id: Q9UJX6
gene_symbol: ANAPC2
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  ANAPC2 encodes anaphase-promoting complex subunit 2, the cullin-like scaffold of the APC/C catalytic
  module. In the APC/C E3 ubiquitin ligase, ANAPC2 works with the RING subunit ANAPC11 and ubiquitin-conjugating
  enzymes to ubiquitinate cell-cycle substrates, promoting ordered proteasomal degradation during
  mitotic progression and mitotic exit. Structural and biochemical studies place ANAPC2 in the
  APC/C catalytic platform, and APC/C activity is regulated by coactivators, phosphorylation,
  checkpoint inhibitors, and substrate adaptors in nuclear and cytosolic cell-cycle contexts.
alternative_products:
- name: '1'
  id: Q9UJX6-1
- name: '2'
  id: Q9UJX6-2
  sequence_note: VSP_008463
existing_annotations:
- term:
    id: GO:0007091
    label: metaphase/anaphase transition of mitotic cell cycle
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      ANAPC2 is part of the APC/C module that controls mitotic chromosome segregation and mitotic
      exit, so the metaphase/anaphase transition annotation is supported.
    action: ACCEPT
    reason: >-
      This captures a central APC/C cell-cycle role rather than a distant phenotype. The IBA transfer
      is consistent with structural and biochemical evidence that APC/C is a ubiquitin ligase
      essential for mitotic progression.
    supported_by:
    - reference_id: PMID:16364912
      supporting_text: >-
        The anaphase-promoting complex/cyclosome (APC/C) is a ubiquitin ligase with essential
        functions in mitosis, meiosis, and G1 phase of the cell cycle.
    - reference_id: PMID:26083744
      supporting_text: >-
        These structures define the architecture of all APC/C subunits, the position of the catalytic
        module
- term:
    id: GO:0070979
    label: protein K11-linked ubiquitination
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      APC/C-dependent K11-linked ubiquitin-chain assembly is a well-supported output of the ANAPC2-containing
      APC/C catalytic module.
    action: ACCEPT
    reason: >-
      K11-linked ubiquitination is a core APC/C activity, and ANAPC2 is part of the catalytic
      Apc2-Apc11 module that positions the E2 machinery for substrate ubiquitination.
    supported_by:
    - reference_id: PMID:18485873
      supporting_text: >-
        We find that the APC/C triggers substrate degradation by assembling K11-linked ubiquitin
        chains
    - reference_id: PMID:29033132
      supporting_text: >-
        engineered a bispecific antibody to detect K11/K48-linked chains and identified mitotic
        regulators, misfolded nascent polypeptides, and pathological Huntingtin variants as their
        endogenous substrates.
    - reference_id: PMID:16364912
      supporting_text: >-
        bound substrates are ubiquitinated by E2 enzymes that interact with a hetero-dimer of
        the RING subunit Apc11 and the cullin Apc2
- term:
    id: GO:0005680
    label: anaphase-promoting complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: >-
      ANAPC2 is a core subunit of the anaphase-promoting complex/cyclosome.
    action: ACCEPT
    reason: >-
      This is the most specific cellular-component annotation for ANAPC2. Structural studies place
      Apc2 in APC/C particles and in the catalytic platform with Apc11.
    supported_by:
    - reference_id: PMID:16364912
      supporting_text: >-
        These proteins are located on the same side of the asymmetric APC/C, implying that this
        is where substrates are ubiquitinated.
    - reference_id: PMID:26083744
      supporting_text: >-
        These structures define the architecture of all APC/C subunits, the position of the catalytic
        module
- term:
    id: GO:0010498
    label: proteasomal protein catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      APC/C ubiquitination of cell-cycle substrates leads to proteasome-mediated degradation.
    action: ACCEPT
    reason: >-
      The term is broad but appropriate for ANAPC2 as an APC/C catalytic-module scaffold because
      APC/C controls ordered degradation of cell-cycle proteins through ubiquitin-dependent proteasomal
      proteolysis.
    supported_by:
    - reference_id: PMID:26083744
      supporting_text: >-
        Two cullin-RING E3 ubiquitin ligases, the APC/C and SCF, catalyze the ubiquitination of
        multiple cell cycle proteins to regulate their proteasome-mediated proteolysis.
    - reference_id: PMID:27120157
      supporting_text: >-
        In eukaryotes, the anaphase-promoting complex (APC/C, also known as the cyclosome) regulates
        the ubiquitin-dependent proteolysis of specific cell-cycle proteins to coordinate chromosome
        segregation in mitosis and entry into the G1 phase.
- term:
    id: GO:0031461
    label: cullin-RING ubiquitin ligase complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: part_of
  review:
    summary: >-
      ANAPC2 belongs to a cullin-like RING E3 module, but the specific complex is APC/C rather
      than a generic CRL complex.
    action: MODIFY
    reason: >-
      The broad cullin-RING ubiquitin ligase complex annotation is mechanistically related but
      less precise for ANAPC2. The more accurate cellular-component term is anaphase-promoting
      complex.
    proposed_replacement_terms:
    - id: GO:0005680
      label: anaphase-promoting complex
    supported_by:
    - reference_id: PMID:16364912
      supporting_text: >-
        bound substrates are ubiquitinated by E2 enzymes that interact with a hetero-dimer of
        the RING subunit Apc11 and the cullin Apc2
    - reference_id: PMID:26083744
      supporting_text: >-
        the catalytic module comprising the RING subunit Apc11 and the C-terminal domain of Apc2
        (Apc2CTD)
    - reference_id: file:human/ANAPC2/ANAPC2-uniprot.txt
      supporting_text: >-
        Belongs to the cullin family.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23708001
  qualifier: enables
  review:
    summary: >-
      This protein-binding record reflects APC/C interactions with Emi1/Ube2S regulatory machinery,
      but the generic term is not informative as a core ANAPC2 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Protein binding is true but over-general. The same evidence is better interpreted in the
      context of ANAPC2's APC/C scaffold and E2-positioning role.
    supported_by:
    - reference_id: PMID:23708001
      supporting_text: >-
        the carboxy-terminal tail of Emi1 antagonizes chain elongation by Ube2S, by competitively
        preventing its binding to the APC cullin subunit
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26083744
  qualifier: enables
  review:
    summary: >-
      The structural study supports APC/C subunit and E2/regulator interactions, but generic protein
      binding is not a useful core molecular-function annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Protein binding does not describe ANAPC2's specific activity; the informative function is
      cullin-like APC/C scaffold activity and contribution to ubiquitin ligase activity.
    supported_by:
    - reference_id: PMID:26083744
      supporting_text: >-
        These structures define the architecture of all APC/C subunits, the position of the catalytic
        module
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      This high-throughput binary interactome record is useful interaction context but not a core
      ANAPC2 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The HuRI-style protein-binding annotation records physical interaction data without establishing
      a specific ANAPC2 molecular activity or pathway role.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: >-
        HuRI provides an unbiased genome-scale scaffold with which to coordinate this information
        as it emerges.
