Affinage

ANAPC11

Anaphase-promoting complex subunit 11 · UniProt Q9NYG5

Length
84 aa
Mass
9.8 kDa
Annotated
2026-04-28
15 papers in source corpus 12 papers cited in narrative 12 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ANAPC11 is the RING-H2 finger subunit of the anaphase-promoting complex/cyclosome (APC/C) E3 ubiquitin ligase, serving as the catalytic core that recruits E2 ubiquitin-conjugating enzymes and catalyzes polyubiquitin chain formation on cell-cycle substrates including cyclin B1, securin, and FOXO3 (PMID:10230407, PMID:10922056, PMID:37573356). Together with the cullin-related subunit APC2, ANAPC11 forms a minimal heterodimeric ubiquitin ligase module sufficient for substrate ubiquitination; its activity depends on Zn²⁺-coordinating cysteine/histidine residues in the RING-H2 domain that are essential for E2 interaction and are sensitive to oxidative inactivation by H₂O₂ (PMID:11739784, PMID:15256223). In human APC/C, coactivators CDH1/CDC20 induce a conformational change in the APC2–APC11 module to permit E2 engagement, whereas free unassembled APC11 is degraded by the ubiquitin-proteasome system to prevent spurious substrate ubiquitination outside the holoenzyme (PMID:31162950, PMID:22417125). Loss of ANAPC11 function causes mitotic arrest with stabilized cyclins in Drosophila neuroblasts and altered cell-cycle distribution in human cells (PMID:22417125, PMID:23007976).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 1999 High

    Establishing that APC11 is the RING-finger E3 ligase subunit of the APC/C resolved how the complex catalyzes ubiquitination, showing that APC11 immunocomplexes perform E1/E2-dependent polyubiquitin chain synthesis and that RING finger integrity is required for ligase activity but not subunit interactions.

    Evidence In vitro ubiquitin ligase assay with immunoprecipitated APC11, RING finger mutagenesis

    PMID:10230407

    Open questions at the time
    • Substrate specificity determinants not defined
    • Role of other APC/C subunits in catalysis unclear
    • No structural model of APC11 at this point
  2. 2000 High

    Demonstrating that APC11 alone (without other APC/C subunits) can catalyze multiubiquitin chain synthesis and substrate ubiquitination — and that it directly binds E2 enzymes like Ubc4 — established APC11 as the minimal catalytic unit of the APC/C, conserved from yeast to humans.

    Evidence In vitro reconstitution with recombinant APC11 and E2 enzymes, direct binding assays, yeast viability experiments

    PMID:10888670 PMID:10922056

    Open questions at the time
    • Destruction-box-dependent substrate selectivity reduced with APC11 alone — mechanism of selectivity by holoenzyme unknown
    • How APC11 cooperates with APC2 was not yet mapped
  3. 2001 High

    Reconstitution of the APC2–APC11 heterodimer showed it is the minimal catalytic module sufficient for cyclin B1 and securin ubiquitination, mapped E2 binding to APC2's cullin homology domain and APC11 directly, and revealed a 1:3 Zn²⁺ binding stoichiometry essential for APC11 function.

    Evidence Baculoviral reconstitution of human APC2/APC11, in vitro ubiquitin ligase assay, Zn²⁺ binding measurements

    PMID:11739784

    Open questions at the time
    • No structural detail of APC2–APC11 interface
    • How coactivators regulate this module unknown
    • Contribution of Zn²⁺ beyond structural integrity not resolved
  4. 2004 High

    Showing that H₂O₂ oxidizes RING-H2 cysteines, releases Zn²⁺, and disrupts APC11–Ubc4 interaction — delaying mitotic exit in HeLa cells — revealed a redox-regulatory mechanism for APC/C activity.

    Evidence In vitro H₂O₂ treatment of purified APC11, Zn²⁺ release assay, co-IP in HeLa cells, cell cycle analysis

    PMID:15256223

    Open questions at the time
    • Physiological relevance of oxidative regulation not demonstrated in vivo
    • Which specific cysteines are oxidized not mapped
    • Whether other APC/C subunits are co-regulated by ROS unknown
  5. 2012 High

    Genetic studies in Drosophila and RNAi in human cells demonstrated that APC11 loss causes metaphase arrest with stabilized cyclins in vivo, confirming its essential role in cell-cycle progression beyond in vitro catalysis.

