{"gene":"CDC23","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":1990,"finding":"CDC23 contains multiple copies of a novel 34-amino acid repeating motif (the TPR motif), which defines a family of proteins involved in mitosis and RNA synthesis. The TPR units are predicted to form amphipathic alpha-helical regions punctuated by proline-induced turns.","method":"Sequence analysis, quantitative motif identification","journal":"Cell","confidence":"Medium","confidence_rationale":"Tier 1 (structural/sequence analysis) / Moderate — foundational structural characterization, but purely computational/sequence-based without in vitro functional validation","pmids":["2404612"],"is_preprint":false},{"year":1998,"finding":"Yeast Cdc23 (as an APC/C component) is required for the degradation of Cdc20 during S phase and early mitosis; Cdc20 instability during S phase and mitosis depends on CDC23 and CDC27 but is not mediated by the Cdc20 destruction box.","method":"Genetic analysis, cell cycle protein stability assays in S. cerevisiae mutants","journal":"Current biology : CB","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with defined substrate phenotype, single lab","pmids":["9651679"],"is_preprint":false},{"year":1998,"finding":"Human CDC23 encodes a 591-amino acid TPR-repeat protein (9 TPR units) that is a subunit of the human APC/C, mapping to chromosome 5q31, with 30% identity and 51% similarity to S. cerevisiae CDC23.","method":"cDNA cloning, genomic structure analysis, sequence homology","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cDNA cloning and structural characterization of human protein, single lab","pmids":["9790767"],"is_preprint":false},{"year":1999,"finding":"Fission yeast Cut23 (APC8 ortholog) is a subunit of the APC/cyclosome required for metaphase-anaphase transition; Cut23's TPR repeat domain mediates its function, and its protein level fluctuates during the cell cycle (possibly ubiquitinated and degraded in a cell-cycle-dependent fashion). Cut23 may not be a stable core component of the APC/cyclosome.","method":"Temperature-sensitive mutant screen, sucrose gradient centrifugation, cell biology assays in S. pombe","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical fractionation and genetic analysis, single lab","pmids":["10526233"],"is_preprint":false},{"year":1996,"finding":"Yeast CDC23 directly interacts with the SIN1 nuclear protein via CDC23's TPR repeats; the N-terminal domain of SIN1 is sufficient to bind the TPR-containing portion of CDC23 in vitro.","method":"Yeast two-hybrid, in vitro binding with recombinant proteins","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two-hybrid plus in vitro pulldown, single lab","pmids":["8710860"],"is_preprint":false},{"year":2002,"finding":"The destruction box (D box) of the mitotic cyclin Clb2 directly interacts with the APC/C subunit Cdc23 but not with five other APC/C subunits tested; mutations in the Clb2 D box abolish this interaction both in vivo (two-hybrid) and in vitro, providing the first evidence for direct substrate-APC/C subunit interaction.","method":"Yeast two-hybrid, in vitro binding assay, D-box mutagenesis","journal":"Archives of biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two-hybrid plus in vitro pulldown with mutagenesis, single lab","pmids":["12413490"],"is_preprint":false},{"year":2002,"finding":"Fission yeast Plo1 (polo-like kinase) physically interacts with the APC/cyclosome through the noncatalytic polo-box domain of Plo1 and the TPR domain of Cut23/Apc8; a cut23 mutation specifically disrupting this interaction causes metaphase arrest that is rescued by high Plo1 expression, indicating this interaction is required for mitotic progression.","method":"Co-immunoprecipitation, genetic epistasis, overexpression rescue in S. pombe","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, domain mapping, specific separation-of-function mutation, and genetic rescue in a single study","pmids":["11777938"],"is_preprint":false},{"year":2001,"finding":"Human CDC23 (APC component) forms a complex with the small GTPase Rac (Rac1, Rac2, Rac3) in mammalian cell lysates, suggesting Rac may regulate specific APC-dependent proteolytic processes through directed subcellular localization.","method":"Co-immunoprecipitation in mammalian cells","journal":"International journal of molecular medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP, single lab, no functional follow-up on the CDC23 interaction specifically","pmids":["11445862"],"is_preprint":false},{"year":2011,"finding":"Knockdown of CDC23 in human thyroid cancer cells causes accumulation of cyclin B1 and securin, and arrest in S and G2/M phases; the effect on proliferation and cell cycle is reversed by triple knockdown of CDC23, cyclin B1, and securin, placing CDC23 upstream of cyclin B1 and securin degradation in controlling cell cycle progression.","method":"siRNA knockdown, cell