- term:
    id: GO:0010629
    label: negative regulation of gene expression
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Negative regulation of gene expression is an indirect orthology-transferred process annotation,
      likely reflecting downstream APC/C substrate degradation rather than a direct ANAPC2 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      ANAPC2's core role is APC/C scaffold-dependent ubiquitination. A broad gene-expression regulation
      term loses the mechanistic APC/C context and should not be treated as a core annotation
      for human ANAPC2.
    supported_by:
    - reference_id: file:human/ANAPC2/ANAPC2-uniprot.txt
      supporting_text: >-
        Together with the RING-H2 protein ANAPC11, constitutes the catalytic component of the
        anaphase promoting complex/cyclosome
- term:
    id: GO:0031915
    label: positive regulation of synaptic plasticity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Synaptic plasticity is a broad orthology-derived neuronal process annotation and overstates
      the local ANAPC2 evidence; the cited UniProt text more directly supports presynaptic differentiation
      context.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      APC/C-CDC20 has neuronal roles by similarity, but the record does not establish human ANAPC2
      as a direct synaptic-plasticity regulator. In PN context this should not be treated as core
      proteostasis evidence.
    supported_by:
    - reference_id: file:human/ANAPC2/ANAPC2-uniprot.txt
      supporting_text: >-
        CDC20-APC/C-induced degradation of NEUROD2 drives presynaptic differentiation
- term:
    id: GO:0045773
    label: positive regulation of axon extension
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Positive regulation of axon extension is an over-specific orthology-transferred neuronal
      process annotation for ANAPC2.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The local UniProt text supports CDC20-APC/C presynaptic vesicle clustering and differentiation
      context by similarity, not axon extension specifically. ANAPC2's conserved core function
      is the APC/C scaffold/catalytic module.
    supported_by:
    - reference_id: file:human/ANAPC2/ANAPC2-uniprot.txt
      supporting_text: >-
        CDC20-APC/C complex positively regulates the formation of synaptic vesicle clustering
        at active zone to the presynaptic membrane in postmitotic neurons
- term:
    id: GO:0050775
    label: positive regulation of dendrite morphogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Positive regulation of dendrite morphogenesis is an over-specific orthology-transferred
      neuronal process annotation for ANAPC2.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The local UniProt text supports CDC20-APC/C presynaptic vesicle clustering and differentiation
      context by similarity, not dendrite morphogenesis specifically. ANAPC2's conserved core
      function is the APC/C scaffold/catalytic module.
    supported_by:
    - reference_id: file:human/ANAPC2/ANAPC2-uniprot.txt
      supporting_text: >-
        CDC20-APC/C complex positively regulates the formation of synaptic vesicle clustering
        at active zone to the presynaptic membrane in postmitotic neurons
- term:
    id: GO:0090129
    label: positive regulation of synapse maturation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Synapse maturation is retained as non-core orthology-derived context for CDC20-APC/C neuronal
      roles, not as ANAPC2's defining molecular function.
    action: KEEP_AS_NON_CORE
    reason: >-
      UniProt records CDC20-APC/C neuronal effects by similarity, but ANAPC2's conserved core
      function is the APC/C scaffold/catalytic module. These process terms should not drive PN
      proteostasis projection for ANAPC2.
    supported_by:
    - reference_id: file:human/ANAPC2/ANAPC2-uniprot.txt
      supporting_text: >-
        CDC20-APC/C-induced degradation of NEUROD2 drives presynaptic differentiation
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: >-
      Protein ubiquitination is a broad but correct process annotation for ANAPC2-containing APC/C.
    action: ACCEPT
    reason: >-
      ANAPC2 is part of the APC/C E3 ubiquitin ligase catalytic module, and APC/C catalyzes substrate
      ubiquitination through E2 enzymes.
    supported_by:
    - reference_id: PMID:16364912
      supporting_text: >-
        bound substrates are ubiquitinated by E2 enzymes that interact with a hetero-dimer of
        the RING subunit Apc11 and the cullin Apc2
    - reference_id: PMID:26083744
      supporting_text: >-
        the catalytic module comprising the RING subunit Apc11 and the C-terminal domain of Apc2
        (Apc2CTD)
    - reference_id: PMID:26083744
      supporting_text: >-
        Two cullin-RING E3 ubiquitin ligases, the APC/C and SCF, catalyze the ubiquitination of
        multiple cell cycle proteins to regulate their proteasome-mediated proteolysis.
- term:
    id: GO:0005680
    label: anaphase-promoting complex
  evidence_type: IPI
  original_reference_id: PMID:27120157
  qualifier: part_of
  review:
    summary: >-
      ANAPC2 is a core subunit of the anaphase-promoting complex/cyclosome.
    action: ACCEPT
    reason: >-
      This is the most specific cellular-component annotation for ANAPC2. Structural studies place
      Apc2 in APC/C particles and in the catalytic platform with Apc11.
    supported_by:
    - reference_id: PMID:16364912
      supporting_text: >-
        These proteins are located on the same side of the asymmetric APC/C, implying that this
        is where substrates are ubiquitinated.
    - reference_id: PMID:26083744
      supporting_text: >-
        These structures define the architecture of all APC/C subunits, the position of the catalytic
        module
- term:
    id: GO:0007346
    label: regulation of mitotic cell cycle
  evidence_type: NAS
  original_reference_id: PMID:15678131
  qualifier: involved_in
  review:
    summary: >-
      ANAPC2 supports mitotic cell-cycle regulation through APC/C-mediated ubiquitination and
      degradation of cell-cycle regulators.
    action: ACCEPT
    reason: >-
      This is a central biological process for APC/C rather than a secondary phenotype. The review
      article and structural work both support APC/C as a key cell-cycle ubiquitin ligase.
    supported_by:
    - reference_id: PMID:15678131
      supporting_text: >-
        Two different ubiquitin ligases play an important role in the cell cycle: the SCF (Skp1/Cullin/F-box)
        and the anaphase-promoting complex (APC).
    - reference_id: PMID:26083744
      supporting_text: >-
        Two cullin-RING E3 ubiquitin ligases, the APC/C and SCF, catalyze the ubiquitination of
        multiple cell cycle proteins to regulate their proteasome-mediated proteolysis.
- term:
    id: GO:0031145
    label: anaphase-promoting complex-dependent catabolic process
  evidence_type: NAS
  original_reference_id: PMID:15678131
  qualifier: involved_in
  review:
    summary: >-
      APC/C-dependent catabolic process is directly aligned with ANAPC2's role in APC/C substrate
      ubiquitination and proteasomal degradation.
    action: ACCEPT
    reason: >-
      ANAPC2 is part of the APC/C catalytic module, and APC/C-dependent ubiquitination of cell-cycle
      substrates is a core output of the complex.
    supported_by:
    - reference_id: PMID:26083744
      supporting_text: >-
        Two cullin-RING E3 ubiquitin ligases, the APC/C and SCF, catalyze the ubiquitination of
        multiple cell cycle proteins to regulate their proteasome-mediated proteolysis.
