{"gene":"TG_230710","gene_symbol":"CDC48","run_date":"2026-09-08T11:06:50","timeline":{"discoveries":[{"year":2017,"finding":"CDC48AP (an AAA ATPase/CDC48 family member localized to the apicoplast) is required for translocation of apicoplast proteins across the periplastid membrane during protein import, functioning together with the plastid ubiquitin-like protein PUBL as part of an apicoplast-specific ERAD-like complex.","method":"Conditional null mutants, genetic complementation, functional import assays","journal":"mBio","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional null mutants with specific import phenotype, genetic complementation, and mutagenesis of PUBL residues in a single rigorous study","pmids":["28655825"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2013,"finding":"TgNoAP1, a novel AAA-ATPase/CDC48 family member, localizes to the nucleolus during G1/S phases of the cell cycle and is required for 28S rRNA processing; a temperature-sensitive allele (tyrosine-to-cysteine change upstream of the second AAA+ domain) causes conditional protein instability, G1-phase cell cycle arrest, and defective pre-rRNA processing. TgNoAP1 interacts with components of snoRNP and R2TP complexes.","method":"Temperature-sensitive mutant mapping by genetic complementation, knock-in of point mutation, localization by microscopy, co-immunoprecipitation with snoRNP/R2TP factors, rRNA processing assay","journal":"Molecular microbiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic complementation, knock-in mutagenesis, rRNA processing assay, and protein interaction studies in a single study with multiple orthogonal methods","pmids":["23964771"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]}],"current_model":"In Toxoplasma gondii, two CDC48-family AAA-ATPases serve distinct roles: CDC48AP acts at the apicoplast periplastid membrane as part of an ERAD-like machinery to translocate nucleus-encoded proteins into the apicoplast (together with the ubiquitin-like protein PUBL), while TgNoAP1 localizes to the nucleolus during G1/S and is required for pre-rRNA (28S rRNA) processing and ribosome biogenesis, interacting with snoRNP and R2TP complexes, with its loss causing G1-phase cell cycle arrest."},"narrative":{"mechanistic_narrative":"In Toxoplasma gondii, the CDC48 family comprises two distinct AAA-ATPases that operate in separate cellular compartments. CDC48AP localizes to the apicoplast and is required for translocation of nucleus-encoded apicoplast proteins across the periplastid membrane, functioning with the plastid ubiquitin-like protein PUBL as part of an apicoplast-specific ERAD-like import machinery [PMID:28655825]. The second family member, TgNoAP1, localizes to the nucleolus during G1/S phase and is required for 28S pre-rRNA processing, interacting with components of the snoRNP and R2TP complexes; its loss via a temperature-sensitive allele causes conditional protein instability and G1-phase cell cycle arrest [PMID:23964771]. Beyond these two studies, no further mechanistic detail on CDC48 family function has been characterized in the available corpus.","teleology":[{"year":2013,"claim":"Established that a nucleolar CDC48-family AAA-ATPase couples ribosome biogenesis to cell cycle progression in Toxoplasma, answering whether this protein family has a role beyond membrane-associated functions.","evidence":"Temperature-sensitive mutant mapping by genetic complementation, knock-in point mutation, microscopy, co-immunoprecipitation with snoRNP/R2TP factors, and rRNA processing assay in T. gondii","pmids":["23964771"],"confidence":"High","gaps":["The direct enzymatic role of TgNoAP1 ATPase activity in pre-rRNA processing is not resolved","The molecular mechanism linking rRNA processing defect to G1 arrest is not defined"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2017,"claim":"Established that a second CDC48-family AAA-ATPase drives apicoplast protein import, answering how nucleus-encoded proteins are translocated across the periplastid membrane via an ERAD-like route.","evidence":"Conditional null mutants, genetic complementation, functional import assays, and PUBL residue mutagenesis in T. gondii","pmids":["28655825"],"confidence":"High","gaps":["The full set of translocated substrates is not defined","The structural organization of the CDC48AP/PUBL ERAD-like complex is not resolved","How CDC48AP recognizes ubiquitin-like PUBL-tagged cargo is not established"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":null,"claim":"Whether and how the two CDC48-family ATPases are functionally or evolutionarily related, and their respective substrate spectra, remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No shared cofactor or regulatory logic linking the two paralogs is characterized","No structural model exists for either ATPase in Toxoplasma"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["Apicoplast ERAD-like import complex (CDC48AP + PUBL)","snoRNP complex","R2TP complex"],"partners":["PUBL (PLASTID UBIQUITIN-LIKE PROTEIN)","SNORNP COMPONENTS","R2TP COMPLEX COMPONENTS"],"other_free_text":["Two distinct CDC48-family AAA-ATPases operate in Toxoplasma gondii: CDC48AP at the apicoplast periplastid membrane and TgNoAP1 in the nucleolus.","A temperature-sensitive TgNoAP1 allele (tyrosine-to-cysteine change upstream of the second AAA+ domain) causes conditional protein instability and G1-phase cell cycle arrest."]