Affinage

CDC23

Cell division cycle protein 23 homolog · UniProt Q9UJX2

Round 2 corrected
Length
597 aa
Mass
68.8 kDa
Annotated
2026-04-28
56 papers in source corpus 16 papers cited in narrative 16 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CDC23 (APC8) is a TPR-repeat-containing core structural subunit of the anaphase-promoting complex/cyclosome (APC/C), the essential E3 ubiquitin ligase that drives mitotic progression by targeting cyclins and securin for proteasomal degradation (PMID:2404612, PMID:9790767, PMID:18485873). CDC23 undergoes CDK1-mediated mitotic phosphorylation that promotes Cdc20 binding and APC/C activation, and its C-terminal disordered loop recruits the CDK adaptor Cks2 to stimulate phosphorylation of the Apc1 autoinhibitory loop, synergizing with the Cdc27 loop for full activation (PMID:14657031, PMID:38776225). The TPR domain of CDC23 mediates interaction with polo-like kinase required for metaphase-to-anaphase transition and directly contacts the destruction box of the mitotic cyclin Clb2, linking it to substrate recognition (PMID:11777938, PMID:12413490). Homozygous missense variants in CDC23 (p.Y329C, p.R330C) cause female infertility through oocyte maturation arrest associated with reduced APC/C subunit levels and accumulation of securin and cyclin B1 (PMID:37768355).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 1990 High

    Identification of the TPR motif in CDC23 established a structural framework for understanding how a repetitive α-helical fold could underpin protein-protein interactions in cell cycle regulators.

    Evidence Quantitative sequence analysis and cloning of yeast CDC23 revealing iterated 34-amino acid repeats

    PMID:2205535 PMID:2404612

    Open questions at the time
    • No functional assay linking TPR repeats to APC/C activity
    • Mammalian homolog not yet cloned
  2. 1998 High

    Cloning of human CDC23 and its assignment as an APC/C subunit, combined with genetic evidence that Cdc23 controls Cdc20 degradation, placed CDC23 within the ubiquitin-dependent cell cycle machinery.

    Evidence cDNA cloning and Northern blot of human CDC23; genetic stability assays in S. cerevisiae showing Cdc23/Cdc27-dependent, D-box-independent Cdc20 turnover

    PMID:9651679 PMID:9790767

    Open questions at the time
    • Mechanism of D-box-independent Cdc20 degradation unknown
    • Physical interaction between CDC23 and substrates not yet shown
  3. 2002 Medium

    Demonstration that CDC23's TPR domain directly contacts the destruction box of cyclin Clb2 and interacts with polo-like kinase revealed dual roles in substrate recognition and mitotic signaling.

    Evidence Yeast two-hybrid and in vitro binding with D-box mutants (Clb2); reciprocal Co-IP and genetic rescue of cut23-Plo1 interaction in fission yeast

    PMID:11777938 PMID:12413490

    Open questions at the time
    • Substrate selectivity mechanism (why Clb2 but not other cyclins) unresolved
    • Whether the Plk and substrate-binding surfaces on the TPR domain overlap is unknown
  4. 2003 High

    Mass spectrometry-based phosphosite mapping showed that CDC23 is heavily phosphorylated by CDK1 during mitosis, and CDK1 phosphorylation suffices for Cdc20 binding, establishing the kinase-driven activation switch for the APC/C.

    Evidence MS phosphoproteomics on purified human APC/C; in vitro CDK1 and Plk1 kinase assays coupled to Cdc20 binding

    PMID:14657031

    Open questions at the time
    • Contribution of individual CDC23 phosphosites versus other TPR subunits not dissected
    • In vivo validation of phosphosite requirements lacking
  5. 2011 Medium

    Functional knockdown in human cells demonstrated that CDC23 is required for cyclin B1 and securin turnover, and epistasis experiments confirmed these substrates mediate the cell cycle arrest phenotype.