cycle analysis, western blot, triple knockdown epistasis in human cancer cells","journal":"Endocrine-related cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis by triple knockdown with defined substrates, single lab","pmids":["21990323"],"is_preprint":false},{"year":2016,"finding":"Crystal structure of the N-terminal domain of Cdc23 (APC8/CDC23 subunit of human APC/C) was determined to 3.1 Å resolution by sulfur SAD phasing, revealing its structural organization.","method":"X-ray crystallography, sulfur SAD phasing","journal":"Acta crystallographica. Section D, Structural biology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — crystal structure determined but functional validation not described in this abstract","pmids":["26960127"],"is_preprint":false},{"year":2023,"finding":"Homozygous missense variants in CDC23 (p.Y329C and p.R330C) cause female infertility with oocyte maturation defects; p.Y329C decreases CDC23 protein level, while p.R330C changes CDC23 subcellular localization in HeLa cells and mouse oocytes. Knock-in mice (Cdc23Y329C/Y329C) accumulate securin and cyclin B1 in oocytes, and this phenotype is rescued by AZ3146 (Mps1 inhibitor) treatment.","method":"Patient variant identification, in vitro mutagenesis, subcellular localization imaging, knock-in mouse model, western blot for APC/C substrates, pharmacological rescue","journal":"Human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods including patient variants, cellular localization, knock-in mouse model, substrate accumulation analysis, and pharmacological rescue","pmids":["37768355"],"is_preprint":false},{"year":2024,"finding":"The C-terminal disordered loop domain of Apc8 (CDC23 ortholog) directly recruits the CDK adaptor protein Xe-p9/Cks2, positioning the Xe-p9-CDK-CycB complex near the Apc1-300L autoinhibitory loop. This stimulates phosphorylation and removal of Apc1-300L, prompting formation of active APC/C-Cdc20. Without both Apc8-L and Apc3-L, APC/C is rendered inactive during mitosis.","method":"Systematic loop-deletion mutagenesis of APC/C, functional APC/C activity assays, Xenopus egg extract system","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution-based mutagenesis with multiple deletion mutants, defined biochemical mechanism, multiple orthogonal experiments in a single study","pmids":["38776225"],"is_preprint":false},{"year":2024,"finding":"Cryo-EM structures of S. cerevisiae APC/C reveal that the CDC20 C-box binding site on APC8 (Cdc23) is not blocked by a phospho-regulatable auto-inhibitory segment of APC1 (in contrast to human APC/C), indicating distinct regulatory mechanisms between yeast and human APC/C despite overall conserved architecture.","method":"Cryo-EM structure determination of S. cerevisiae APC/C complexes","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — cryo-EM structure with mechanistic comparison, preprint, single study","pmids":["bio_10.1101_2024.06.19.599685"],"is_preprint":true}],"current_model":"CDC23/APC8 is a TPR-repeat-containing core structural subunit of the APC/C E3 ubiquitin ligase that directly contacts APC/C substrates (via D-box interactions), recruits activating kinase complexes (CDK-CycB via Cks2/Xe-p9 through its C-terminal disordered loop) to relieve APC1-mediated autoinhibition and activate APC/C-Cdc20 during mitosis, interacts with polo-like kinase through its TPR domain to promote mitotic progression, and controls the timely degradation of cyclin B1 and securin to drive the metaphase-to-anaphase transition and complete oocyte maturation."},"narrative":{"mechanistic_narrative":"CDC23 (APC8) is a tetratricopeptide-repeat (TPR) subunit of the anaphase-promoting complex/cyclosome (APC/C) E3 ubiquitin ligase that drives mitotic and meiotic cell-cycle progression by promoting the timely destruction of cyclin B1 and securin [PMID:2404612, PMID:21990323]. Its TPR domain serves as a protein-protein interaction surface: it directly binds the destruction box of mitotic cyclin substrates, providing direct substrate-APC/C contact [PMID:12413490], and it recruits polo-like kinase via the kinase's polo-box domain to enable mitotic progression [PMID:11777938]. CDC23 also contributes to APC/C activation: its C-terminal disordered loop recruits the CDK adaptor Cks2/Xe-p9 together with CDK-CycB, positioning the kinase to phosphorylate and remove the APC1 autoinhibitory loop and thereby generate active APC/C-Cdc20 [PMID:38776225], and APC8 carries the CDC20 C-box binding site within the complex [PMID:bio_10.1101_2024.06.19.599685]. Loss of CDC23 in human cells causes accumulation of cyclin B1 and securin with S and G2/M arrest [PMID:21990323]. Homozygous missense variants (p.Y329C, p.R330C) cause female infertility with oocyte maturation defects, with the knock-in oocytes accumulating securin and cyclin B1 [PMID:37768355].","teleology":[{"year":1990,"claim":"Established that CDC23 is built from a