Affinage

ANAPC10

Anaphase-promoting complex subunit 10 · UniProt Q9UM13

Length
185 aa
Mass
21.3 kDa
Annotated
2026-04-28
30 papers in source corpus 16 papers cited in narrative 16 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ANAPC10 (APC10/DOC1) is a conserved core subunit of the anaphase-promoting complex/cyclosome (APC/C) E3 ubiquitin ligase that functions as a substrate co-receptor essential for mitotic progression and regulated protein degradation. Together with the coactivator (Cdc20 or Cdh1), APC10 forms a bipartite D-box co-receptor within the APC/C inner cavity, directly contacting the destruction-box degron of substrates to enhance binding affinity and promote processive polyubiquitination of mitotic cyclins and other APC/C targets (PMID:21107322, PMID:12402045, PMID:12574115). APC10 anchors to the APC/C via its C-terminus binding to CDC27/APC3, while a distinct surface on its β-sandwich jellyroll fold mediates substrate recognition in a D-box-dependent manner (PMID:11524682, PMID:15649358). Disruption of APC10 in mouse causes the oligosyndactylism phenotype and a cell-autonomous metaphase-to-anaphase block, and genetic loss in yeast, Drosophila, and mammalian systems consistently results in mitotic arrest with accumulation of cyclin B substrates (PMID:11247669, PMID:9348530, PMID:18297794).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1997 High

    Identifying DOC1/APC10 as a component of the 20S APC/C required for mitotic cyclin proteolysis established that this gene encodes a subunit of the core cell-cycle ubiquitin ligase machinery.

    Evidence Genetic screen for mitotic arrest mutants in budding yeast with sucrose gradient co-sedimentation and in vivo cyclin degradation assays

    PMID:9348530

    Open questions at the time
    • No biochemical mechanism for how APC10 contributes to APC/C activity
    • No structural information
  2. 1998 High

    Demonstration that fission yeast Apc10 is essential for viability and required for B-type cyclin ubiquitination confirmed the conserved role of this subunit across divergent yeast species.

    Evidence Genetic mutant analysis, in vivo ubiquitination assays, and co-immunoprecipitation in S. pombe

    PMID:9736616

    Open questions at the time
    • Role in substrate recognition versus structural integrity of APC/C not distinguished
  3. 1999 High

    Biochemical identification of human APC10/DOC1 as a constitutive APC/C subunit extended the finding to mammals and defined the conserved DOC domain present in other ubiquitin-pathway proteins.

    Evidence Biochemical fractionation and mass spectrometry of purified human APC/C

    PMID:10318877

    Open questions at the time
    • No functional data in human cells
    • Subcellular dynamics during cell cycle not resolved
  4. 2001 High

    Crystal structure of human APC10 revealed a β-sandwich jellyroll fold and demonstrated that its C-terminus anchors to CDC27/APC3, providing the first structural framework for understanding APC10 within the APC/C.

    Evidence X-ray crystallography at 1.6 Å resolution with biochemical binding assays

    PMID:11524682

    Open questions at the time
    • Which surface of APC10 contacts substrates was unknown
    • No structure of APC10 in the context of the intact APC/C
  5. 2001 Medium

    Mapping the mouse oligosyndactylism (Os) mutation to disruption of Apc10/Doc1 demonstrated that APC10 is essential for the metaphase-to-anaphase transition in mammals.

    Evidence Genetic mapping and molecular characterization of three independent mouse alleles

    PMID:11247669

    Open questions at the time
    • No biochemical reconstitution of APC/C activity in these mutant cells
    • Cell-autonomous versus tissue-level contribution not fully resolved
  6. 2002 High

    Reconstitution experiments established that APC10/DOC1 is a processivity factor: APC lacking DOC1 exhibits greatly increased K_M for cyclin substrates, and recombinant DOC1 fully restores processive polyubiquitination.