    Evidence siRNA knockdown of CDC23 in thyroid cancer cells with flow cytometry and triple-knockdown rescue of proliferation

    PMID:21990323

    Open questions at the time
    • Performed in a single cancer cell line
    • Whether CDC23 depletion affects APC/C integrity versus catalytic activity not distinguished
  6. 2016 Medium

    Determination of the crystal structure of the CDC23 N-terminal TPR domain provided the first atomic-resolution view of this APC/C scaffold subunit.

    Evidence X-ray crystallography at 3.1 Å using sulfur SAD phasing of human Cdc23 N-terminal domain

    PMID:26960127

    Open questions at the time
    • Only N-terminal domain resolved; full-length structure in APC/C context not obtained at this resolution
    • No structure-function mutagenesis reported
  7. 2023 High

    Identification of CDC23 loss-of-function variants as a cause of human female infertility linked oocyte maturation defects to impaired APC/C-mediated securin and cyclin B1 degradation, with pharmacological rescue confirming the pathway.

    Evidence Patient homozygous missense variants (Y329C, R330C), Cdc23 knock-in mouse model, western blot for APC subunit levels, AZ3146 rescue

    PMID:37768355

    Open questions at the time
    • Only two families studied
    • How decreased CDC23 protein level secondarily reduces APC4 not mechanistically explained
  8. 2024 High

    Biochemical reconstitution revealed that the CDC23 C-terminal disordered loop recruits Cks2 to position CDK-cyclin B for Apc1 autoinhibitory loop phosphorylation, defining the molecular logic of mitotic APC/C activation.

    Evidence Systematic loop-deletion mutagenesis of APC/C subunits with reconstituted activation assays

    PMID:38776225

    Open questions at the time
    • Structural basis of Cks2 recruitment to the Apc8 loop not determined at atomic resolution
    • Whether this mechanism operates identically in oocytes versus somatic cells is untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • The relative contributions of CDC23's multiple interaction surfaces (substrate D-box binding, Plk docking, Cks2 recruitment) to APC/C function in different cell types and developmental contexts remain to be dissected, and a complete high-resolution structure of the CDC23 C-terminal loop within the APC/C is lacking.
  • No structural model of the full-length CDC23 C-terminal disordered loop bound to Cks2
  • Cell-type-specific requirements for CDC23-mediated APC/C activation not systematically tested
  • Whether the Rac-CDC23 interaction has physiological relevance is unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 3 GO:0060090 molecular adaptor activity 1
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-1640170 Cell Cycle 5 R-HSA-392499 Metabolism of proteins 2 R-HSA-1474165 Reproduction 1
Partners
APC1CDC20CDC27CKS2CLB2PLK1
Complex memberships
APC/C

