search?query=VCF2"},"sequence":{"accession":"Q5XKR9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5XKR9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5XKR9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5XKR9"}},"corpus_meta":[{"pmid":"10190360","id":"PMC_10190360","title":"Pulmonary embolus after vena cava filter placement.","date":"1999","source":"The American surgeon","url":"https://pubmed.ncbi.nlm.nih.gov/10190360","citation_count":20,"is_preprint":false},{"pmid":"37713320","id":"PMC_37713320","title":"The FAM104 proteins VCF1/2 promote the nuclear localization of p97/VCP.","date":"2023","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/37713320","citation_count":6,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":2553,"output_tokens":682,"usd":0.008944},"stage2":{"model":"claude-opus-4-6","input_tokens":3863,"output_tokens":2108,"usd":0.108022},"total_usd":0.116966,"stage1_batch_id":"msgbatch_01BparvgRZ9S2LMidvaoo86K","stage2_batch_id":"msgbatch_01NkBfv9SVZWthhS7j6mU6G3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2023,\n      \"finding\": \"VCF2 (FAM104 family member) directly binds p97/VCP via a novel alpha-helical motif and associates with p97-UFD1-NPL4 and p97-UBXN2B complexes in cells\",\n      \"method\": \"Direct binding assay (pulldown), Co-immunoprecipitation, identification of novel alpha-helical binding motif\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, direct binding demonstrated, novel motif characterized, multiple orthogonal methods in single study\",\n      \"pmids\": [\"37713320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"VCF2 localizes to the nucleus and promotes nuclear import of p97/VCP; loss of VCF1/2 results in reduced nuclear p97 levels\",\n      \"method\": \"Subcellular fractionation, live-cell imaging, loss-of-function (knockout/knockdown) with quantification of nuclear p97 levels\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment with functional consequence (reduced nuclear p97), loss-of-function phenotype clearly linked to nuclear import mechanism\",\n      \"pmids\": [\"37713320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Loss of VCF1/2 causes slow growth and hypersensitivity to p97 chemical inhibition in the absence and presence of DNA damage, indicating FAM104 proteins are critical regulators of nuclear p97 functions\",\n      \"method\": \"Loss-of-function (knockout) with growth assays and chemical inhibitor sensitivity assays under basal and DNA-damage conditions\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype, but pathway placement inferred from chemical inhibitor sensitivity rather than direct epistasis\",\n      \"pmids\": [\"37713320\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"VCF2 (FAM104 family member) is a nuclear cofactor of p97/VCP that directly binds p97 via a novel alpha-helical motif, associates with p97-UFD1-NPL4 and p97-UBXN2B complexes, and promotes the nuclear import of p97, with its loss reducing nuclear p97 levels and causing hypersensitivity to p97 inhibition and DNA damage.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"VCF2 is a nuclear cofactor of the AAA-ATPase p97/VCP that directly binds p97 through a novel alpha-helical motif and associates with p97-UFD1-NPL4 and p97-UBXN2B complexes [PMID:37713320]. VCF2 localizes to the nucleus and promotes nuclear import of p97; loss of VCF2 (and its paralog VCF1) reduces nuclear p97 levels, causes slow growth, and confers hypersensitivity to p97 chemical inhibition and DNA damage, establishing VCF2 as a critical regulator of nuclear p97 functions [PMID:37713320].\",\n  \"teleology\": [\n    {\n      \"year\": 2023,\n      \"claim\": \"Establishing how VCF2 engages p97/VCP: direct binding through a novel alpha-helical motif and co-complex formation with p97-UFD1-NPL4 and p97-UBXN2B resolved the molecular basis of VCF2-p97 interaction and placed VCF2 within the p97 cofactor network.\",\n      \"evidence\": \"Direct pulldown binding assays, reciprocal co-immunoprecipitation, and motif characterization in human cells (eLife)\",\n      \"pmids\": [\"37713320\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural model of the VCF2 alpha-helical motif bound to p97\",\n        \"Whether VCF2 and VCF1 bind p97 competitively or cooperatively is unresolved\",\n        \"Stoichiometry of VCF2 within p97-UFD1-NPL4 and p97-UBXN2B complexes is unknown\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defining VCF2's cellular function: demonstration that VCF2 promotes nuclear import of p97, with its loss reducing nuclear p97 levels and causing slow growth and hypersensitivity to p97 inhibition and DNA damage, established VCF2 as a gatekeeper of nuclear p97 availability.