    Evidence In vitro ubiquitination with purified budding yeast APC, kinetic analysis, and complementation with recombinant Doc1

    PMID:12402045

    Open questions at the time
    • Whether DOC1 directly contacts substrate or acts allosterically was unresolved
    • No identification of the substrate-binding surface
  7. 2003 High

    Demonstration that APC10 contributes to both D-box and KEN-box substrate recognition in a coactivator-dependent manner distinguished its substrate-binding role from the purely structural role of Apc9.

    Evidence Purified APC in vitro ubiquitylation and native gel substrate binding assays comparing APC lacking Doc1p versus Apc9p

    PMID:12574115

    Open questions at the time
    • Direct physical contact with D-box degron not yet demonstrated
    • Whether DOC1 forms a co-receptor with coactivator was hypothetical
  8. 2004 High

    Site-directed mutagenesis of Doc1 separated the C-terminal APC-anchoring function from a distinct substrate-recognition surface, demonstrating that D-box-dependent substrate binding maps to a conserved face of the β-sandwich.

    Evidence In vitro processivity assays, site-directed mutagenesis, in vivo cell cycle analysis in budding yeast

    PMID:15649358

    Open questions at the time
    • Atomic-resolution view of the DOC1–substrate interface not available
    • Relative contributions of coactivator and DOC1 to D-box affinity not quantified
  9. 2010 High

    Cryo-EM and NMR studies directly demonstrated that APC10 and the coactivator Cdh1 together form a bipartite D-box co-receptor within the central cavity of the APC/C, resolving the longstanding question of how DOC1 contacts substrate.

    Evidence Single-particle cryo-EM (~10 Å) of yeast APC/C-Cdh1 with D-box peptide plus NMR titration detecting specific D-box–Apc10 interactions; complemented by EM difference mapping showing substrate and DOC1 proximity to the cullin-RING module

    PMID:21107322 PMID:21186364

    Open questions at the time
    • High-resolution atomic model of D-box–APC10 interface not yet determined
    • Contribution to KEN-box recognition at structural level unresolved
  10. 2019 Medium

    Discovery that the pseudosubstrate inhibitor Acm1 suppresses APC/C partly by disrupting the Doc1/Apc10 interaction through an extended D-box motif redefined the D-box as a 12-residue element and revealed a regulatory mechanism targeting the DOC1 co-receptor.

    Evidence In vivo degradation assays, biochemical processivity analysis, and mutagenesis of the D-box C-terminal extension in budding yeast

    PMID:31562243

    Open questions at the time
    • Structural basis of extended D-box contact with APC10 not determined
    • Generality of extended D-box among other APC/C substrates unclear
  11. 2021 Medium

    APC10 was found to interact with NLRP3 in a cell-cycle-dependent manner, promoting inflammasome activation during interphase and dissociating during mitosis, suggesting a non-canonical role linking cell-cycle state to innate immune signaling.

    Evidence Co-immunoprecipitation and NLRP3 inflammasome activation assays with cell-cycle synchronization in human cells

    PMID:34407203

    Open questions at the time
    • Interaction not independently replicated
    • Whether effect on NLRP3 requires intact APC/C or is a moonlighting function of APC10 alone is unknown
    • No structural or domain-mapping data for the APC10–NLRP3 interface

Open questions

Synthesis pass · forward-looking unresolved questions
  • A high-resolution structure of the APC10–D-box interface at atomic detail, the mechanism by which APC10 contributes to KEN-box recognition, and independent validation of the APC10–NLRP3 interaction remain open questions.
  • No atomic-resolution co-structure of APC10 bound to a D-box peptide within the full APC/C
  • KEN-box contribution at structural level unresolved
  • Non-canonical interactions (NLRP3, Smad3) not replicated or structurally characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4
Localization
GO:0005634 nucleus 2 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-1640170 Cell Cycle 7 R-HSA-392499 Metabolism of proteins 4
Partners
APC1CDC16CDC20CDC27CDH1NLRP3SMAD3
Complex memberships
APC/C