    - reference_id: PMID:27120157
      supporting_text: >-
        In eukaryotes, the anaphase-promoting complex (APC/C, also known as the cyclosome) regulates
        the ubiquitin-dependent proteolysis of specific cell-cycle proteins to coordinate chromosome
        segregation in mitosis and entry into the G1 phase.
    - reference_id: PMID:18485873
      supporting_text: >-
        The anaphase-promoting complex (APC/C) orchestrates progression through mitosis by decorating
        cell-cycle regulators with ubiquitin chains.
- term:
    id: GO:0051445
    label: regulation of meiotic cell cycle
  evidence_type: NAS
  original_reference_id: PMID:15678131
  qualifier: involved_in
  review:
    summary: >-
      Regulation of meiotic cell cycle is plausible APC/C biology but is not the main context
      for this human ANAPC2 review.
    action: KEEP_AS_NON_CORE
    reason: >-
      APC/C has essential meiotic functions, but the strongest ANAPC2 evidence here centers on
      the APC/C catalytic module and mitotic cell-cycle proteolysis. Retain as non-core.
    supported_by:
    - reference_id: PMID:16364912
      supporting_text: >-
        The anaphase-promoting complex/cyclosome (APC/C) is a ubiquitin ligase with essential
        functions in mitosis, meiosis, and G1 phase of the cell cycle.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Nucleoplasm is retained as APC/C reaction/localization context rather than a core molecular
      function.
    action: KEEP_AS_NON_CORE
    reason: >-
      ANAPC2 participates in APC/C reactions assigned to nuclear cell-cycle contexts, but localization
      terms are supportive context and not the gene product's core function.
    supported_by:
    - reference_id: PMID:26083744
      supporting_text: >-
        These structures define the architecture of all APC/C subunits, the position of the catalytic
        module
- term:
    id: GO:0005680
    label: anaphase-promoting complex
  evidence_type: NAS
  original_reference_id: PMID:27120157
  qualifier: part_of
  review:
    summary: >-
      ANAPC2 is a core subunit of the anaphase-promoting complex/cyclosome.
    action: ACCEPT
    reason: >-
      This is the most specific cellular-component annotation for ANAPC2. Structural studies place
      Apc2 in APC/C particles and in the catalytic platform with Apc11.
    supported_by:
    - reference_id: PMID:16364912
      supporting_text: >-
        These proteins are located on the same side of the asymmetric APC/C, implying that this
        is where substrates are ubiquitinated.
    - reference_id: PMID:26083744
      supporting_text: >-
        These structures define the architecture of all APC/C subunits, the position of the catalytic
        module
- term:
    id: GO:0141198
    label: protein branched polyubiquitination
  evidence_type: IDA
  original_reference_id: PMID:29033132
  qualifier: involved_in
  review:
    summary: >-
      Branched ubiquitin-chain assembly is supported for APC/C-dependent cell-cycle and protein-quality-control
      substrates.
    action: ACCEPT
    reason: >-
      The K11/K48 branched-chain paper supports APC/C-linked heterotypic ubiquitin chains, and
      ANAPC2 is part of the APC/C catalytic module that enables this output.
    supported_by:
    - reference_id: PMID:29033132
      supporting_text: >-
        engineered a bispecific antibody to detect K11/K48-linked chains and identified mitotic
        regulators, misfolded nascent polypeptides, and pathological Huntingtin variants as their
        endogenous substrates.
    - reference_id: PMID:29033132
      supporting_text: >-
        these conjugates promote rapid proteasomal clearance of aggregation-prone proteins.
    - reference_id: PMID:16364912
      supporting_text: >-
        bound substrates are ubiquitinated by E2 enzymes that interact with a hetero-dimer of
        the RING subunit Apc11 and the cullin Apc2
- term:
    id: GO:0031145
    label: anaphase-promoting complex-dependent catabolic process
  evidence_type: IDA
  original_reference_id: PMID:29033132
  qualifier: involved_in
  review:
    summary: >-
      APC/C-dependent catabolic process is directly aligned with ANAPC2's role in APC/C substrate
      ubiquitination and proteasomal degradation.
    action: ACCEPT
    reason: >-
      ANAPC2 is part of the APC/C catalytic module, and APC/C-dependent ubiquitination of cell-cycle
      substrates is a core output of the complex.
    supported_by:
    - reference_id: PMID:26083744
      supporting_text: >-
        Two cullin-RING E3 ubiquitin ligases, the APC/C and SCF, catalyze the ubiquitination of
        multiple cell cycle proteins to regulate their proteasome-mediated proteolysis.
    - reference_id: PMID:27120157
      supporting_text: >-
        In eukaryotes, the anaphase-promoting complex (APC/C, also known as the cyclosome) regulates
        the ubiquitin-dependent proteolysis of specific cell-cycle proteins to coordinate chromosome
        segregation in mitosis and entry into the G1 phase.
    - reference_id: PMID:18485873
      supporting_text: >-
        The anaphase-promoting complex (APC/C) orchestrates progression through mitosis by decorating
        cell-cycle regulators with ubiquitin chains.
- term:
    id: GO:0070936
    label: protein K48-linked ubiquitination
  evidence_type: IDA
  original_reference_id: PMID:29033132
  qualifier: involved_in
  review:
    summary: >-
      K48-linked ubiquitination is supported as part of APC/C-generated K11/K48 heterotypic chains
      and proteasomal clearance outputs.
    action: ACCEPT
    reason: >-
      Although APC/C is especially associated with K11-linked chains, the cited evidence supports
      K11/K48 branched conjugates that promote proteasomal clearance.
    supported_by:
    - reference_id: PMID:29033132
      supporting_text: >-
        engineered a bispecific antibody to detect K11/K48-linked chains and identified mitotic
        regulators, misfolded nascent polypeptides, and pathological Huntingtin variants as their
        endogenous substrates.
    - reference_id: PMID:29033132
      supporting_text: >-
        these conjugates promote rapid proteasomal clearance of aggregation-prone proteins.
- term:
    id: GO:0070979
    label: protein K11-linked ubiquitination
  evidence_type: IDA
  original_reference_id: PMID:29033132
  qualifier: involved_in
  review:
    summary: >-
      APC/C-dependent K11-linked ubiquitin-chain assembly is a well-supported output of the ANAPC2-containing
      APC/C catalytic module.
    action: ACCEPT
    reason: >-
      K11-linked ubiquitination is a core APC/C activity, and ANAPC2 is part of the catalytic
      Apc2-Apc11 module that positions the E2 machinery for substrate ubiquitination.
    supported_by:
    - reference_id: PMID:18485873
      supporting_text: >-
        We find that the APC/C triggers substrate degradation by assembling K11-linked ubiquitin
        chains
    - reference_id: PMID:29033132
      supporting_text: >-
        engineered a bispecific antibody to detect K11/K48-linked chains and identified mitotic
        regulators, misfolded nascent polypeptides, and pathological Huntingtin variants as their
        endogenous substrates.