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1990 CDC23 encodes a protein containing a novel repeating 34-amino acid motif (the TPR motif) reiterated several times; this motif defines a new family of proteins shared among genes required for mitosis and RNA synthesis, and is predicted to consist of amphipathic alpha-helical regions punctuated by proline-induced turns. Quantitative sequence analysis, cloning and characterization of CDC23 gene Cell High 2404612
1990 The CDC23 gene of S. cerevisiae encodes a protein of 626 amino acids with four contiguous TPR repeats and a potential Ca2+-binding site near its N-terminus, expressed as a 2.4–2.5 kb transcript. Cloning, nucleotide sequencing, and ORF analysis Gene Medium 2205535
1996 Yeast CDC23 directly interacts with the nuclear protein SIN1 (a transcriptional repressor involved in mitotic chromosome segregation); the N-terminus of SIN1 is sufficient to bind the TPR repeat domains of CDC23 in vitro. Yeast two-hybrid system, in vitro binding with recombinant proteins Proceedings of the National Academy of Sciences of the United States of America Medium 8710860
1998 Human CDC23 encodes a 591-amino acid, 68.3 kDa protein with 9 TPR units, mapping to chromosome 5q31; it is a component of the anaphase-promoting complex (APC/C), ubiquitously expressed, with 30% identity and 51% similarity to S. cerevisiae Cdc23. cDNA cloning, genomic mapping, sequence analysis, Northern blot Genomics Medium 9790767
1998 The APC/C subunits Cdc23 and Cdc27 are required for the degradation of the APC activator Cdc20 during S phase and early mitosis; this degradation occurs through a mechanism that does not depend on the Cdc20 destruction box, revealing a D-box-independent proteolytic pathway mediated by these APC components. Genetic analysis in S. cerevisiae, cell cycle protein stability assays, mutant analysis Current biology : CB High 9651679
1999 Fission yeast Cut23 (the S. pombe homolog of Cdc23/APC8) is identified as a subunit of the APC/cyclosome; it contains TPR repeats, its levels fluctuate during the cell cycle (possibly regulated by ubiquitination and degradation), and it is required for metaphase-anaphase progression. Cut23 interacts with polo kinase Plo1 through its TPR domain. Temperature-sensitive mutant screen, sucrose gradient centrifugation, genetic analysis Genes to cells : devoted to molecular & cellular mechanisms Medium 10526233
2001 The small GTPase Rac forms a complex with the APC component CDC23 in mammalian cell lysates, suggesting that activated Rac may regulate APC/C function or subcellular localization through direct interaction with CDC23. Co-immunoprecipitation from mammalian cell lysates, yeast two-hybrid International journal of molecular medicine Low 11445862
2002 The APC/C subunit Cdc23 directly interacts with the destruction box (D-box) of the mitotic cyclin Clb2, but not with D-boxes of Clb1, Clb3, or Clb5; mutations in the Clb2 D-box inhibit interaction with Cdc23 both in vivo and in vitro, providing the first evidence for direct APC/C substrate recognition by a specific APC subunit. Yeast two-hybrid, in vitro binding assay, D-box mutant analysis Archives of biochemistry and biophysics Medium 12413490
2002 Fission yeast polo-like kinase Plo1 physically interacts with the APC/cyclosome through the noncatalytic polo-box domain of Plo1 and the TPR domain of Cut23 (APC8/Cdc23 homolog); a cut23 mutation that specifically disrupts the Plo1 interaction causes metaphase arrest that can be rescued by high Plo1 expression, indicating this interaction is required for mitotic progression. Co-immunoprecipitation, genetic analysis with cut23 separation-of-function mutation, rescue by Plo1 overexpression The Journal of cell biology High 11777938
2003 Mitotic phosphorylation of the human APC/C occurs on at least 43 sites, with 32 sites clustered in Apc1 and the TPR subunits Cdc27, Cdc16, Cdc23, and Apc7; at least 15 mitosis-specific sites are generated by CDK1 and 3 by Plk1 in vitro. CDK1-mediated APC phosphorylation (but not Plk1) is sufficient for increased Cdc20 binding and APC activation. Mass spectrometry phosphoproteomics, in vitro kinase assays with CDK1 and Plk1, Cdc20 binding assays The EMBO journal High 14657031
2008 The human APC/C assembles K11-linked ubiquitin chains on substrates; the TEK-box surface of ubiquitin, homologous to motifs in APC/C substrates, enables the APC/C to switch from substrate lysines to ubiquitin lysines during chain elongation. CDC23 (as part of the APC/C) participates in this ubiquitin chain assembly mechanism. In vitro ubiquitination assays, ubiquitin chain topology analysis, mutagenesis Cell High 18485873
2011 Functional knockdown of CDC23 in human thyroid cancer cells causes accumulation of cells in S and G2/M phases, inhibits proliferation, tumor spheroid formation, and anchorage-independent growth, with significant accumulation of cyclin B1 and securin protein; triple knockdown of CDC23, cyclin B1, and securin reverses the proliferation and cell cycle effects, placing CDC23 upstream of cyclin B1 and securin degradation. siRNA knockdown, cell cycle analysis by flow cytometry, western blotting, triple knockdown rescue experiment, in vitro proliferation and colony assays Endocrine-related cancer Medium 21990323
2016 The crystal structure of the N-terminal domain of human Cdc23 (Cdc23(Nterm)), a subunit of the APC/C, was determined by sulfur SAD phasing to 3.1 Å resolution, providing structural insight into the TPR-containing APC/C subunit. 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 alters CDC23 localization in HeLa cells and mouse oocytes. Knock-in mice (Cdc23Y329C/Y329C) show low CDC23 and APC4 levels and accumulation of securin and cyclin B1 in oocytes; treatment with AZ3146 (a Mps1 kinase inhibitor) rescues the phenotype. Patient variant identification, in vitro expression assays, immunofluorescence localization, knock-in mouse model, western blotting, pharmacological rescue Human genetics High 37768355
2024 The C-terminal disordered loop of APC8 (Cdc23 homolog) directly recruits the CDK adaptor protein Xe-p9/Cks2, positioning the CDK-cyclin B complex near the autoinhibitory Apc1-300L loop; this stimulates phosphorylation and removal of Apc1-300L to form active APC/C-Cdc20. Apc8-L acts synergistically with Apc3-L (Cdc27 loop) for full mitotic APC/C activation. Systematic loop-deletion mutant analysis of APC/C, biochemical reconstitution, protein interaction assays Cell reports High 38776225
2024 Comparative cryo-EM structures of S. cerevisiae APC/C reveal that APC8 (Cdc23) contributes to overall scaffold architecture; unlike in human APC/C where the CDC20 C-box binding site of APC8 is sterically blocked by the phospho-regulatable Apc1 autoinhibitory segment, S. cerevisiae APC/C shows no evidence of this autoinhibitory segment blocking APC8, indicating species-specific differences in coactivator-mediated APC/C activation mechanisms. Cryo-EM structure determination of multiple S. cerevisiae APC/C complexes, comparative structural analysis with human APC/C bioRxivpreprint Medium bio_10.1101_2024.06.19.599685