repeating 34-residue motif (the TPR), defining a structural module shared among mitotic and RNA-synthesis proteins and predicting an alpha-helical protein-interaction scaffold.","evidence":"Sequence and motif analysis identifying multiple TPR units","pmids":["2404612"],"confidence":"Medium","gaps":["Purely computational; no functional validation of the TPR units","Does not assign a biochemical activity to the repeats"]},{"year":1996,"claim":"Showed the TPR repeats function as a protein-interaction surface by demonstrating direct binding to the nuclear protein SIN1, the first defined CDC23 partner.","evidence":"Yeast two-hybrid and in vitro binding with recombinant proteins in S. cerevisiae","pmids":["8710860"],"confidence":"Medium","gaps":["Functional consequence of the SIN1 interaction for APC/C activity not established","Single lab, no structural detail of the interface"]},{"year":1998,"claim":"Placed CDC23 functionally within the APC/C and linked it to substrate degradation by showing its requirement for Cdc20 turnover during S phase and early mitosis.","evidence":"Genetic analysis and protein stability assays in S. cerevisiae mutants; cDNA cloning of the human ortholog","pmids":["9651679","9790767"],"confidence":"Medium","gaps":["Mechanism of Cdc20 destabilization independent of its destruction box unclear","Direct versus indirect role of CDC23 in this turnover not resolved"]},{"year":1999,"claim":"Confirmed the APC8 ortholog (Cut23) is required for the metaphase-anaphase transition and that the TPR domain mediates this function, while raising the question of whether it is a stable core subunit.","evidence":"Temperature-sensitive mutant screen and sucrose gradient fractionation in S. pombe","pmids":["10526233"],"confidence":"Medium","gaps":["Stoichiometry and stability of Cut23 within the complex left ambiguous","Cell-cycle ubiquitination of Cut23 inferred but not directly demonstrated"]},{"year":2002,"claim":"Identified CDC23 as the direct substrate-docking subunit by showing the mitotic cyclin destruction box binds CDC23 specifically among APC/C subunits, and established a polo-kinase recruitment role required for mitotic progression.","evidence":"Two-hybrid and in vitro binding with D-box mutagenesis (Clb2); reciprocal Co-IP, domain mapping, and separation-of-function mutant rescue (Plo1/Cut23) in S. pombe","pmids":["12413490","11777938"],"confidence":"High","gaps":["Structural basis of D-box recognition by the TPR domain not defined","How polo-kinase binding mechanistically promotes anaphase onset unresolved"]},{"year":2011,"claim":"Defined CDC23's cellular role in human cells as acting upstream of cyclin B1 and securin destruction to permit cell-cycle progression.","evidence":"siRNA knockdown with triple-knockdown epistasis and substrate western blots in human thyroid cancer cells","pmids":["21990323"],"confidence":"Medium","gaps":["Does not distinguish direct catalytic contribution from scaffolding within APC/C","Generality beyond thyroid cancer cells not tested"]},{"year":2016,"claim":"Provided atomic-level structural information on the N-terminal domain of human CDC23.","evidence":"X-ray crystallography at 3.1 Å by sulfur SAD phasing","pmids":["26960127"],"confidence":"Medium","gaps":["Functional interpretation of the structure not described","Full-length and complex-bound conformations not resolved"]},{"year":2023,"claim":"Connected CDC23 to human disease, establishing that point mutations causing reduced protein level or mislocalization cause oocyte maturation failure and female infertility via APC/C substrate accumulation.","evidence":"Patient variant identification, localization imaging, knock-in mouse model with substrate analysis, and Mps1-inhibitor pharmacological rescue","pmids":["37768355"],"confidence":"High","gaps":["Why p.R330C alters localization at the molecular level not defined","Whether spindle-checkpoint (Mps1) hyperactivation is the sole downstream cause unclear"]},{"year":2024,"claim":"Defined a mechanistic activation role: the CDC23/Apc8 C-terminal disordered loop recruits Cks2/Xe-p9-CDK-CycB to phosphorylate and displace the APC1 autoinhibitory loop, generating active APC/C-Cdc20.","evidence":"Systematic loop-deletion mutagenesis and APC/C activity assays in Xenopus egg extracts; cryo-EM of S. cerevisiae APC/C (preprint)","pmids":["38776225","bio_10.1101_2024.06.19.599685"],"confidence":"High","gaps":["Quantitative contribution of the Apc8 loop versus the Apc3 loop in vivo not separated","Yeast versus human autoinhibition differences imply species-specific regulation requiring reconciliation"]},{"year":null,"claim":"How CDC23's substrate-docking (D-box), kinase-recruitment, and autoinhibition-relief functions are integrated and temporally coordinated during a single mitotic activation cycle remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of CDC23 simultaneously engaging a D-box substrate and the Cks2-CDK