Affinage

ANAPC11

Anaphase-promoting complex subunit 11 · UniProt Q9NYG5

Length
84 aa
Mass
9.8 kDa
Annotated
2026-06-09
15 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ANAPC11 is the catalytic RING-H2 finger subunit of the anaphase-promoting complex/cyclosome (APC/C), the multisubunit E3 ubiquitin ligase that drives ubiquitin-dependent proteolysis of cell-cycle regulators (PMID:10230407, PMID:11739784). It functions as the catalytic core by directly binding the E2 ubiquitin-conjugating enzyme (Ubc4/UbcH10) and coordinating Zn2+ through its RING-H2 domain to catalyze isopeptide-bond formation and polyubiquitin chain synthesis; RING-H2 integrity is strictly required for ligase activity (PMID:10230407, PMID:10922056, PMID:10888670). Together with the cullin-related subunit APC2, ANAPC11 forms the minimal heterodimeric ligase module sufficient to ubiquitinate APC/C substrates such as securin and cyclin B1, with APC11 contributing the E2-docking and chain-building activity (PMID:10922056, PMID:11739784, PMID:22417125). This activity is required for mitotic progression: loss of ANAPC11 causes metaphase arrest, accumulation of mitotic cyclins, and altered cell-cycle distribution, and the gene is essential for viability (PMID:10888670, PMID:22417125, PMID:23007976, PMID:10487928). Its catalytic function is regulated by oxidative stress—H2O2 oxidizes cysteine residues, releases the coordinated zinc, disrupts E2 (Ubc4) binding, and inhibits substrate ubiquitination, delaying mitotic exit (PMID:15256223)—and by ubiquitin-proteasome-mediated turnover of unassembled APC11 that prevents spurious substrate ubiquitination outside the holoenzyme (PMID:31162950). In cancer contexts, ANAPC11 promotes ubiquitination of additional substrates including UBA52 (driving cyclin B1 degradation) and FOXO3 (destabilizing it and downregulating p21 and GULP1), with knockout suppressing tumor growth and metastasis (PMID:31814919, PMID:37573356).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1999 High

    Established that APC11 is an essential gene and that its RING finger is the catalytic element of the APC/C ligase, answering whether the activity resided in a defined subunit.

    Evidence Yeast gene disruption (essentiality); in vitro ligase assay with immunocomplexes and RING-finger mutagenesis; co-IP showing APC11–APC2 interaction

    PMID:10230407 PMID:10487928

    Open questions at the time
    • Did not define the minimal sufficient module
    • E2 specificity not yet mapped to APC11 directly
  2. 2000 High

    Showed APC11 with E1 and UBC4 is sufficient to build polyubiquitin chains and ubiquitinate securin and cyclin B, and that this requires the RING-H2 domain and direct E2 binding, pinpointing APC11 as the catalytic engine.

    Evidence In vitro ubiquitination with recombinant proteins; RING-H2 mutagenesis; direct E2 binding assay; yeast genetic essentiality

    PMID:10888670 PMID:10922056

    Open questions at the time
    • Role of APC2/cullin-like partner in physiological context unresolved
    • Reduced D-box dependency of minimal system not reconciled with holoenzyme substrate selection
  3. 2001 High

    Defined the minimal APC2:APC11 heterodimer as the catalytic ligase module and characterized Zn2+ coordination, mapping where E2 enzymes dock and which metal ions matter for catalysis.

    Evidence Baculoviral reconstitution of human APC2/APC11; in vitro ubiquitination; Zn2+-binding stoichiometry; domain mapping

    PMID:11739784

    Open questions at the time
    • Structural basis of E2 positioning not resolved
    • How module integrates into holoenzyme regulation unclear
  4. 2001 Low

    Provided initial subcellular localization of human ANAPC11 across cell lines.

    Evidence Transfection-based localization imaging in AML 12, HepG2, C2C12

    PMID:11573242

    Open questions at the time
    • Single lab, single method with no functional link to localization
    • Overexpression artifact not excluded
    • Endogenous localization not assessed
  5. 2004 High

    Linked APC11 catalytic activity to redox regulation, showing oxidative stress disables the ligase by stripping its zinc and blocking E2 binding.