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 DOC1/APC10 (budding yeast) was identified as a component of the 20S anaphase-promoting complex (APC/cyclosome) required for mitotic cyclin proteolysis; doc1 mutants arrest as large-budded cells with high Clb2 levels and fail to degrade Clb2 in G1. Doc1 co-sediments at 20S with Cdc27 in sucrose gradients. Genetic screen for mitotic arrest mutants, sucrose gradient sedimentation, in vivo cyclin degradation assays Molecular biology of the cell High 9348530
1998 Fission yeast Apc10 is required for ubiquitination and degradation of mitotic B-type cyclins and is essential for viability; apc10 mutants show chromosome segregation defects and fail to arrest at G1 upon nutrient starvation. A subpopulation of Apc10 co-immunoprecipitates with the APC/cyclosome. Genetic mutant analysis, in vivo ubiquitination assays, co-immunoprecipitation The EMBO journal High 9736616
1999 Human APC10/DOC1 is a genuine subunit of the human APC/C throughout the cell cycle, as shown by biochemical fractionation and mass spectrometric identification. The DOC domain (APC10 homology region) was defined and found in cullins and HECT-domain proteins, suggesting a conserved role in ubiquitination. Biochemical fractionation, mass spectrometry, sequence analysis The Journal of biological chemistry High 10318877
1999 Human APC10/DOC1 binds to APC core subunits throughout the cell cycle and localizes to centrosomes and mitotic spindles during mitosis, to kinetochores from prophase to anaphase, and to the midbody during telophase/cytokinesis. Co-immunoprecipitation, immunofluorescence localization throughout cell cycle stages Oncogene Medium 10498862
2001 Crystal structure of human APC10/DOC1 at 1.6 Å resolution reveals a beta-sandwich jellyroll fold with structural similarity to ligand-binding domains. Biochemical experiments demonstrate that the C-terminus of APC10 binds to CDC27/APC3, a TPR-containing APC subunit. X-ray crystallography, biochemical binding assay Nature structural biology High 11524682
2001 Disruption of the mouse Apc10/Doc1 gene underlies the oligosyndactylism (Os) mutation and causes a cell-autonomous block in the metaphase-to-anaphase transition, establishing APC10/DOC1 as essential for mitotic progression in mammals. Genetic mapping and molecular characterization of radiation-induced and transgene-induced mouse mutations Genomics Medium 11247669
2002 Crystal structure of yeast Doc1/Apc10 at 2.2 Å resolution reveals a beta-sandwich related to galactose oxidase, coagulation factor C2 domain, and XRCC1; invariant residues among Doc1/Apc10 sequences map to a beta-sheet surface implicated in biomolecular interactions and APC function. X-ray crystallography, sequence analysis and mapping of temperature-sensitive mutant residues Journal of molecular biology High 11884135
2002 Doc1/Apc10 (budding yeast) is a processivity factor for the APC: APC lacking Doc1 (APC^doc1Δ) shows a large increase in apparent K_M for cyclin substrate, indicating that Doc1 stimulates processive polyubiquitination by limiting substrate dissociation. Recombinant Doc1 addition fully restores enzyme function to APC^doc1Δ. In vitro ubiquitination assay with purified APC, kinetic analysis, reconstitution with recombinant Doc1 Nature cell biology High 12402045