module","Mechanistic basis of the Rac association with the APC/C is uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[8,11]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5,6,11]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,9]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1,8,11]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[8,11]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[10]}],"complexes":["APC/C (anaphase-promoting complex/cyclosome)"],"partners":["CDC27","PLK1/PLO1","CDC20","CKS2","RAC1","SIN1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UJX2","full_name":"Cell division cycle protein 23 homolog","aliases":["Anaphase-promoting complex subunit 8","APC8","Cyclosome subunit 8"],"length_aa":597,"mass_kda":68.8,"function":"Component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of the cell cycle (PubMed:18485873). The APC/C complex acts by mediating ubiquitination and subsequent degradation of target proteins: it mainly mediates the formation of 'Lys-11'-linked polyubiquitin chains and, to a lower extent, the formation of 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains (PubMed:18485873). The APC/C complex catalyzes assembly of branched 'Lys-11'-/'Lys-48'-linked branched ubiquitin chains on target proteins (PubMed:29033132)","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q9UJX2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/CDC23","classification":"Common 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SUBUNIT 10; ANAPC10","url":"https://www.omim.org/entry/613745"},{"mim_id":"609110","title":"F-BOX ONLY PROTEIN 43; FBXO43","url":"https://www.omim.org/entry/609110"},{"mim_id":"603462","title":"CELL DIVISION CYCLE 23; CDC23","url":"https://www.omim.org/entry/603462"},{"mim_id":"603461","title":"CELL DIVISION CYCLE 16; CDC16","url":"https://www.omim.org/entry/603461"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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Cdc23/Mcm10 in generating the ribonucleotide imprint at the mat1 locus in fission yeast.","date":"2019","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/30759238","citation_count":7,"is_preprint":false},{"pmid":"26960127","id":"PMC_26960127","title":"Data collection with a tailored X-ray beam size at 2.69 Å wavelength (4.6 keV): sulfur SAD phasing of Cdc23(Nterm).","date":"2016","source":"Acta crystallographica. Section D, Structural biology","url":"https://pubmed.ncbi.nlm.nih.gov/26960127","citation_count":6,"is_preprint":false},{"pmid":"37274472","id":"PMC_37274472","title":"CDC23 knockdown suppresses the proliferation, migration and invasion of liver cancer via the EMT process.","date":"2023","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/37274472","citation_count":5,"is_preprint":false},{"pmid":"38776225","id":"PMC_38776225","title":"The C-terminal disordered loop domain of Apc8 unlocks APC/C mitotic activation.","date":"2024","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/38776225","citation_count":2,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.06.19.599685","title":"A comparative study of the cryo-EM structures of  <i>S. cerevisiae</i>  and human anaphase-promoting complex/cyclosome (APC/C)","date":"2024-06-20","source":"bioRxiv","url":"https://doi.org/10.1101/2024.06.19.599685","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14068,"output_tokens":2950,"usd":0.043227,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10322,"output_tokens":3133,"usd":0.064967,"stage2_stop_reason":"end_turn"},"total_usd":0.108194,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1990,\n      \"finding\": \"CDC23 contains multiple copies of a novel 34-amino acid repeating motif (the TPR motif), which defines a family of proteins involved in mitosis and RNA synthesis. The TPR units are predicted to form amphipathic alpha-helical regions punctuated by proline-induced turns.\",\n      \"method\": \"Sequence analysis, quantitative motif identification\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 (structural/sequence analysis) / Moderate — foundational structural characterization, but purely computational/sequence-based without in vitro functional validation\",\n      \"pmids\": [\"2404612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Yeast Cdc23 (as an APC/C component) is required for the degradation of Cdc20 during S phase and early mitosis; Cdc20 instability during S phase and mitosis depends on CDC23 and CDC27 but is not mediated by the Cdc20 destruction box.\",\n      \"method\": \"Genetic analysis, cell cycle protein stability assays in S. cerevisiae mutants\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with defined substrate phenotype, single lab\",\n      \"pmids\": [\"9651679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Human CDC23 encodes a 591-amino acid TPR-repeat protein (9 TPR units) that is a subunit of the human APC/C, mapping to chromosome 5q31, with 30% identity and 51% similarity to S. cerevisiae CDC23.