    Evidence In vitro zinc-release and ubiquitination assays with purified protein; co-IP in H2O2-treated HeLa cells; mitotic exit timing

    PMID:15256223

    Open questions at the time
    • Physiological oxidant levels and reversibility in vivo not defined
    • Which specific cysteines are oxidized not mapped
  6. 2006 Medium

    Confirmed conservation of APC11 catalytic activity against cyclin B in a non-mammalian ortholog.

    Evidence In vitro ubiquitination with recombinant goldfish proteins (E1, E2-C, APC11)

    PMID:16971785

    Open questions at the time
    • Single study in ortholog
    • No in vivo validation
  7. 2012 High

    Demonstrated in intact metazoan and human cells that APC11 is required for mitotic progression and forms a ternary E2-binding complex with APC2, connecting biochemistry to cell-cycle phenotype.

    Evidence Drosophila null allele rescue and complementation, co-IP, immunofluorescence; siRNA knockdown with rescue and flow cytometry in HEK293T

    PMID:22417125 PMID:23007976

    Open questions at the time
    • Full substrate spectrum in vivo not enumerated
    • Mechanism of coactivator-dependent activation not addressed
  8. 2019 Medium

    Revealed a quality-control layer: unassembled APC11 retains aberrant ligase activity and is degraded by the proteasome to prevent inappropriate substrate ubiquitination.

    Evidence In vivo yeast overexpression, proteasome inhibition, substrate ubiquitination readouts

    PMID:31162950

    Open questions at the time
    • Single lab/study
    • Degradation machinery targeting unassembled APC11 not identified
  9. 2019 Medium

    Identified UBA52 as an APC11 ubiquitination substrate that drives cyclin B1 degradation, extending APC11 function into a cancer-relevant degradation pathway.

    Evidence Co-IP, shRNA/siRNA knockdown, cell-cycle analysis, xenograft, overexpression rescue/epistasis

    PMID:31814919

    Open questions at the time
    • Direct vs indirect ubiquitination not fully separated
    • Single lab
  10. 2023 Medium

    Established FOXO3 as an ANAPC11 substrate whose destabilization links the ligase to tumor growth and metastasis via p21/GULP1 downregulation.

    Evidence Co-IP/mass spectrometry, CRISPR-Cas9 knockout, ubiquitination assay, in vivo xenograft and lymph node metastasis model

    PMID:37573356

    Open questions at the time
    • Whether ubiquitination occurs via the APC/C holoenzyme or APC11 alone unclear
    • Single lab
  11. 2024 Medium

    Resolved species-specific differences in catalytic module activation, showing yeast apo-APC/C pre-positions the APC2:APC11 module for E2 binding whereas human APC/C requires coactivator-induced conformational change.

    Evidence Cryo-EM of multiple S. cerevisiae APC/C complexes with comparative analysis (preprint)

    PMID:bio_10.1101_2024.06.19.599685

    Open questions at the time
    • Preprint, not peer-reviewed
    • Medium resolution
    • Functional consequence of pre-positioning not tested biochemically

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ANAPC11 substrate selection is partitioned between its action within the holoenzyme versus its intrinsic minimal-module activity, and how redox/coactivator regulation integrates in physiological human cells, remains unresolved.
  • No high-resolution human APC2:APC11–E2–substrate structure in the corpus
  • Endogenous human substrate spectrum incompletely defined
  • In vivo significance of oxidative regulation not quantified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 4 GO:0140096 catalytic activity, acting on a protein 4 GO:0008092 cytoskeletal protein binding 2
Localization
GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-1640170 Cell Cycle 4 R-HSA-392499 Metabolism of proteins 4
Partners
APC2FOXO3UBA52UBC4UBE2C
Complex memberships
APC/CAPC2:APC11 catalytic module