\",\n      \"evidence\": \"Subcellular fractionation, live-cell imaging, and knockout/knockdown growth and drug-sensitivity assays in human cells (eLife)\",\n      \"pmids\": [\"37713320\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism of nuclear import facilitation (carrier-dependent vs. direct escort) is uncharacterized\",\n        \"Specific nuclear p97 substrates affected by VCF2 loss remain unidentified\",\n        \"Pathway placement relies on inhibitor sensitivity rather than direct epistasis with known p97-dependent nuclear pathways\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular mechanism by which VCF2 promotes p97 nuclear import, the identity of nuclear p97 substrates dependent on VCF2, and the division of labor between VCF1 and VCF2 remain open questions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No import receptor or NLS-dependent mechanism identified for VCF2-mediated p97 nuclear entry\",\n        \"Functional redundancy versus specialization of VCF1 and VCF2 not dissected\",\n        \"In vivo physiological roles (organism-level phenotype) are 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:0005634\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0009609507\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"VCP\", \"UFD1\", \"NPLOC4\", \"UBXN2B\"],\n    \"other_free_text\": []\n  }\n}\n```\n\nWait, I need to fix the pathway entry. Let me correct that:\n\n```json\n{\n  \"mechanistic_narrative\": \"VCF2 is a nuclear cofactor of the AAA-ATPase p97/VCP that directly binds p97 through a novel alpha-helical motif and associates with p97-UFD1-NPL4 and p97-UBXN2B complexes [PMID:37713320]. VCF2 localizes to the nucleus and promotes nuclear import of p97; loss of VCF2 (and its paralog VCF1) reduces nuclear p97 levels, causes slow growth, and confers hypersensitivity to p97 chemical inhibition and DNA damage, establishing VCF2 as a critical regulator of nuclear p97 functions [PMID:37713320].\",\n  \"teleology\": [\n    {\n      \"year\": 2023,\n      \"claim\": \"Establishing how VCF2 engages p97/VCP: direct binding through a novel alpha-helical motif and co-complex formation with p97-UFD1-NPL4 and p97-UBXN2B resolved the molecular basis of VCF2-p97 interaction and placed VCF2 within the p97 cofactor network.\",\n      \"evidence\": \"Direct pulldown binding assays, reciprocal co-immunoprecipitation, and motif characterization in human cells (eLife)\",\n      \"pmids\": [\"37713320\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural model of the VCF2 alpha-helical motif bound to p97\",\n        \"Whether VCF2 and VCF1 bind p97 competitively or cooperatively is unresolved\",\n        \"Stoichiometry of VCF2 within p97-UFD1-NPL4 and p97-UBXN2B complexes is unknown\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defining VCF2's cellular function: demonstration that VCF2 promotes nuclear import of p97, with its loss reducing nuclear p97 levels and causing slow growth and hypersensitivity to p97 inhibition and DNA damage, established VCF2 as a gatekeeper of nuclear p97 availability.\",\n      \"evidence\": \"Subcellular fractionation, live-cell imaging, and knockout/knockdown growth and drug-sensitivity assays in human cells (eLife)\",\n      \"pmids\": [\"37713320\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism of nuclear import facilitation (carrier-dependent vs. direct escort) is uncharacterized\",\n        \"Specific nuclear p97 substrates affected by VCF2 loss remain unidentified\",\n        \"Pathway placement relies on inhibitor sensitivity rather than direct epistasis with known p97-dependent nuclear pathways\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular mechanism by which VCF2 promotes p97 nuclear import, the identity of nuclear p97 substrates dependent on VCF2, and the division of labor between VCF1 and VCF2 remain open questions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No import receptor or NLS-dependent mechanism identified for VCF2-mediated p97 nuclear entry\",\n        \"Functional redundancy versus specialization of VCF1 and VCF2 not dissected\",\n        \"In vivo physiological roles (organism-level phenotype) are 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:0005634\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"VCP\", \"UFD1\", \"NPLOC4\", \"UBXN2B\"],\n    \"other_free_text\": []\n  }\n}\n```"}