\",\n      \"method\": \"cDNA cloning, genomic structure analysis, sequence homology\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cDNA cloning and structural characterization of human protein, single lab\",\n      \"pmids\": [\"9790767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Fission yeast Cut23 (APC8 ortholog) is a subunit of the APC/cyclosome required for metaphase-anaphase transition; Cut23's TPR repeat domain mediates its function, and its protein level fluctuates during the cell cycle (possibly ubiquitinated and degraded in a cell-cycle-dependent fashion). Cut23 may not be a stable core component of the APC/cyclosome.\",\n      \"method\": \"Temperature-sensitive mutant screen, sucrose gradient centrifugation, cell biology assays in S. pombe\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical fractionation and genetic analysis, single lab\",\n      \"pmids\": [\"10526233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Yeast CDC23 directly interacts with the SIN1 nuclear protein via CDC23's TPR repeats; the N-terminal domain of SIN1 is sufficient to bind the TPR-containing portion of CDC23 in vitro.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding with recombinant proteins\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two-hybrid plus in vitro pulldown, single lab\",\n      \"pmids\": [\"8710860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The destruction box (D box) of the mitotic cyclin Clb2 directly interacts with the APC/C subunit Cdc23 but not with five other APC/C subunits tested; mutations in the Clb2 D box abolish this interaction both in vivo (two-hybrid) and in vitro, providing the first evidence for direct substrate-APC/C subunit interaction.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding assay, D-box mutagenesis\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two-hybrid plus in vitro pulldown with mutagenesis, single lab\",\n      \"pmids\": [\"12413490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Fission yeast Plo1 (polo-like kinase) physically interacts with the APC/cyclosome through the noncatalytic polo-box domain of Plo1 and the TPR domain of Cut23/Apc8; a cut23 mutation specifically disrupting this interaction causes metaphase arrest that is rescued by high Plo1 expression, indicating this interaction is required for mitotic progression.\",\n      \"method\": \"Co-immunoprecipitation, genetic epistasis, overexpression rescue in S. pombe\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, domain mapping, specific separation-of-function mutation, and genetic rescue in a single study\",\n      \"pmids\": [\"11777938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Human CDC23 (APC component) forms a complex with the small GTPase Rac (Rac1, Rac2, Rac3) in mammalian cell lysates, suggesting Rac may regulate specific APC-dependent proteolytic processes through directed subcellular localization.\",\n      \"method\": \"Co-immunoprecipitation in mammalian cells\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP, single lab, no functional follow-up on the CDC23 interaction specifically\",\n      \"pmids\": [\"11445862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Knockdown of CDC23 in human thyroid cancer cells causes accumulation of cyclin B1 and securin, and arrest in S and G2/M phases; the effect on proliferation and cell cycle is reversed by triple knockdown of CDC23, cyclin B1, and securin, placing CDC23 upstream of cyclin B1 and securin degradation in controlling cell cycle progression.\",\n      \"method\": \"siRNA knockdown, cell cycle analysis, western blot, triple knockdown epistasis in human cancer cells\",\n      \"journal\": \"Endocrine-related cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis by triple knockdown with defined substrates, single lab\",\n      \"pmids\": [\"21990323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Crystal structure of the N-terminal domain of Cdc23 (APC8/CDC23 subunit of human APC/C) was determined to 3.1 Å resolution by sulfur SAD phasing, revealing its structural organization.\",\n      \"method\": \"X-ray crystallography, sulfur SAD phasing\",\n      \"journal\": \"Acta crystallographica. Section D, Structural biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — crystal structure determined but functional validation not described in this abstract\",\n      \"pmids\": [\"26960127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Homozygous missense variants in CDC23 (p.Y329C and p.R330C) cause female infertility with oocyte maturation defects; p.Y329C decreases CDC23 protein level, while p.R330C changes CDC23 subcellular localization in HeLa cells and mouse oocytes. Knock-in mice (Cdc23Y329C/Y329C) accumulate securin and cyclin B1 in oocytes, and this phenotype is rescued by AZ3146 (Mps1 inhibitor) treatment.