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 APC11 (and its homologs ROC1/ROC2) immunocomplexes can catalyze isopeptide ligations to form polyubiquitin chains in an E1- and E2-dependent manner; APC11 specifically interacts with APC2 (a cullin-related APC subunit), while ROC1/ROC2 interact with all cullins; ROC1/APC11 RING finger mutations completely abolished ligase activity without disrupting associated protein interactions. In vitro ubiquitin ligase assay with immunocomplexes; mutagenesis of RING finger; co-immunoprecipitation Molecular cell High 10230407
2000 APC11 alone is sufficient to synthesize multiubiquitin chains in the presence of E1 and UBC4; APC11 and UBC4 together can ubiquitinate securin and cyclin B with reduced D-box dependency; the RING-H2 finger domain is required for ubiquitination activity. In vitro ubiquitination assay with recombinant E. coli-expressed proteins; RING finger mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 10922056
2000 Yeast Apc11p RING-H2 finger is essential for cell viability; Apc11p directly interacts with the Ubc4 E2 enzyme; purified Apc11p mediates E1- and E2-dependent ubiquitination of substrates including Clb2p in vitro; E3 activity requires RING-H2 finger integrity but does not require the cullin-like Apc2p subunit. Genetic viability assay (yeast); direct binding assay with purified recombinant proteins; in vitro ubiquitination assay; RING-H2 mutagenesis Molecular biology of the cell High 10888670
2001 A heterodimeric complex of APC2 and APC11 is the minimal ubiquitin ligase module of the human APC/C, sufficient to ubiquitinate securin and cyclin B1 with Ubc4 or UbcH10; APC11 and UbcH10 both bind the C-terminal cullin homology domain of APC2, while Ubc4 interacts with APC11 directly; APC11 binds Zn2+ at a 1:3 molar ratio and the third Zn2+ ion is not essential for ligase activity; with Ubc4, Zn2+ ions alone can catalyze ubiquitination of cyclin B1. Baculoviral reconstitution of human APC2/APC11 complex; in vitro ubiquitination assay; Zn2+-binding experiments; mutagenesis; binding domain mapping Molecular biology of the cell High 11739784
2001 Human ANAPC11 protein is distributed diffusely in the cytoplasm and nucleus with discrete accumulation in granular structures, as determined by transfection-based localization experiments in AML 12, HepG2, and C2C12 cell lines. Transfection and subcellular localization imaging Journal of cellular biochemistry Low 11573242
2004 Exposure of purified APC11 to H2O2 (0.1–1 mM) releases bound zinc via oxidation of cysteine residues, impairs physical interaction between APC11 and Ubc4, and inhibits APC11-mediated ubiquitination of cyclin B1; in HeLa cells, exogenous H2O2 blocked co-immunoprecipitation of Ubc4 with APC11, inhibited cyclin B1 and securin ubiquitination and degradation, and delayed mitotic exit. In vitro ubiquitination assay with purified proteins; zinc release assay; co-immunoprecipitation in H2O2-treated HeLa cells; mitotic exit timing assay Free radical biology & medicine High 15256223
2006 Recombinant goldfish APC11 possesses ubiquitinating activity against cyclin B; a reconstituted in vitro system comprising purified E1, E2-C (UBC4 type), and APC11 is sufficient to ubiquitinate cyclin B. In vitro ubiquitination assay with recombinant proteins from goldfish (ortholog) Zoological science Medium 16971785
2012 Drosophila Apc11 (encoded by lemmingA) is essential for mitotic progression; loss-of-function causes metaphase arrest with condensed scattered chromosomes and polyploidy, and accumulation of cyclin A and cyclin B; LmgA/Apc11 interacts with Morula/Apc2 and together they form a binding site for Vihar (E2-C type ubiquitin-conjugating enzyme), establishing a ternary complex. Drosophila genetic null allele rescue; yeast complementation; co-immunoprecipitation/interaction assays; immunofluorescence Cell division High 22417125
2012 siRNA knockdown of Apc11 in HEK293T cells leads to reduced time in G2/M phase and increased time in G1 phase (not apoptosis); this cell cycle distribution phenotype is rescued by co-transfection of an Apc11 expression plasmid, confirming specificity. siRNA knockdown in HEK293T cells; flow cytometry cell cycle analysis; rescue experiment Genetics and molecular research : GMR Medium 23007976
1999 Targeted disruption of APC11 (YDL008w) in S. cerevisiae is non-viable, establishing that APC11 is an essential gene. Systematic gene disruption (KanMX cassette replacement) in haploid yeast Yeast (Chichester, England) Medium 10487928
2019 Unassembled (excess) Apc11 in yeast can ubiquitinate APC/C substrates independently of the fully assembled APC/C holoenzyme in living cells; the ubiquitin-proteasome system mediates degradation of unassembled Apc11, serving as a quality-control mechanism to prevent spurious substrate ubiquitination outside the holoenzyme context. In vivo yeast experiments with Apc11 overexpression; proteasome inhibition; substrate ubiquitination assays in living yeast FASEB journal Medium 31162950
2019 APC11 mediates ubiquitination of UBA52 (ubiquitin-ribosomal fusion protein), which in turn promotes degradation of CCNB1 (cyclin B1); knockdown of APC11 causes G2/M arrest and reduced clonal formation even with UBA52 overexpression, placing APC11 upstream of UBA52 in CCNB1 degradation. Co-immunoprecipitation; shRNA/siRNA knockdown; cell cycle analysis; xenograft tumor assay; overexpression rescue experiments American journal of translational research Medium 31814919
2023 ANAPC11 interacts with and promotes ubiquitination of FOXO3, leading to decreased FOXO3 protein stability, downregulation of p21 and GULP1; CRISPR knockout of ANAPC11 inhibits tumor growth and lymph node metastasis in vivo. Co-immunoprecipitation coupled with mass spectrometry; CRISPR-Cas9 knockout; ubiquitination assay; in vivo xenograft/LN metastasis model Cell death & disease Medium 37573356
2024 Cryo-EM structures of S. cerevisiae APC/C reveal that in contrast to human APC/C (where coactivator induces a conformational change of the APC2:APC11 catalytic module to permit E2 binding), in yeast apo-APC/C the APC2:APC11 catalytic module is already positioned to bind E2, indicating species-specific differences in coactivator-mediated stimulation of E2 recruitment. Cryo-EM structural determination of multiple S. cerevisiae APC/C complexes (apo, CDH1-substrate ternary, phosphorylated); comparative structural analysis with human APC/C bioRxivpreprint Medium bio_10.1101_2024.06.19.599685

