Affinage

Showing CDC23 — ANAPC8 is a alias.

CDC23

Cell division cycle protein 23 homolog · UniProt Q9UJX2

Length
597 aa
Mass
68.8 kDa
Annotated
2026-06-09
26 papers in source corpus 13 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 2/5 claims corpus-supported (40%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1990 Medium

    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

    PMID:2404612

    Open questions at the time
    • Purely computational; no functional validation of the TPR units
    • Does not assign a biochemical activity to the repeats
  2. 1996 Medium

    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

    PMID:8710860

    Open questions at the time
    • Functional consequence of the SIN1 interaction for APC/C activity not established
    • Single lab, no structural detail of the interface
  3. 1998 Medium

    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

    PMID:9651679 PMID:9790767

    Open questions at the time
    • Mechanism of Cdc20 destabilization independent of its destruction box unclear
    • Direct versus indirect role of CDC23 in this turnover not resolved
  4. 1999 Medium

    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

    PMID:10526233

    Open questions at the time
    • Stoichiometry and stability of Cut23 within the complex left ambiguous
    • Cell-cycle ubiquitination of Cut23 inferred but not directly demonstrated
  5. 2002 High

    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

    PMID:11777938 PMID:12413490

    Open questions at the time
    • Structural basis of D-box recognition by the TPR domain not defined
    • How polo-kinase binding mechanistically promotes anaphase onset unresolved
  6. 2011 Medium

    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

    PMID:21990323

    Open questions at the time
    • Does not distinguish direct catalytic contribution from scaffolding within APC/C
    • Generality beyond thyroid cancer cells not tested
  7. 2016 Medium

    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

    PMID:26960127

    Open questions at the time
    • Functional interpretation of the structure not described
    • Full-length and complex-bound conformations not resolved
  8. 2023 High

    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

    PMID:37768355

    Open questions at the time
    • Why p.R330C alters localization at the molecular level not defined
    • Whether spindle-checkpoint (Mps1) hyperactivation is the sole downstream cause unclear
  9. 2024 High

    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)

    PMID:38776225 PMID:bio_10.1101_2024.06.19.599685

    Open questions at the time
    • 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

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0005198 structural molecule activity 2 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005634 nucleus 1
Pathway
R-HSA-1640170 Cell Cycle 3 R-HSA-392499 Metabolism of proteins 2 R-HSA-1474165 Reproduction 1
Partners
CDC20CDC27CKS2PLK1/PLO1RAC1SIN1
Complex memberships
APC/C (anaphase-promoting complex/cyclosome)

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1990 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. Sequence analysis, quantitative motif identification Cell Medium 2404612
1998 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. Genetic analysis, cell cycle protein stability assays in S. cerevisiae mutants Current biology : CB Medium 9651679
1998 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. cDNA cloning, genomic structure analysis, sequence homology Genomics Medium 9790767
1999 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. Temperature-sensitive mutant screen, sucrose gradient centrifugation, cell biology assays in S. pombe Genes to cells : devoted to molecular & cellular mechanisms Medium 10526233
1996 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. Yeast two-hybrid, in vitro binding with recombinant proteins Proceedings of the National Academy of Sciences of the United States of America Medium 8710860
2002 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. Yeast two-hybrid, in vitro binding assay, D-box mutagenesis Archives of biochemistry and biophysics Medium 12413490
2002 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. Co-immunoprecipitation, genetic epistasis, overexpression rescue in S. pombe The Journal of cell biology High 11777938
2001 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. Co-immunoprecipitation in mammalian cells International journal of molecular medicine Low 11445862
2011 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. siRNA knockdown, cell cycle analysis, western blot, triple knockdown epistasis in human cancer cells Endocrine-related cancer Medium 21990323
2016 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. X-ray crystallography, sulfur SAD phasing Acta crystallographica. Section D, Structural biology Medium 26960127
2023 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. Patient variant identification, in vitro mutagenesis, subcellular localization imaging, knock-in mouse model, western blot for APC/C substrates, pharmacological rescue Human genetics High 37768355
2024 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. Systematic loop-deletion mutagenesis of APC/C, functional APC/C activity assays, Xenopus egg extract system Cell reports High 38776225
2024 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. Cryo-EM structure determination of S. cerevisiae APC/C complexes bioRxivpreprint Medium bio_10.1101_2024.06.19.599685