    - reference_id: PMID:16364912
      supporting_text: >-
        bound substrates are ubiquitinated by E2 enzymes that interact with a hetero-dimer of
        the RING subunit Apc11 and the cullin Apc2
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-174057
  qualifier: located_in
  review:
    summary: >-
      Nucleoplasm is retained as APC/C reaction/localization context rather than a core molecular
      function.
    action: KEEP_AS_NON_CORE
    reason: >-
      ANAPC2 participates in APC/C reactions assigned to nuclear cell-cycle contexts, but localization
      terms are supportive context and not the gene product's core function.
    supported_by:
    - reference_id: Reactome:R-HSA-174057
      supporting_text: >-
        Cdh1 is multiubiquitinated by the APC/C:Cdh1 complex prior to degradation by the 26S proteasome.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-174058
  qualifier: located_in
  review:
    summary: >-
      Nucleoplasm is retained as APC/C reaction/localization context rather than a core molecular
      function.
    action: KEEP_AS_NON_CORE
    reason: >-
      ANAPC2 participates in APC/C reactions assigned to nuclear cell-cycle contexts, but localization
      terms are supportive context and not the gene product's core function.
    supported_by:
    - reference_id: Reactome:R-HSA-174058
      supporting_text: >-
        At the beginning of this reaction, 1 molecule of 'multiubiquitinated Cdh1 associated with
        APC/C' is present. At the end of this reaction, 1 molecule of 'phosphorylated anaphase
        promoting complex (APC/C)', and 3 molecules of 'ubiquitin' are present.<br><br> This reaction
        takes place in the 'nucleoplasm' and  is mediated by the 'endopeptidase activity' of '26S
        proteasome'.<br>
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-174079
  qualifier: located_in
  review:
    summary: >-
      Nucleoplasm is retained as APC/C reaction/localization context rather than a core molecular
      function.
    action: KEEP_AS_NON_CORE
    reason: >-
      ANAPC2 participates in APC/C reactions assigned to nuclear cell-cycle contexts, but localization
      terms are supportive context and not the gene product's core function.
    supported_by:
    - reference_id: Reactome:R-HSA-174079
      supporting_text: >-
        At the G1/S transition, the Cdh1 subunit of the APC:Cdh1 complex is phosphorylated by
        Cyclin A:Cdk2 and  dissociates from APC/C. This inactivates APC/C and permits the accumulation
        of cell cycle proteins required for DNA synthesis and entry into mitosis.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-174119
  qualifier: located_in
  review:
    summary: >-
      Nucleoplasm is retained as APC/C reaction/localization context rather than a core molecular
      function.
    action: KEEP_AS_NON_CORE
    reason: >-
      ANAPC2 participates in APC/C reactions assigned to nuclear cell-cycle contexts, but localization
      terms are supportive context and not the gene product's core function.
    supported_by:
    - reference_id: Reactome:R-HSA-174119
      supporting_text: >-
        Phosphorylation of the APC/C is believed to be required for its activation. While the
        identity of the essential phosphorylation sites and  the kinase(s) responsible  are not
        known with certainty, in vitro studies have shown that the Apc1 and the tetratricopeptide
        repeat (TPR) subunits Cdc27, Cdc16, Cdc23 and Apc7 are phosphorylated and that the Cdk1
        and Plk1 kinases may play a role.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-174132
  qualifier: located_in
  review:
    summary: >-
      Nucleoplasm is retained as APC/C reaction/localization context rather than a core molecular
      function.
    action: KEEP_AS_NON_CORE
    reason: >-
      ANAPC2 participates in APC/C reactions assigned to nuclear cell-cycle contexts, but localization
      terms are supportive context and not the gene product's core function.
    supported_by:
    - reference_id: Reactome:R-HSA-174132
      supporting_text: >-
        Phosphorylation of the APC/C is believed to be required for its activation. While the
        identity of the essential phosphorylation sites and  the kinase(s) responsible  are not
        known with certainty, in vitro studies have shown that the Apc1 and the tetratricopeptide
        repeat (TPR) subunits Cdc27, Cdc16, Cdc23 and Apc7 are phosphorylated and that the Cdk1
        and Plk1 kinases may play a role.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-174139
  qualifier: located_in
  review:
    summary: >-
      Nucleoplasm is retained as APC/C reaction/localization context rather than a core molecular
      function.
    action: KEEP_AS_NON_CORE
    reason: >-
      ANAPC2 participates in APC/C reactions assigned to nuclear cell-cycle contexts, but localization
      terms are supportive context and not the gene product's core function.
    supported_by:
    - reference_id: Reactome:R-HSA-174139
      supporting_text: >-
        Following its phosphorylation, Cdh1 dissociates from the APC/C, rendering the APC/C inactive.
        This allows the stabilization of proteins required for subsequent cell cycle progression.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-188191
  qualifier: located_in
  review:
    summary: >-
      Nucleoplasm is retained as APC/C reaction/localization context rather than a core molecular
      function.
    action: KEEP_AS_NON_CORE
    reason: >-
      ANAPC2 participates in APC/C reactions assigned to nuclear cell-cycle contexts, but localization
      terms are supportive context and not the gene product's core function.
    supported_by:
    - reference_id: Reactome:R-HSA-188191
      supporting_text: >-
        SKP2 is degraded by the anaphase promoting complex/Cyclosome and its activator FZR1 (Cdh1)
        [APC/C(Cdh1)] (Bashir et al, 2004; Wei et al, 2004). The tight regulation of APC/C(Cdh1)
        activity ensures the timely elimination SKP2 and, thus, plays a critical role in controlling
        the M/G1 transition (mitotic exit). APC/C:Cdh1-mediated degradation of SKP2 depends on
        RB1, as RB1 recruits SKP2 to the APC/C:Cdh1 complex, by simultaneously interacting with
        SKP2 and FZR1. RB1 does not undergo APC/C:Cdh1-mediated ubiquitination (Binne et al. 2007).