Source papers

Stage 0 corpus · 56 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
2005 Towards a proteome-scale map of the human protein-protein interaction network. Nature 2090 16189514
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2006 A probability-based approach for high-throughput protein phosphorylation analysis and site localization. Nature biotechnology 1336 16964243
2004 Large-scale characterization of HeLa cell nuclear phosphoproteins. Proceedings of the National Academy of Sciences of the United States of America 1159 15302935
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2001 Checkpoint inhibition of the APC/C in HeLa cells is mediated by a complex of BUBR1, BUB3, CDC20, and MAD2. The Journal of cell biology 726 11535616
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1994 Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. Gene 492 8125298
2015 Widespread macromolecular interaction perturbations in human genetic disorders. Cell 454 25910212
2008 Mechanism of ubiquitin-chain formation by the human anaphase-promoting complex. Cell 442 18485873
2011 SIRT2 maintains genome integrity and suppresses tumorigenesis through regulating APC/C activity. Cancer cell 441 22014574
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
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 438 2404612
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2016 Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing. Cell 423 26871637
2010 Systematic analysis of human protein complexes identifies chromosome segregation proteins. Science (New York, N.Y.) 421 20360068
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2001 Anaphase-promoting complex/cyclosome-dependent proteolysis of human cyclin A starts at the beginning of mitosis and is not subject to the spindle assembly checkpoint. The Journal of cell biology 372 11285280
2000 Mitotic regulation of the APC activator proteins CDC20 and CDH1. Molecular biology of the cell 363 10793135
2000 Characterization of vertebrate cohesin complexes and their regulation in prophase. The Journal of cell biology 358 11076961
2003 Mitotic regulation of the human anaphase-promoting complex by phosphorylation. The EMBO journal 341 14657031
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2004 Phosphoproteomic analysis of the developing mouse brain. Molecular & cellular proteomics : MCP 291 15345747
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 41 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