Source papers

Stage 0 corpus · 26 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1990 A repeating amino acid motif in CDC23 defines a family of proteins and a new relationship among genes required for mitosis and RNA synthesis. Cell 440 2404612
1998 The regulation of Cdc20 proteolysis reveals a role for APC components Cdc23 and Cdc27 during S phase and early mitosis. Current biology : CB 197 9651679
2003 Fission yeast Cdc23/Mcm10 functions after pre-replicative complex formation to promote Cdc45 chromatin binding. Molecular biology of the cell 89 12972571
2003 The Cdc23 (Mcm10) protein is required for the phosphorylation of minichromosome maintenance complex by the Dfp1-Hsk1 kinase. Proceedings of the National Academy of Sciences of the United States of America 73 12604790
2017 GmILPA1, Encoding an APC8-like Protein, Controls Leaf Petiole Angle in Soybean. Plant physiology 49 28336772
2001 Characterization of Schizosaccharomyces pombe mcm7(+) and cdc23(+) (MCM10) and interactions with replication checkpoints. Genetics 42 11606526
2005 Nuclear distribution and chromatin association of DNA polymerase alpha-primase is affected by TEV protease cleavage of Cdc23 (Mcm10) in fission yeast. BMC molecular biology 36 15941470
1999 Fission yeast APC/cyclosome subunits, Cut20/Apc4 and Cut23/Apc8, in regulating metaphase-anaphase progression and cellular stress responses. Genes to cells : devoted to molecular & cellular mechanisms 34 10526233
1998 The essential schizosaccharomyces pombe cdc23 DNA replication gene shares structural and functional homology with the Saccharomyces cerevisiae DNA43 (MCM10) gene. Current genetics 32 9745018
2002 Fission yeast Cdc23 interactions with DNA replication initiation proteins. Current genetics 31 12185500
2018 Silencing of lncRNA LINC00514 inhibits the malignant behaviors of papillary thyroid cancer through miR-204-3p/CDC23 axis. Biochemical and biophysical research communications 30 30553447
2002 Polo boxes and Cut23 (Apc8) mediate an interaction between polo kinase and the anaphase-promoting complex for fission yeast mitosis. The Journal of cell biology 28 11777938
1998 Human CDC23: cDNA cloning, mapping to 5q31, genomic structure, and evaluation as a candidate tumor suppressor gene in myeloid leukemias. Genomics 24 9790767
2011 CDC23 regulates cancer cell phenotype and is overexpressed in papillary thyroid cancer. Endocrine-related cancer 22 21990323
2004 Caenorhabditis elegans lin-35/Rb, efl-1/E2F and other synthetic multivulva genes negatively regulate the anaphase-promoting complex gene mat-3/APC8. Genetics 17 15238519
2002 The destruction box of the cyclin Clb2 binds the anaphase-promoting complex/cyclosome subunit Cdc23. Archives of biochemistry and biophysics 14 12413490
2006 The CENP-B homolog, Abp1, interacts with the initiation protein Cdc23 (MCM10) and is required for efficient DNA replication in fission yeast. Cell division 13 17112379
2001 The small GTPase Rac interacts with ubiquitination complex proteins Cullin-1 and CDC23. International journal of molecular medicine 13 11445862
1996 Association of yeast SIN1 with the tetratrico peptide repeats of CDC23. Proceedings of the National Academy of Sciences of the United States of America 11 8710860
2023 Homozygous variants in CDC23 cause female infertility characterized by oocyte maturation defects. Human genetics 9 37768355
2024 Molecular Regulation of Porcine Skeletal Muscle Development: Insights from Research on CDC23 Expression and Function. International journal of molecular sciences 8 38612477
2019 Role of Cdc23/Mcm10 in generating the ribonucleotide imprint at the mat1 locus in fission yeast. Nucleic acids research 7 30759238
1990 Cloning and nucleotide sequence of the CDC23 gene of Saccharomyces cerevisiae. Gene 7 2205535
2016 Data collection with a tailored X-ray beam size at 2.69 Å wavelength (4.6 keV): sulfur SAD phasing of Cdc23(Nterm). Acta crystallographica. Section D, Structural biology 6 26960127
2023 CDC23 knockdown suppresses the proliferation, migration and invasion of liver cancer via the EMT process. Oncology letters 5 37274472
2024 The C-terminal disordered loop domain of Apc8 unlocks APC/C mitotic activation. Cell reports 2 38776225

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