    Evidence Drosophila lmgA mutant phenotype in neuroblasts; siRNA knockdown with rescue in HEK293T cells

    PMID:22417125 PMID:23007976

    Open questions at the time
    • HEK293T knockdown showed G1 accumulation rather than mitotic arrest — context-dependent effects unexplained
    • Whether APC11 has functions outside canonical APC/C not addressed
  6. 2019 Medium

    Discovery that free unassembled APC11 can ubiquitinate APC/C substrates independently and is itself degraded by the proteasome revealed a quality-control mechanism preventing spurious substrate ubiquitination outside the holoenzyme.

    Evidence Yeast genetics, in vivo ubiquitination assay, proteasome inhibitor experiments

    PMID:31162950

    Open questions at the time
    • E3 ligase responsible for free APC11 degradation not identified
    • Whether this mechanism operates in mammalian cells untested
    • Quantitative contribution of free APC11 to substrate turnover unclear
  7. 2023 Medium

    Identification of FOXO3 as an APC11-dependent ubiquitination substrate in bladder cancer cells expanded the substrate repertoire beyond canonical cell-cycle targets and linked ANAPC11 to tumor growth and metastasis.

    Evidence CRISPR-Cas9 knockout, IP-MS substrate identification, ubiquitination assay, in vivo tumor model

    PMID:37573356

    Open questions at the time
    • Whether FOXO3 ubiquitination requires the full APC/C holoenzyme or APC2–APC11 alone not determined
    • APC/C coactivator involved not identified
    • Single-lab finding awaiting independent replication
  8. 2024 High

    Cryo-EM structures revealed that in human APC/C, coactivator binding induces a conformational change in the APC2–APC11 catalytic module to permit E2 access, providing a structural explanation for coactivator-dependent activation.

    Evidence Cryo-EM of multiple APC/C complex states (apo, CDH1-substrate ternary, phosphorylated) (preprint)

    PMID:bio_10.1101_2024.06.19.599685

    Open questions at the time
    • Preprint not yet peer-reviewed
    • Dynamics of conformational change not captured at high resolution
    • How phosphorylation modulates APC2–APC11 repositioning not fully resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • The full scope of APC11-dependent substrates beyond canonical cell-cycle regulators, the E3 ligase controlling free APC11 turnover, and the physiological significance of redox regulation of APC11 remain unresolved.
  • Comprehensive substrate profiling for APC11-dependent ubiquitination lacking
  • Identity of E3 ligase targeting free APC11 unknown
  • In vivo validation of ROS-mediated APC11 regulation absent

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0016874 ligase activity 3
Localization
GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-392499 Metabolism of proteins 5 R-HSA-1640170 Cell Cycle 4
Partners
APC2CDC20CDH1FOXO3UBC4UBCH10
Complex memberships
APC/C