\",\n      \"method\": \"Patient variant identification, in vitro mutagenesis, subcellular localization imaging, knock-in mouse model, western blot for APC/C substrates, pharmacological rescue\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods including patient variants, cellular localization, knock-in mouse model, substrate accumulation analysis, and pharmacological rescue\",\n      \"pmids\": [\"37768355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The C-terminal disordered loop domain of Apc8 (CDC23 ortholog) directly recruits the CDK adaptor protein Xe-p9/Cks2, positioning the Xe-p9-CDK-CycB complex near the Apc1-300L autoinhibitory loop. This stimulates phosphorylation and removal of Apc1-300L, prompting formation of active APC/C-Cdc20. Without both Apc8-L and Apc3-L, APC/C is rendered inactive during mitosis.\",\n      \"method\": \"Systematic loop-deletion mutagenesis of APC/C, functional APC/C activity assays, Xenopus egg extract system\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution-based mutagenesis with multiple deletion mutants, defined biochemical mechanism, multiple orthogonal experiments in a single study\",\n      \"pmids\": [\"38776225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM structures of S. cerevisiae APC/C reveal that the CDC20 C-box binding site on APC8 (Cdc23) is not blocked by a phospho-regulatable auto-inhibitory segment of APC1 (in contrast to human APC/C), indicating distinct regulatory mechanisms between yeast and human APC/C despite overall conserved architecture.\",\n      \"method\": \"Cryo-EM structure determination of S. cerevisiae APC/C complexes\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — cryo-EM structure with mechanistic comparison, preprint, single study\",\n      \"pmids\": [\"bio_10.1101_2024.06.19.599685\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"CDC23/APC8 is a TPR-repeat-containing core structural subunit of the APC/C E3 ubiquitin ligase that directly contacts APC/C substrates (via D-box interactions), recruits activating kinase complexes (CDK-CycB via Cks2/Xe-p9 through its C-terminal disordered loop) to relieve APC1-mediated autoinhibition and activate APC/C-Cdc20 during mitosis, interacts with polo-like kinase through its TPR domain to promote mitotic progression, and controls the timely degradation of cyclin B1 and securin to drive the metaphase-to-anaphase transition and complete oocyte maturation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CDC23 (APC8) is a tetratricopeptide-repeat (TPR) subunit of the anaphase-promoting complex/cyclosome (APC/C) E3 ubiquitin ligase that drives mitotic and meiotic cell-cycle progression by promoting the timely destruction of cyclin B1 and securin [#0, #8]. Its TPR domain serves as a protein-protein interaction surface: it directly binds the destruction box of mitotic cyclin substrates, providing direct substrate-APC/C contact [#5], and it recruits polo-like kinase via the kinase's polo-box domain to enable mitotic progression [#6]. CDC23 also contributes to APC/C activation: its C-terminal disordered loop recruits the CDK adaptor Cks2/Xe-p9 together with CDK-CycB, positioning the kinase to phosphorylate and remove the APC1 autoinhibitory loop and thereby generate active APC/C-Cdc20 [#11], and APC8 carries the CDC20 C-box binding site within the complex [#12]. Loss of CDC23 in human cells causes accumulation of cyclin B1 and securin with S and G2/M arrest [#8]. Homozygous missense variants (p.Y329C, p.R330C) cause female infertility with oocyte maturation defects, with the knock-in oocytes accumulating securin and cyclin B1 [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 1990,\n      \"claim\": \"Established that CDC23 is built from a repeating 34-residue motif (the TPR), defining a structural module shared among mitotic and RNA-synthesis proteins and predicting an alpha-helical protein-interaction scaffold.\",\n      \"evidence\": \"Sequence and motif analysis identifying multiple TPR units\",\n      \"pmids\": [\"2404612\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Purely computational; no functional validation of the TPR units\", \"Does not assign a biochemical activity to the repeats\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Showed the TPR repeats function as a protein-interaction surface by demonstrating direct binding to the nuclear protein SIN1, the first defined CDC23 partner.\",\n      \"evidence\": \"Yeast two-hybrid and in vitro binding with recombinant proteins in S. cerevisiae\",\n      \"pmids\": [\"8710860\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the SIN1 interaction for APC/C activity not established\", \"Single lab, no structural detail of the interface\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Placed CDC23 functionally within the APC/C and linked it to substrate degradation by showing its requirement for Cdc20 turnover during S phase and early mitosis.