},"strain_conflicts":[]},"prefetch_data":{},"corpus_meta":[{"pmid":"28655825","id":"PMC_28655825","title":"A Plastid Protein That Evolved from Ubiquitin and Is Required for Apicoplast Protein Import in Toxoplasma gondii.","date":"2017","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/28655825","citation_count":28,"is_preprint":false},{"pmid":"23964771","id":"PMC_23964771","title":"A nucleolar AAA-NTPase is required for parasite division.","date":"2013","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/23964771","citation_count":14,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":3615,"output_tokens":727,"usd":0.010875,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5472,"output_tokens":2029,"usd":0.039043,"stage2_stop_reason":"end_turn"},"total_usd":0.049918,"stage1_batch_id":"msgbatch_01WokvBYTB6JLnYrpD4rXnyV","stage2_batch_id":"msgbatch_01M7hsQDvz6AqVC9DLVjQzzc","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2017,\n      \"finding\": \"CDC48AP (an AAA ATPase/CDC48 family member localized to the apicoplast) is required for translocation of apicoplast proteins across the periplastid membrane during protein import, functioning together with the plastid ubiquitin-like protein PUBL as part of an apicoplast-specific ERAD-like complex.\",\n      \"method\": \"Conditional null mutants, genetic complementation, functional import assays\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional null mutants with specific import phenotype, genetic complementation, and mutagenesis of PUBL residues in a single rigorous study\",\n      \"pmids\": [\"28655825\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TgNoAP1, a novel AAA-ATPase/CDC48 family member, localizes to the nucleolus during G1/S phases of the cell cycle and is required for 28S rRNA processing; a temperature-sensitive allele (tyrosine-to-cysteine change upstream of the second AAA+ domain) causes conditional protein instability, G1-phase cell cycle arrest, and defective pre-rRNA processing. TgNoAP1 interacts with components of snoRNP and R2TP complexes.\",\n      \"method\": \"Temperature-sensitive mutant mapping by genetic complementation, knock-in of point mutation, localization by microscopy, co-immunoprecipitation with snoRNP/R2TP factors, rRNA processing assay\",\n      \"journal\": \"Molecular microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic complementation, knock-in mutagenesis, rRNA processing assay, and protein interaction studies in a single study with multiple orthogonal methods\",\n      \"pmids\": [\"23964771\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"In Toxoplasma gondii, two CDC48-family AAA-ATPases serve distinct roles: CDC48AP acts at the apicoplast periplastid membrane as part of an ERAD-like machinery to translocate nucleus-encoded proteins into the apicoplast (together with the ubiquitin-like protein PUBL), while TgNoAP1 localizes to the nucleolus during G1/S and is required for pre-rRNA (28S rRNA) processing and ribosome biogenesis, interacting with snoRNP and R2TP complexes, with its loss causing G1-phase cell cycle arrest.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"In Toxoplasma gondii, the CDC48 family comprises two distinct AAA-ATPases that operate in separate cellular compartments. CDC48AP localizes to the apicoplast and is required for translocation of nucleus-encoded apicoplast proteins across the periplastid membrane, functioning with the plastid ubiquitin-like protein PUBL as part of an apicoplast-specific ERAD-like import machinery [#0]. The second family member, TgNoAP1, localizes to the nucleolus during G1/S phase and is required for 28S pre-rRNA processing, interacting with components of the snoRNP and R2TP complexes; its loss via a temperature-sensitive allele causes conditional protein instability and G1-phase cell cycle arrest [#1]. Beyond these two studies, no further mechanistic detail on CDC48 family function has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established that a nucleolar CDC48-family AAA-ATPase couples ribosome biogenesis to cell cycle progression in Toxoplasma, answering whether this protein family has a role beyond membrane-associated functions.