Source papers

Stage 0 corpus · 15 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 ROC1, a homolog of APC11, represents a family of cullin partners with an associated ubiquitin ligase activity. Molecular cell 410 10230407
2001 APC2 Cullin protein and APC11 RING protein comprise the minimal ubiquitin ligase module of the anaphase-promoting complex. Molecular biology of the cell 156 11739784
2000 The RING-H2 finger protein APC11 and the E2 enzyme UBC4 are sufficient to ubiquitinate substrates of the anaphase-promoting complex. Proceedings of the National Academy of Sciences of the United States of America 156 10922056
2000 The APC11 RING-H2 finger mediates E2-dependent ubiquitination. Molecular biology of the cell 151 10888670
2019 Degradation of CCNB1 mediated by APC11 through UBA52 ubiquitination promotes cell cycle progression and proliferation of non-small cell lung cancer cells. American journal of translational research 39 31814919
2004 The RING-H2-finger protein APC11 as a target of hydrogen peroxide. Free radical biology & medicine 28 15256223
2020 LncRNA BCAR4 promotes liver cancer progression by upregulating ANAPC11 expression through sponging miR‑1261. International journal of molecular medicine 19 32319544
2023 The APC/C E3 ligase subunit ANAPC11 mediates FOXO3 protein degradation to promote cell proliferation and lymph node metastasis in urothelial bladder cancer. Cell death & disease 15 37573356
2012 lemmingA encodes the Apc11 subunit of the APC/C in Drosophila melanogaster that forms a ternary complex with the E2-C type ubiquitin conjugating enzyme, Vihar and Morula/Apc2. Cell division 8 22417125
2012 Knockdown expression of Apc11 leads to cell-cycle distribution reduction in G2/M phase. Genetics and molecular research : GMR 8 23007976
2019 Regulation of the anaphase promoting complex/cyclosome by the degradation of its unassembled catalytic subunit, Apc11. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 6 31162950
1999 Disruption and functional analysis of seven ORFs on chromosome IV: YDL057w, YDL012c, YDL010w, YDL009c, YDL008w (APC11), YDL005c (MED2) and YDL003w (MCD1). Yeast (Chichester, England) 6 10487928
2018 Overexpression of APC11 predicts worse survival in lung adenocarcinoma. OncoTargets and therapy 5 30410368
2001 Molecular cloning and characterization of a RING-H2 finger protein, ANAPC11, the human homolog of yeast Apc11p. Journal of cellular biochemistry 3 11573242
2006 Molecular cloning of cDNA encoding APC11, a catalytic component of anaphase-promoting-complex (APC/C), from goldfish (Carassius auratus), and establishment of in vitro ubiquitinating system. Zoological science 1 16971785

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