2003 Yeast Doc1p/Apc10 plays a specific role in substrate recognition by APC-coactivator complexes: APC lacking Doc1p has impaired E3 ligase activity, and this defect is distinct from the structural role of Apc9p. Doc1p/Apc10 contributes to substrate binding (both D-box and KEN-box substrates) and requires coactivator. Purified APC in vitro ubiquitylation assay, native gel substrate binding assay, APC lacking Doc1p or Apc9p The EMBO journal High 12574115
2004 Point mutations in Doc1 (budding yeast) define two functionally distinct regions: the C-terminus anchors Doc1 to the APC but does not influence substrate recognition, while the opposite face is required for enhancing substrate binding; stimulation of substrate binding by Doc1 requires an intact destruction (D)-box. DOC1 mutations eliminating substrate recognition cause mitotic delay with accumulated APC substrates in vivo. In vitro ubiquitination processivity assays, site-directed mutagenesis, in vivo cell cycle analysis Current biology High 15649358
2004 Human APC10 physically interacts with Smad3 (via distinct MH2 subdomains) and forms a complex with Smad3, HEF1, and CDH1, enabling APC/C-mediated ubiquitination and degradation of HEF1 downstream of TGF-β signaling. Co-immunoprecipitation, domain mapping, overexpression of APC10 and CDH1 with HEF1 protein level assessment BMC cell biology Medium 15144564
2007 Loss-of-function of Drosophila Apc10/Doc1 causes mitotic arrest (high mitotic index, metaphase-like arrest, aneuploidy/polyploidy) in larval neuroblasts and accumulation of cyclin B, consistent with disabled APC/C ubiquitination activity. Genetic loss-of-function mutants, immunofluorescence for cyclin B accumulation, mitotic index analysis Acta biologica Hungarica Medium 18297794
2010 Cryo-EM structure (~10 Å) of yeast APC/C(Cdh1) bound to a D-box peptide reveals that Cdh1 and Apc10 together form a co-receptor for the D-box degron within the central cavity of the APC/C. NMR spectroscopy directly demonstrates specific D-box–Apc10 interactions, confirming that Apc10 directly contributes to D-box recognition. Single-particle cryo-electron microscopy, NMR spectroscopy, difference map analysis Nature High 21107322
2010 Doc1/Apc10 (human and yeast) interacts with Cdc27, Cdc16, and Apc1 and is located in the inner cavity of the APC/C near the cullin-RING module (Apc2-Apc11). Substrates bind in the inner cavity in close proximity to Doc1 and coactivator Cdh1, and induce conformational changes in Apc2-Apc11, supporting a bipartite substrate receptor composed of the coactivator and Doc1. Electron microscopy, biochemical interaction mapping, APC/C subunit localization by EM difference maps Nature structural & molecular biology High 21186364
2019 The APC/C pseudosubstrate inhibitor Acm1 suppresses APC/C activity partly by disrupting the normal interaction with Doc1/Apc10 during processive ubiquitylation; a conserved C-terminal extension of the Acm1 D-box is necessary and sufficient for this inhibition. The D-box was redefined as a 12-amino acid motif whose extended region contacts Doc1/Apc10. In vivo substrate degradation assays, biochemical processivity analysis, site-directed mutagenesis of D-box extension The Journal of biological chemistry Medium 31562243
2021 Human APC10 interacts with NLRP3 during interphase to promote NLRP3 inflammasome activation; during mitosis, APC10 dissociates from NLRP3 to repress inflammatory responses, functioning as a cell-cycle-dependent switch for inflammasome activation. Co-immunoprecipitation, cell-cycle stage-specific analysis, NLRP3 inflammasome activation assays FEBS letters Medium 34407203