\",\n      \"evidence\": \"Temperature-sensitive mutant mapping by genetic complementation, knock-in point mutation, microscopy, co-immunoprecipitation with snoRNP/R2TP factors, and rRNA processing assay in T. gondii\",\n      \"pmids\": [\n        \"23964771\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The direct enzymatic role of TgNoAP1 ATPase activity in pre-rRNA processing is not resolved\",\n        \"The molecular mechanism linking rRNA processing defect to G1 arrest is not defined\"\n      ],\n      \"attribution\": [\n        {\n          \"species\": \"Toxoplasma gondii\",\n          \"strain\": \"\"\n        }\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established that a second CDC48-family AAA-ATPase drives apicoplast protein import, answering how nucleus-encoded proteins are translocated across the periplastid membrane via an ERAD-like route.\",\n      \"evidence\": \"Conditional null mutants, genetic complementation, functional import assays, and PUBL residue mutagenesis in T. gondii\",\n      \"pmids\": [\n        \"28655825\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The full set of translocated substrates is not defined\",\n        \"The structural organization of the CDC48AP/PUBL ERAD-like complex is not resolved\",\n        \"How CDC48AP recognizes ubiquitin-like PUBL-tagged cargo is not established\"\n      ],\n      \"attribution\": [\n        {\n          \"species\": \"Toxoplasma gondii\",\n          \"strain\": \"\"\n        }\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether and how the two CDC48-family ATPases are functionally or evolutionarily related, and their respective substrate spectra, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No shared cofactor or regulatory logic linking the two paralogs is characterized\",\n        \"No structural model exists for either ATPase in Toxoplasma\"\n      ],\n      \"attribution\": [\n        {\n          \"species\": \"Toxoplasma gondii\",\n          \"strain\": \"\"\n        }\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0016887\",\n        \"supporting_discovery_ids\": [0, 1],\n        \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n      },\n      {\n        \"term_id\": \"GO:0030674\",\n        \"supporting_discovery_ids\": [0],\n        \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n      }\n    ],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0009528\",\n        \"supporting_discovery_ids\": [0],\n        \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n      },\n      {\n        \"term_id\": \"GO:0005730\",\n        \"supporting_discovery_ids\": [1],\n        \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n      }\n    ],\n    \"pathway\": [\n      {\n        \"term_id\": \"GO:0045037\",\n        \"supporting_discovery_ids\": [0],\n        \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n      },\n      {\n        \"term_id\": \"GO:0006364\",\n        \"supporting_discovery_ids\": [1],\n        \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n      },\n      {\n        \"term_id\": \"GO:0042254\",\n        \"supporting_discovery_ids\": [1],\n        \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n      }\n    ],\n    \"complexes\": [\n      \"Apicoplast ERAD-like import complex (CDC48AP + PUBL)\",\n      \"snoRNP complex\",\n      \"R2TP complex\"\n    ],\n    \"partners\": [\n      \"PUBL (plastid ubiquitin-like protein)\",\n      \"snoRNP components\",\n      \"R2TP complex components\"\n    ],\n    \"other_free_text\": [\n      \"Two distinct CDC48-family AAA-ATPases operate in Toxoplasma gondii: CDC48AP at the apicoplast periplastid membrane and TgNoAP1 in the nucleolus.\",\n      \"A temperature-sensitive TgNoAP1 allele (tyrosine-to-cysteine change upstream of the second AAA+ domain) causes conditional protein instability and G1-phase cell cycle arrest.\"\n    ]\n  },\n  \"strain_conflicts\": []\n}","audit_flag":null,"strains":[{"strain":"ME49","gene_id":"TGME49_230710","name":"CDC48","product":"cell division protein CDC48","uniprot_acc":"S8GB07","chromosome":"TGME49_chrVIII","start_pos":994671},{"strain":"GT1","gene_id":"TGGT1_230710","name":null,"product":"cell division protein CDC48","uniprot_acc":null,"chromosome":"TGGT1_chrVIII","start_pos":989816},{"strain":"RH88","gene_id":"TGRH88_075110","name":null,"product":"cell division protein CDC48","uniprot_acc":null,"chromosome":"CM023089","start_pos":6101329},{"strain":"VEG","gene_id":"TGVEG_230710","name":null,"product":"cell division protein CDC48","uniprot_acc":"A0A0F7UXP4","chromosome":"TGVEG_chrVIII","start_pos":1000215}]}