{"gene":"VCF2","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2023,"finding":"VCF2 (FAM104B) directly binds p97/VCP via a novel alpha-helical motif, associates with p97-UFD1-NPL4 and p97-UBXN2B complexes in cells, localizes to the nucleus, and promotes nuclear import of p97; loss of VCF2 results in reduced nuclear p97 levels, slow growth, and hypersensitivity to p97 inhibition.","method":"Direct binding established by pulldown/Co-IP with mutagenesis of the alpha-helical motif; complex association by Co-immunoprecipitation in cells; subcellular localization by imaging/fractionation; loss-of-function (knockdown/knockout) with growth and drug-sensitivity phenotypic readouts","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, direct binding via defined novel motif, subcellular localization with functional consequence (nuclear p97 levels), and loss-of-function phenotype; multiple orthogonal methods in a single rigorous study","pmids":["37713320"],"is_preprint":false}],"current_model":"VCF2 (FAM104B) 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 nuclear import of p97, with its loss causing reduced nuclear p97 levels, slow growth, and hypersensitivity to p97 inhibition."},"narrative":{"mechanistic_narrative":"VCF2 (FAM104B) is a nuclear cofactor of the AAA+ ATPase p97/VCP that couples p97 to its nuclear functions by directly binding p97 through a novel alpha-helical motif [PMID:37713320]. VCF2 associates with the canonical p97-UFD1-NPL4 and p97-UBXN2B complexes in cells and localizes to the nucleus, where it promotes nuclear import of p97 [PMID:37713320]. Consistent with this role, loss of VCF2 reduces nuclear p97 levels and produces slow growth and hypersensitivity to p97 inhibition [PMID:37713320]. Beyond [PMID:37713320], no further mechanistic detail has been characterized in the available corpus.","teleology":[{"year":2023,"claim":"Established that VCF2/FAM104B is a bona fide p97/VCP cofactor that binds p97 directly via a defined motif and governs the nuclear pool of p97, answering how p97 is delivered to and functions in the nucleus.","evidence":"Pulldown/Co-IP with mutagenesis of the alpha-helical binding motif, reciprocal Co-IP for complex association, imaging/fractionation for localization, and knockdown/knockout with growth and drug-sensitivity readouts in cells","pmids":["37713320"],"confidence":"High","gaps":["Structural basis of the alpha-helical motif engaging p97 not resolved at atomic resolution","Mechanism by which VCF2 drives nuclear import of p97 (import machinery, cargo handoff) not defined","Substrates or nuclear processes downstream of VCF2-dependent p97 import not identified"]},{"year":null,"claim":"Whether VCF2 selects or processes specific p97 substrates in the nucleus, and how its activity is regulated, remains unknown.","evidence":"","pmids":[],"confidence":"High","gaps":["No nuclear substrate of the VCF2-p97 axis characterized","Regulation of VCF2 expression or activity unexplored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0]}],"complexes":["p97-UFD1-NPL4","p97-UBXN2B"],"partners":["VCP","UFD1","NPLOC4","UBXN2B"],"other_free_text":[]}},"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":3322,"output_tokens":436,"usd":0.008253,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6689,"output_tokens":1062,"usd":0.029997,"stage2_stop_reason":"end_turn"},"total_usd":0.03825,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2023,\n      \"finding\": \"VCF2 (FAM104B) directly binds p97/VCP via a novel alpha-helical motif, associates with p97-UFD1-NPL4 and p97-UBXN2B complexes in cells, localizes to the nucleus, and promotes nuclear import of p97; loss of VCF2 results in reduced nuclear p97 levels, slow growth, and hypersensitivity to p97 inhibition.\",\n      \"method\": \"Direct binding established by pulldown/Co-IP with mutagenesis of the alpha-helical motif; complex association by Co-immunoprecipitation in cells; subcellular localization by imaging/fractionation; loss-of-function (knockdown/knockout) with growth and drug-sensitivity phenotypic readouts\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, direct binding via defined novel motif, subcellular localization with functional consequence (nuclear p97 levels), and loss-of-function phenotype; multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"37713320\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"VCF2 (FAM104B) 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 nuclear import of p97, with its loss causing reduced nuclear p97 levels, slow growth, and hypersensitivity to p97 inhibition.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"VCF2 (FAM104B) is a nuclear cofactor of the AAA+ ATPase p97/VCP that couples p97 to its nuclear functions by directly binding p97 through a novel alpha-helical motif [#0]. VCF2 associates with the canonical p97-UFD1-NPL4 and p97-UBXN2B complexes in cells and localizes to the nucleus, where it promotes nuclear import of p97 [#0]. Consistent with this role, loss of VCF2 reduces nuclear p97 levels and produces slow growth and hypersensitivity to p97 inhibition [#0]. Beyond [#0], no further mechanistic detail has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2023,\n      \"claim\": \"Established that VCF2/FAM104B is a bona fide p97/VCP cofactor that binds p97 directly via a defined motif and governs the nuclear pool of p97, answering how p97 is delivered to and functions in the nucleus.\",\n      \"evidence\": \"Pulldown/Co-IP with mutagenesis of the alpha-helical binding motif, reciprocal Co-IP for complex association, imaging/fractionation for localization, and knockdown/knockout with growth and drug-sensitivity readouts in cells\",\n      \"pmids\": [\"37713320\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of the alpha-helical motif engaging p97 not resolved at atomic resolution\",\n        \"Mechanism by which VCF2 drives nuclear import of p97 (import machinery, cargo handoff) not defined\",\n        \"Substrates or nuclear processes downstream of VCF2-dependent p97 import not identified\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether VCF2 selects or processes specific p97 substrates in the nucleus, and how its activity is regulated, remains unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No nuclear substrate of the VCF2-p97 axis characterized\",\n        \"Regulation of VCF2 expression or activity unexplored\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\"p97-UFD1-NPL4\", \"p97-UBXN2B\"],\n    \"partners\": [\"VCP\", \"UFD1\", \"NPLOC4\", \"UBXN2B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":3,"faith_total":3,"faith_pct":100.0}}