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-188371
  qualifier: located_in
  review:
    summary: >-
      Nucleoplasm is retained as APC/C reaction/localization context rather than a core molecular
      function.
    action: KEEP_AS_NON_CORE
    reason: >-
      ANAPC2 participates in APC/C reactions assigned to nuclear cell-cycle contexts, but localization
      terms are supportive context and not the gene product's core function.
    supported_by:
    - reference_id: Reactome:R-HSA-188371
      supporting_text: >-
        Cyclin A-Cdk2 prevents unscheduled APC reactivation during S phase by binding and subsequently
        phosphorylating Cdh1. Phosphorylation-dependent dissociation of the Cdh1-activating subunit
        inhibits the APC/C.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3788705
  qualifier: located_in
  review:
    summary: >-
      Nucleoplasm is retained as APC/C reaction/localization context rather than a core molecular
      function.
    action: KEEP_AS_NON_CORE
    reason: >-
      ANAPC2 participates in APC/C reactions assigned to nuclear cell-cycle contexts, but localization
      terms are supportive context and not the gene product's core function.
    supported_by:
    - reference_id: Reactome:R-HSA-3788705
      supporting_text: >-
        At the G1/S transition, the Cdh1 (FZR1) subunit of the APC/C:Cdh1 complex is phosphorylated
        by Cyclin A:Cdk2 (CCNA:CDK2) and dissociates from APC/C. This inactivates APC/C and permits
        the accumulation of cell cycle proteins required for DNA synthesis and entry into mitosis
        (Lukas et al. 1999).  Activation of the ATM kinase by DNA damage in the form of double
        strand breaks results in TP53-mediated induction of CDKN1A (p21) expression. CDKN1A binds
        CCNA:CDK2 complex and prevents it from phosphorylating Cdh1 (Takahashi et al. 2012).
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3788708
  qualifier: located_in
  review:
    summary: >-
      Nucleoplasm is retained as APC/C reaction/localization context rather than a core molecular
      function.
    action: KEEP_AS_NON_CORE
    reason: >-
      ANAPC2 participates in APC/C reactions assigned to nuclear cell-cycle contexts, but localization
      terms are supportive context and not the gene product's core function.
    supported_by:
    - reference_id: Reactome:R-HSA-3788708
      supporting_text: >-
        Cyclin A-Cdk2 (CCNA:CDK2) prevents unscheduled APC reactivation during S phase by binding
        and subsequently phosphorylating FZR1 (Cdh1). Phosphorylation-dependent dissociation of
        the Cdh1-activating subunit inhibits the APC/C (Sorensen et al. 2001). DNA damage activates
        ATM kinase, resulting in TP53-mediated induction of CDKN1A (p21) expression. CDKN1A binds
        CCNA:CDK2 complex and prevents its association with Cdh1 (Takahashi et al. 2012).
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3788724
  qualifier: located_in
  review:
    summary: >-
      Nucleoplasm is retained as APC/C reaction/localization context rather than a core molecular
      function.
    action: KEEP_AS_NON_CORE
    reason: >-
      ANAPC2 participates in APC/C reactions assigned to nuclear cell-cycle contexts, but localization
      terms are supportive context and not the gene product's core function.
    supported_by:
    - reference_id: Reactome:R-HSA-3788724
      supporting_text: >-
        Cdh1:APC/C complex, stabilized by the DNA damage-induced ATM-TP53-CDKN1A axis, ubiquitinates
        EHMT1 (GLP) and EHMT2 (G9a) histone methyltransferases, targeting them for degradation
        (Takahashi et al. 2012).
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3788725
  qualifier: located_in
  review:
    summary: >-
      Nucleoplasm is retained as APC/C reaction/localization context rather than a core molecular
      function.
    action: KEEP_AS_NON_CORE
    reason: >-
      ANAPC2 participates in APC/C reactions assigned to nuclear cell-cycle contexts, but localization
      terms are supportive context and not the gene product's core function.
    supported_by:
    - reference_id: Reactome:R-HSA-3788725
      supporting_text: >-
        Cdh1 (FZR1) is able to bind both G9a (EHMT2) and GLP (EHMT1) (Takahashi et al. 2012).
        EHMT1 and EHMT2 histone methyltransferases were shown to function as a heterodimer in
        vivo (Tachibana et al. 2005).
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-68712
  qualifier: located_in
  review:
    summary: >-
      Nucleoplasm is retained as APC/C reaction/localization context rather than a core molecular
      function.
    action: KEEP_AS_NON_CORE
    reason: >-
      ANAPC2 participates in APC/C reactions assigned to nuclear cell-cycle contexts, but localization
      terms are supportive context and not the gene product's core function.
    supported_by:
    - reference_id: Reactome:R-HSA-68712
      supporting_text: >-
        From the end of anaphase and throughout G1, the Cdh1 (FZR1) containing anaphase-promoting
        complex (APC/C:Cdh1) ubiquitinates geminin (GMNN), targeting it for degradation and enabling
        release of CDT1 and the subsequent association of CDT1 with the replication origins.The
        presence of an APC destruction box in geminin and its APC/C-mediated ubiquitination and
        degradation was first demonstrated in Xenopus egg extracts (McGarry and Kirschner 1998)
        and was later confirmed in human cells, where it was shown to largely depend on Cdh1 and
        not Cdc20 component of the APC/C (Pfleger et al. 2001; Di Fiore and Pines 2007; Machida
        and Dutta 2007). Emi1 (FBXO5) mediated inhibition of the APC/C:Cdh1 complex in S and G2
        phases is needed for stabilization of geminin and prevention of re-replication (Di Fiore
        and Pines 2007; Machida and Dutta 2007).
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9686969
  qualifier: located_in
  review:
    summary: >-
      Nucleoplasm is retained as APC/C reaction/localization context rather than a core molecular
      function.
    action: KEEP_AS_NON_CORE
    reason: >-
      ANAPC2 participates in APC/C reactions assigned to nuclear cell-cycle contexts, but localization
      terms are supportive context and not the gene product's core function.
    supported_by:
    - reference_id: Reactome:R-HSA-9686969
      supporting_text: >-
        RB1-dependent polyubiquitination of SKP2 by the APC/C:Cdh1 complex is an important mechanism
        of RB1-mediated cell cycle exit, which contributes to the RB1 tumor suppressive role.
        ABC/C:Cdh1-mediated polyubiquitination targets SKP2 for proteasome-mediated degradation.
        RB1 and APC/C:Cdh1-dependent degradation of SKP2 allows accumulation of CDKN1B (p27Kip1)
        in the cell, as CDKN1B is a target of the SKP2-containing SCF ubiquitin ligase complex.
        CDKN1B acts as a CDK inhibitor, enabling mitotic exit (Ji et al. 2004, Binne et al. 2007).
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9686980
  qualifier: located_in
  review:
    summary: >-
      Nucleoplasm is retained as APC/C reaction/localization context rather than a core molecular
      function.
    action: KEEP_AS_NON_CORE
    reason: >-
      ANAPC2 participates in APC/C reactions assigned to nuclear cell-cycle contexts, but localization
      terms are supportive context and not the gene product's core function.
    supported_by:
    - reference_id: Reactome:R-HSA-9686980
      supporting_text: >-
        The pocket domain of the RB1 tumor suppressor protein binds to the N-terminal domain of
        SKP2, a component of the SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex,
        whose targets include the cyclin-dependent kinase (CDK) inhibitor p27Kip1 (CDKN1B) (Ji
        et al. 2004, Binne et al. 2007). RB1 is able to simultanously interact with SKP2 and with
        FZR1 (Cdh1). FZR1 is a substrate-specific adapter for the anaphase promoting complex/cyclosome
        (APC/C). The interaction with FZR1 involves a different subregion of the pocket domain
        than the interaction with SKP2, and is partially dependent on the LxCxE binding cleft
        (Binne et al. 2007).