Source papers

Stage 0 corpus · 30 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Structures of APC/C(Cdh1) with substrates identify Cdh1 and Apc10 as the D-box co-receptor. Nature 172 21107322
2003 Doc1 mediates the activity of the anaphase-promoting complex by contributing to substrate recognition. The EMBO journal 165 12574115
2002 The Doc1 subunit is a processivity factor for the anaphase-promoting complex. Nature cell biology 116 12402045
2005 The APC subunit Doc1 promotes recognition of the substrate destruction box. Current biology : CB 105 15649358
1998 Apc10 and Ste9/Srw1, two regulators of the APC-cyclosome, as well as the CDK inhibitor Rum1 are required for G1 cell-cycle arrest in fission yeast. The EMBO journal 88 9736616
2010 Substrate binding on the APC/C occurs between the coactivator Cdh1 and the processivity factor Doc1. Nature structural & molecular biology 86 21186364
1997 A novel yeast screen for mitotic arrest mutants identifies DOC1, a new gene involved in cyclin proteolysis. Molecular biology of the cell 79 9348530
1999 Characterization of the DOC1/APC10 subunit of the yeast and the human anaphase-promoting complex. The Journal of biological chemistry 78 10318877
2001 Crystal structure of the APC10/DOC1 subunit of the human anaphase-promoting complex. Nature structural biology 77 11524682
1995 Deleted in oral cancer-1 (doc-1), a novel oral tumor suppressor gene. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 71 7557027
1998 Cloning, mapping, expression, function, and mutation analyses of the human ortholog of the hamster putative tumor suppressor gene Doc-1. The Journal of biological chemistry 54 9506968
2017 DOC1-Dependent Recruitment of NURD Reveals Antagonism with SWI/SNF during Epithelial-Mesenchymal Transition in Oral Cancer Cells. Cell reports 46 28683324
2002 Implications for the ubiquitination reaction of the anaphase-promoting complex from the crystal structure of the Doc1/Apc10 subunit. Journal of molecular biology 42 11884135
2004 Direct interaction between Smad3, APC10, CDH1 and HEF1 in proteasomal degradation of HEF1. BMC cell biology 38 15144564
2003 Differential expression of DOC-1 in microsatellite-unstable human colorectal cancer. Oncogene 33 13679870
1999 Identification of human APC10/Doc1 as a subunit of anaphase promoting complex. Oncogene 22 10498862
1997 Isolation, mapping and mutation analysis of a human cDNA homologous to the doc-1 gene of the Chinese hamster, a candidate tumor suppressor for oral cancer. Genes, chromosomes & cancer 22 9331572
2020 Sox21 Regulates Anapc10 Expression and Determines the Fate of Ectodermal Organ. iScience 21 32674056
2001 Disruption of Apc10/Doc1 in three alleles of oligosyndactylism. Genomics 18 11247669
2004 Apc10.1: an ApcMin/+ intestinal cell line with retention of heterozygosity. International journal of cancer 17 14750170
1999 Identification and mutation analysis of DOC-1R, a DOC-1 growth suppressor-related gene. Biochemical and biophysical research communications 13 10082655
2011 High α-defensin and S100A7 expression and missing DOC-1 down-regulation characterize irritation fibromas of the oral cavity and may counteract malignant transformation. The Journal of craniofacial surgery 9 21187770
2023 The deleted in oral cancer (DOC1 aka CDK2AP1) tumor suppressor gene is downregulated in oral squamous cell carcinoma by multiple microRNAs. Cell death & disease 8 37217493
2009 APC10.1 cells as a model for assessing the efficacy of potential chemopreventive agents in the Apc(Min) mouse model in vivo. European journal of cancer (Oxford, England : 1990) 8 19695862
2021 Docking and ADMET studies for investigating the anticancer potency of Moscatilin on APC10/DOC1 and PKM2 against five clinical drugs. Journal, genetic engineering & biotechnology 7 34665359
2019 The pseudosubstrate inhibitor Acm1 inhibits the anaphase-promoting complex/cyclosome by combining high-affinity activator binding with disruption of Doc1/Apc10 function. The Journal of biological chemistry 7 31562243
2012 Experimental validation of Ankrd17 and Anapc10, two novel meiotic genes predicted by computational models in mice. Biology of reproduction 6 22190705
2021 The APC10 subunit of the anaphase-promoting complex/cyclosome orchestrates NLRP3 inflammasome activation during the cell cycle. FEBS letters 4 34407203
2007 Characterization of the Apc10/Doc1 subunit of the anaphase promoting complex in Drosophila melanogaster. Acta biologica Hungarica 4 18297794
2010 Sequence characterization and promoter identification of porcine APC10 gene. Molecular biology reports 0 20232159