\",\n      \"evidence\": \"Genetic analysis and protein stability assays in S. cerevisiae mutants; cDNA cloning of the human ortholog\",\n      \"pmids\": [\"9651679\", \"9790767\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of Cdc20 destabilization independent of its destruction box unclear\", \"Direct versus indirect role of CDC23 in this turnover not resolved\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Confirmed the APC8 ortholog (Cut23) is required for the metaphase-anaphase transition and that the TPR domain mediates this function, while raising the question of whether it is a stable core subunit.\",\n      \"evidence\": \"Temperature-sensitive mutant screen and sucrose gradient fractionation in S. pombe\",\n      \"pmids\": [\"10526233\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and stability of Cut23 within the complex left ambiguous\", \"Cell-cycle ubiquitination of Cut23 inferred but not directly demonstrated\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identified CDC23 as the direct substrate-docking subunit by showing the mitotic cyclin destruction box binds CDC23 specifically among APC/C subunits, and established a polo-kinase recruitment role required for mitotic progression.\",\n      \"evidence\": \"Two-hybrid and in vitro binding with D-box mutagenesis (Clb2); reciprocal Co-IP, domain mapping, and separation-of-function mutant rescue (Plo1/Cut23) in S. pombe\",\n      \"pmids\": [\"12413490\", \"11777938\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of D-box recognition by the TPR domain not defined\", \"How polo-kinase binding mechanistically promotes anaphase onset unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined CDC23's cellular role in human cells as acting upstream of cyclin B1 and securin destruction to permit cell-cycle progression.\",\n      \"evidence\": \"siRNA knockdown with triple-knockdown epistasis and substrate western blots in human thyroid cancer cells\",\n      \"pmids\": [\"21990323\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not distinguish direct catalytic contribution from scaffolding within APC/C\", \"Generality beyond thyroid cancer cells not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided atomic-level structural information on the N-terminal domain of human CDC23.\",\n      \"evidence\": \"X-ray crystallography at 3.1 Å by sulfur SAD phasing\",\n      \"pmids\": [\"26960127\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional interpretation of the structure not described\", \"Full-length and complex-bound conformations not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected CDC23 to human disease, establishing that point mutations causing reduced protein level or mislocalization cause oocyte maturation failure and female infertility via APC/C substrate accumulation.\",\n      \"evidence\": \"Patient variant identification, localization imaging, knock-in mouse model with substrate analysis, and Mps1-inhibitor pharmacological rescue\",\n      \"pmids\": [\"37768355\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why p.R330C alters localization at the molecular level not defined\", \"Whether spindle-checkpoint (Mps1) hyperactivation is the sole downstream cause unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a mechanistic activation role: the CDC23/Apc8 C-terminal disordered loop recruits Cks2/Xe-p9-CDK-CycB to phosphorylate and displace the APC1 autoinhibitory loop, generating active APC/C-Cdc20.\",\n      \"evidence\": \"Systematic loop-deletion mutagenesis and APC/C activity assays in Xenopus egg extracts; cryo-EM of S. cerevisiae APC/C (preprint)\",\n      \"pmids\": [\"38776225\", \"bio_10.1101_2024.06.19.599685\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution of the Apc8 loop versus the Apc3 loop in vivo not separated\", \"Yeast versus human autoinhibition differences imply species-specific regulation requiring reconciliation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CDC23's substrate-docking (D-box), kinase-recruitment, and autoinhibition-relief functions are integrated and temporally coordinated during a single mitotic activation cycle remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of CDC23 simultaneously engaging a D-box substrate and the Cks2-CDK module\", \"Mechanistic basis of the Rac association with the APC/C is uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [8, 11]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5, 6, 11]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 8, 11]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [8, 11]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"complexes\": [\"APC/C (anaphase-promoting complex/cyclosome)\"],\n    \"partners\": [\"CDC27\", \"PLK1/Plo1\", \"CDC20\", \"CKS2\", \"RAC1\", \"SIN1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":2,"faith_total":5,"faith_pct":40.0}}