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9687377
  qualifier: located_in
  review:
    summary: >-
      Nucleoplasm is retained as APC/C reaction/localization context rather than a core molecular
      function.
    action: KEEP_AS_NON_CORE
    reason: >-
      ANAPC2 participates in APC/C reactions assigned to nuclear cell-cycle contexts, but localization
      terms are supportive context and not the gene product's core function.
    supported_by:
    - reference_id: Reactome:R-HSA-9687377
      supporting_text: >-
        A tripartite complex formed between RB1, SKP2 and FZR1 (Cdh1) targets SKP2 for the anaphase
        promoting complex/cyclosome (APC/C:Cdh1)-mediated ubiquitination and subsequent proteasome-mediated
        degradation. Both SKP2 and FZR1 interact with the pocket domain of RB1, with amino acid
        residues 637–738 and 772–824 involved in SKP2 binding and the cleft region (amino acids
        753–761), containing the LxCxE motif, involved in FZR1 binding (Binne et al. 2007). RB1
        T738_R775del (RB1 Ex22del) cancer mutant, which lacks exon 22, is able to associate with
        SKP2 but unable to bind FZR1. This mutant is defective in inducing accumulation of CDKN1B
        (p27Kip1) and promoting mitotic exit as it cannot prevent SKP2-mediated ubiquitination
        and degradation of CDKN1B (Ji et al. 2004, Binne et al. 2007). RB1 T738_R775del mutant
        is also defective in E2F binding (Ji et al. 2004). RB1 missense mutant, RB1 R661W, which
        causes low penetrance familial retinoblastoma, is unable to bind to E2Fs but retains the
        ability to bind to SKP2 and FZR2 and to induce CDKN1B accumulation (Ji et al. 2004, Binne
        et al. 2007).
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-141423
  qualifier: located_in
  review:
    summary: >-
      Cytosol is retained as APC/C reaction/localization context rather than a core molecular
      function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Reactome places some APC/C reactions in cytosolic contexts. This supports localization context
      for ANAPC2-containing APC/C but not a defining activity.
    supported_by:
    - reference_id: Reactome:R-HSA-141423
      supporting_text: >-
        In the direct inhibition model, association of the MCC with APCC results in the inactivation
        of APC/C. However, the affinity between MCC and APC/C is not high, so that the inhibition
        is readily reversible. The role of unattached kinetochores is to sensitize the APC/C to
        prolonged inhibition by the MCC.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-174070
  qualifier: located_in
  review:
    summary: >-
      Cytosol is retained as APC/C reaction/localization context rather than a core molecular
      function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Reactome places some APC/C reactions in cytosolic contexts. This supports localization context
      for ANAPC2-containing APC/C but not a defining activity.
    supported_by:
    - reference_id: Reactome:R-HSA-174070
      supporting_text: >-
        Following its dephosphorylation in late mitosis, Cdh1 replaces Cdc20 as the APC/C activator.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-174088
  qualifier: located_in
  review:
    summary: >-
      Cytosol is retained as APC/C reaction/localization context rather than a core molecular
      function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Reactome places some APC/C reactions in cytosolic contexts. This supports localization context
      for ANAPC2-containing APC/C but not a defining activity.
    supported_by:
    - reference_id: Reactome:R-HSA-174088
      supporting_text: >-
        The APC/C:Cdh1 complex recognizes substrates containing  a D box, a KEN box  (Pfleger
        and Kirschner, 2000) or a D box activated  (DAD) domain (Castro et al., 2002).
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-174104
  qualifier: located_in
  review:
    summary: >-
      Cytosol is retained as APC/C reaction/localization context rather than a core molecular
      function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Reactome places some APC/C reactions in cytosolic contexts. This supports localization context
      for ANAPC2-containing APC/C but not a defining activity.
    supported_by:
    - reference_id: Reactome:R-HSA-174104
      supporting_text: >-
        Rape et al. have recently demonstrated that the order in which APC/C targeted proteins
        are degraded is determined by the processivity of multiubiquitination of these substrates.
        Processive substrates acquire a polyubiquitin chain upon binding to the APC/C once and
        are degraded. Distributive substrates bind, dissociate and reassociate with the APC/C
        multiple times before acquiring an ubiquitin chain of sufficient length to insure degradation.  In
        addition, distributive substrates that dissociate from the APC/C with short ubiquitin
        chains are targeted for deubiquitination (Rape et al., 2006). Paradoxically, although
        the multiubiquitination of cyclin A is distributive and later substrates of APC-Cdc20
        such as Securin are processive (Rape et al., 2006), Cyclin A is degraded prior to Securin
        and Cyclin B. The mechanisms insuring this order have not yet be determined.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-174105
  qualifier: located_in
  review:
    summary: >-
      Cytosol is retained as APC/C reaction/localization context rather than a core molecular
      function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Reactome places some APC/C reactions in cytosolic contexts. This supports localization context
      for ANAPC2-containing APC/C but not a defining activity.
    supported_by:
    - reference_id: Reactome:R-HSA-174105
      supporting_text: >-
        Cell cycle proteins mulitubiquitinated by the APC/C are targeted for degradation by the
        26S proteasome.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-174120
  qualifier: located_in
  review:
    summary: >-
      Cytosol is retained as APC/C reaction/localization context rather than a core molecular
      function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Reactome places some APC/C reactions in cytosolic contexts. This supports localization context
      for ANAPC2-containing APC/C but not a defining activity.
    supported_by:
    - reference_id: Reactome:R-HSA-174120
      supporting_text: >-
        Cyclin B is believed to be recognized by the APC/C:Cdc20 complex through its D-box sequence.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-174121
  qualifier: located_in
  review:
    summary: >-
      Cytosol is retained as APC/C reaction/localization context rather than a core molecular
      function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Reactome places some APC/C reactions in cytosolic contexts. This supports localization context
      for ANAPC2-containing APC/C but not a defining activity.
    supported_by:
    - reference_id: Reactome:R-HSA-174121
      supporting_text: >-
        Securin is thought to be recognized by the APC/C:Cdc20 complex through its conserved D-box
        sequence.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-174144
  qualifier: located_in
  review:
    summary: >-
      Cytosol is retained as APC/C reaction/localization context rather than a core molecular
      function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Reactome places some APC/C reactions in cytosolic contexts. This supports localization context
      for ANAPC2-containing APC/C but not a defining activity.
    supported_by:
    - reference_id: Reactome:R-HSA-174144
      supporting_text: >-
        Securin is ubiquitinated by APC/C:Cdc20 (Hagting et al., 2002; Jin et al. 2008).