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 APC11 immunocomplexes catalyze isopeptide ligations to form polyubiquitin chains in an E1- and E2-dependent manner; APC11 specifically interacts with APC2, a cullin-related APC subunit; RING finger mutations abolish ligase activity without affecting associated protein interactions. In vitro ubiquitin ligase assay, immunoprecipitation, mutagenesis Molecular cell High 10230407
2000 APC11 alone is sufficient to catalyze multiubiquitin chain synthesis in the presence of E1 and UBC4; APC11 and UBC4 can ubiquitinate securin and cyclin B with decreased destruction-box dependency; integrity of the RING-H2 finger is required for ubiquitination activity. In vitro ubiquitin ligase assay with recombinant E. coli-expressed proteins, mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 10922056
2000 Yeast Apc11p RING-H2 finger defines minimal ubiquitin ligase activity of the APC; Apc11p directly interacts with Ubc4 E2 enzyme; Apc11p mediates E1- and E2-dependent ubiquitination of substrates including Clb2p in vitro; RING-H2 integrity is essential for budding yeast cell viability. In vitro ubiquitin ligase assay with purified recombinant proteins, direct binding assay, RING finger mutagenesis, yeast genetics Molecular biology of the cell High 10888670
2001 A heterodimeric complex of APC2 and APC11 is sufficient to catalyze ubiquitination of human securin and cyclin B1 with Ubc4 or UbcH10; both APC11 and UbcH10 bind to the C-terminal cullin homology domain of APC2, while Ubc4 interacts with APC11 directly; APC11 binds Zn2+ at a 1:3 molar ratio, and Zn2+ ions alone can catalyze ubiquitination of cyclin B1. Baculoviral reconstitution of human APC2/APC11 complex, in vitro ubiquitin ligase assay, Zn2+-binding experiments, mutagenesis Molecular biology of the cell High 11739784
2004 H2O2 oxidizes cysteine residues in the RING-H2 finger of APC11, releasing bound Zn2+, impairing physical interaction between APC11 and Ubc4, and inhibiting ubiquitination of cyclin B1; in HeLa cells, H2O2 blocks co-immunoprecipitation of Ubc4 with APC11 and delays mitotic exit. In vitro ubiquitin ligase assay with H2O2-treated purified APC11, Zn2+ release assay, co-immunoprecipitation in HeLa cells, cell cycle analysis Free radical biology & medicine High 15256223
2001 Human ANAPC11 is distributed diffusely in both cytoplasm and nucleus with discrete accumulation in granular structures; it encodes an 84-amino acid RING-H2 finger protein homologous to yeast Apc11p and localized to chromosome 17q25. cDNA cloning, Northern blot, transfection and fluorescence microscopy for subcellular localization Journal of cellular biochemistry Medium 11573242
2012 Drosophila Apc11 (LmgA) forms a ternary complex with Apc2/Morula and the E2-C type ubiquitin conjugating enzyme Vihar; Apc11 recruits the E2-C enzyme to the APC/C together with Apc2; loss of lmgA causes metaphase arrest with high cyclin A and cyclin B levels in larval neuroblasts. Genetic rescue experiments, protein interaction assays, mutant phenotype analysis in Drosophila Cell division High 22417125
2012 siRNA knockdown of Apc11 in HEK293T cells causes cell cycle redistribution with less time in G2/M and more time in G1, without inducing apoptosis; this phenotype is specifically rescued by co-transfection of an Apc11 expression plasmid. siRNA knockdown, flow cytometry cell cycle analysis, rescue experiment Genetics and molecular research Medium 23007976
2019 Unassembled (excess) Apc11 in yeast can ubiquitinate APC/C substrates independently of the fully assembled APC/C holoenzyme; the ubiquitin-proteasome system mediates degradation of free Apc11 to prevent spurious substrate ubiquitination outside of the assembled complex. Yeast genetics, in vivo ubiquitination assay, proteasome inhibitor experiments FASEB journal Medium 31162950
2019 APC11 promotes ubiquitination and degradation of CCNB1 (cyclin B1) via UBA52 in NSCLC cells; knockdown of APC11 causes G2/M arrest, and APC11 overexpression drives CCNB1 degradation and cell cycle progression. siRNA/shRNA knockdown, overexpression, co-immunoprecipitation, cell cycle analysis, xenograft model American journal of translational research Medium 31814919
2023 ANAPC11 mediates ubiquitination and proteasomal degradation of the transcription factor FOXO3 in urothelial bladder cancer cells, leading to decreased p21 and GULP1 expression; ANAPC11 knockout inhibits tumor growth and lymph node metastasis in vivo. CRISPR-Cas9 knockout, immunoprecipitation coupled with mass spectrometry, ubiquitination assay, in vivo tumor model Cell death & disease Medium 37573356
2024 Cryo-EM structures reveal that in human APC/C, coactivator (CDH1/CDC20) induces a conformational change of the catalytic module APC2:APC11 to allow E2 binding, whereas in S. cerevisiae APC/C the catalytic module is already pre-positioned to bind E2 without coactivator-induced conformational change. Cryo-EM structural determination of multiple APC/C complexes (apo, CDH1-substrate ternary, phosphorylated) bioRxivpreprint High 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 38 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