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-174157
  qualifier: located_in
  review:
    summary: >-
      Cytosol is retained as APC/C reaction/localization context rather than a core molecular
      function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Reactome places some APC/C reactions in cytosolic contexts. This supports localization context
      for ANAPC2-containing APC/C but not a defining activity.
    supported_by:
    - reference_id: Reactome:R-HSA-174157
      supporting_text: >-
        Mulitubiquitinated Cyclin B is targeted for degradation by the 26S proteasome.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-174171
  qualifier: located_in
  review:
    summary: >-
      Cytosol is retained as APC/C reaction/localization context rather than a core molecular
      function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Reactome places some APC/C reactions in cytosolic contexts. This supports localization context
      for ANAPC2-containing APC/C but not a defining activity.
    supported_by:
    - reference_id: Reactome:R-HSA-174171
      supporting_text: >-
        Cyclin A is believed to be recognized by the APC/C:Cdc20 complex through its D-box sequence,
        which is 10-20 residues longer than the D-box of cyclin B (Geley et al., 2001).
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-174195
  qualifier: located_in
  review:
    summary: >-
      Cytosol is retained as APC/C reaction/localization context rather than a core molecular
      function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Reactome places some APC/C reactions in cytosolic contexts. This supports localization context
      for ANAPC2-containing APC/C but not a defining activity.
    supported_by:
    - reference_id: Reactome:R-HSA-174195
      supporting_text: >-
        At the beginning of this reaction, 3 molecules of 'ubiquitin', and 1 molecule of 'cell
        cycle proteins:phospho-APC/C:Cdh1 complex' are present. At the end of this reaction, 1
        molecule of 'multiubiquitinated cell cycle protein:APC/C:Cdh1 complex' is present.<br><br>
        This reaction takes place in the 'cytosol' and  is mediated by the 'ubiquitin-protein
        ligase activity' of 'cell cycle proteins:phospho-APC/C:Cdh1 complex' (Rape et al.1996).<br>
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-174202
  qualifier: located_in
  review:
    summary: >-
      Cytosol is retained as APC/C reaction/localization context rather than a core molecular
      function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Reactome places some APC/C reactions in cytosolic contexts. This supports localization context
      for ANAPC2-containing APC/C but not a defining activity.
    supported_by:
    - reference_id: Reactome:R-HSA-174202
      supporting_text: >-
        Following ubiquitination, securin is degraded by the 26S proteasome.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-174224
  qualifier: located_in
  review:
    summary: >-
      Cytosol is retained as APC/C reaction/localization context rather than a core molecular
      function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Reactome places some APC/C reactions in cytosolic contexts. This supports localization context
      for ANAPC2-containing APC/C but not a defining activity.
    supported_by:
    - reference_id: Reactome:R-HSA-174224
      supporting_text: >-
        In late mitosis, Cdc20 dissociates from the APC/C and is replaced by the activator Cdh1
        (Ballabeni et al. 2011).
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-174227
  qualifier: located_in
  review:
    summary: >-
      Cytosol is retained as APC/C reaction/localization context rather than a core molecular
      function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Reactome places some APC/C reactions in cytosolic contexts. This supports localization context
      for ANAPC2-containing APC/C but not a defining activity.
    supported_by:
    - reference_id: Reactome:R-HSA-174227
      supporting_text: >-
        At the beginning of this reaction, 1 molecule of 'Cdc20:phospho-APC/C:Cyclin B:Cdc2 complex',
        and 3 molecules of 'ubiquitin' are present. At the end of this reaction, 1 molecule of
        'multiubiquitinated Cyclin B:Cdc2:Cdc20:phospho-APC/C complex' is present.<br><br> This
        reaction takes place in the 'cytosol' and  is mediated by the 'ubiquitin-protein ligase
        activity' of 'Cdc20:Phospho-APC/C'.<br>
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-174238
  qualifier: located_in
  review:
    summary: >-
      Cytosol is retained as APC/C reaction/localization context rather than a core molecular
      function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Reactome places some APC/C reactions in cytosolic contexts. This supports localization context
      for ANAPC2-containing APC/C but not a defining activity.
    supported_by:
    - reference_id: Reactome:R-HSA-174238
      supporting_text: >-
        One model ( the direct inhibition model) describing the inhibition of the APC/C during
        the mitotic spindle checkpoint suggests that the association of the hBUBR1:hBUB3:MAD2*:CDC20  mitotic
        checkpoint complex (MCC) with APC/C results in the inactivation of APC/C. The affinity
        between MCC and APC/C is not high,  thus inhibition is readily reversible when the mitotic
        spindle checkpoint has been satisfied.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-174255
  qualifier: located_in
  review:
    summary: >-
      Cytosol is retained as APC/C reaction/localization context rather than a core molecular
      function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Reactome places some APC/C reactions in cytosolic contexts. This supports localization context
      for ANAPC2-containing APC/C but not a defining activity.
    supported_by:
    - reference_id: Reactome:R-HSA-174255
      supporting_text: >-
        Following multiubiquitination, Cyclin A is targeted for destruction by the 26S proteasome.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-179410
  qualifier: located_in
  review:
    summary: >-
      Cytosol is retained as APC/C reaction/localization context rather than a core molecular
      function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Reactome places some APC/C reactions in cytosolic contexts. This supports localization context
      for ANAPC2-containing APC/C but not a defining activity.
    supported_by:
    - reference_id: Reactome:R-HSA-179410
      supporting_text: >-
        Nek2A does not appear to be recruited to the APC/C by Cdc20 but rather binds directly
        to the APC/C in an interaction involving the NEK2A C-terminal methionine–arginine (MR)
        dipeptide tail (Hayes et al., 2006).
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-179417
  qualifier: located_in
  review:
    summary: >-
      Cytosol is retained as APC/C reaction/localization context rather than a core molecular
      function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Reactome places some APC/C reactions in cytosolic contexts. This supports localization context
      for ANAPC2-containing APC/C but not a defining activity.
    supported_by:
    - reference_id: Reactome:R-HSA-179417
      supporting_text: >-
        Nek2A is ubiquitinated by the APC/C-Cdc20 ubiquitin ligase.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-179421
  qualifier: located_in
  review:
    summary: >-
      Cytosol is retained as APC/C reaction/localization context rather than a core molecular
      function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Reactome places some APC/C reactions in cytosolic contexts. This supports localization context
      for ANAPC2-containing APC/C but not a defining activity.
    supported_by:
    - reference_id: Reactome:R-HSA-179421
      supporting_text: >-
        Nek2A is degraded by the 26S proteasome following ubiquitylation by the E3 ubiquitin ligase
        APC/C: Cdc20.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-69015
  qualifier: located_in
  review:
    summary: >-
      Cytosol is retained as APC/C reaction/localization context rather than a core molecular
      function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Reactome places some APC/C reactions in cytosolic contexts. This supports localization context
      for ANAPC2-containing APC/C but not a defining activity.
    supported_by:
    - reference_id: Reactome:R-HSA-69015
      supporting_text: >-
        At the beginning of this reaction, 1 molecule of 'phosphorylated Cdc6', 1 molecule of
        'ubiquitin', and 1 molecule of 'ATP' are present. At the end of this reaction, 1 molecule
        of 'ubiquitinated Cdc6' is present.<br><br> This reaction takes place in the 'cytosol'
        and  is mediated by the 'endopeptidase activity' of 'anaphase-promoting complex (APC)'.<br>
- term:
    id: GO:0031915
    label: positive regulation of synaptic plasticity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      Synaptic plasticity is a broad orthology-derived neuronal process annotation and overstates
      the local ANAPC2 evidence; the cited UniProt text more directly supports presynaptic differentiation
      context.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      APC/C-CDC20 has neuronal roles by similarity, but the record does not establish human ANAPC2
      as a direct synaptic-plasticity regulator. In PN context this should not be treated as core
      proteostasis evidence.
    supported_by:
    - reference_id: file:human/ANAPC2/ANAPC2-uniprot.txt
      supporting_text: >-
        CDC20-APC/C-induced degradation of NEUROD2 drives presynaptic differentiation
- term:
    id: GO:0090129
    label: positive regulation of synapse maturation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      Synapse maturation is retained as non-core orthology-derived context for CDC20-APC/C neuronal
      roles, not as ANAPC2's defining molecular function.
    action: KEEP_AS_NON_CORE
    reason: >-
      UniProt records CDC20-APC/C neuronal effects by similarity, but ANAPC2's conserved core
      function is the APC/C scaffold/catalytic module. These process terms should not drive PN
      proteostasis projection for ANAPC2.
    supported_by:
    - reference_id: file:human/ANAPC2/ANAPC2-uniprot.txt
      supporting_text: >-
        CDC20-APC/C-induced degradation of NEUROD2 drives presynaptic differentiation
- term:
    id: GO:0005680
    label: anaphase-promoting complex
  evidence_type: IDA
  original_reference_id: PMID:16364912
  qualifier: part_of
  review:
    summary: >-
      ANAPC2 is a core subunit of the anaphase-promoting complex/cyclosome.
    action: ACCEPT
    reason: >-
      This is the most specific cellular-component annotation for ANAPC2. Structural studies place
      Apc2 in APC/C particles and in the catalytic platform with Apc11.
    supported_by:
    - reference_id: PMID:16364912
      supporting_text: >-
        These proteins are located on the same side of the asymmetric APC/C, implying that this
        is where substrates are ubiquitinated.
    - reference_id: PMID:26083744
      supporting_text: >-
        These structures define the architecture of all APC/C subunits, the position of the catalytic
        module
- term:
    id: GO:0070979
    label: protein K11-linked ubiquitination
  evidence_type: IDA
  original_reference_id: PMID:18485873
  qualifier: involved_in
  review:
    summary: >-
      APC/C-dependent K11-linked ubiquitin-chain assembly is a well-supported output of the ANAPC2-containing
      APC/C catalytic module.
    action: ACCEPT
    reason: >-
      K11-linked ubiquitination is a core APC/C activity, and ANAPC2 is part of the catalytic
      Apc2-Apc11 module that positions the E2 machinery for substrate ubiquitination.
    supported_by:
    - reference_id: PMID:18485873
      supporting_text: >-
        We find that the APC/C triggers substrate degradation by assembling K11-linked ubiquitin
        chains
    - reference_id: PMID:29033132
      supporting_text: >-
        engineered a bispecific antibody to detect K11/K48-linked chains and identified mitotic
        regulators, misfolded nascent polypeptides, and pathological Huntingtin variants as their
        endogenous substrates.
    - reference_id: PMID:16364912
      supporting_text: >-
        bound substrates are ubiquitinated by E2 enzymes that interact with a hetero-dimer of
        the RING subunit Apc11 and the cullin Apc2
- term:
    id: GO:0160072
    label: ubiquitin ligase complex scaffold activity
  evidence_type: IC
  original_reference_id: PMID:26083744
  qualifier: enables
  review:
    summary: >-
      PN projects ubiquitin ligase complex scaffold activity for ANAPC2. Gene-level review supports
      this as a conservative NEW annotation because ANAPC2 is the cullin-like APC/C scaffold subunit
      that forms the Apc2-Apc11 catalytic module.
    action: NEW
    reason: >-
      The PN candidate is not accepted solely from taxonomy. It is supported by UniProt cullin-family
      annotation and structural literature describing Apc2 with Apc11 as the APC/C catalytic module.
      This is more specific than generic protein binding and complements existing APC/C component
      annotations.
    additional_reference_ids:
    - file:human/ANAPC2/ANAPC2-notes.md
    supported_by:
    - reference_id: PMID:16364912
      supporting_text: >-
        bound substrates are ubiquitinated by E2 enzymes that interact with a hetero-dimer of
        the RING subunit Apc11 and the cullin Apc2
    - reference_id: PMID:11739784
      supporting_text: >-
        a heterodimeric complex of APC2 and APC11 is sufficient to catalyze the ubiquitination
        of human securin and cyclin B1
    - reference_id: PMID:26083744
      supporting_text: >-
        the catalytic module comprising the RING subunit Apc11 and the C-terminal domain of Apc2
        (Apc2CTD)
    - reference_id: file:human/ANAPC2/ANAPC2-uniprot.txt
      supporting_text: >-
        Belongs to the cullin family.
    - reference_id: file:human/ANAPC2/ANAPC2-notes.md
      supporting_text: >-
        Conservative decision: ANAPC2 is not a canonical cullin like CUL1-CUL5, but the cached
        literature supports a cullin-like APC/C scaffold role.
references:
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs 
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000041
  title: Gene Ontology annotation based on UniPathway vocabulary mapping
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to 
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: PMID:15678131
  title: 'The anaphase-promoting complex: a key factor in the regulation of cell cycle.'
  findings: []
- id: PMID:16364912
  title: Localization of the coactivator Cdh1 and the cullin subunit Apc2 in a cryo-electron
    microscopy model of vertebrate APC/C.
  findings:
  - statement: >-
      APC/C is a ubiquitin ligase with essential mitotic, meiotic, and G1 functions.
  - statement: >-
      Apc2 and Apc11 form the cullin/RING side of APC/C where substrates are ubiquitinated.
  full_text_unavailable: true
- id: PMID:11739784
  title: APC2 Cullin protein and APC11 RING protein comprise the minimal ubiquitin ligase
    module of the anaphase-promoting complex.
  findings:
  - statement: >-
      Human APC2 with APC11 reconstitutes a minimal APC/C ubiquitin ligase module that ubiquitinates
      securin and cyclin B1 with Ubc4 or UbcH10, while lacking substrate specificity alone.
  full_text_unavailable: true
- id: PMID:18485873
  title: Mechanism of ubiquitin-chain formation by the human anaphase-promoting complex.
  findings:
  - statement: >-
      Human APC/C assembles K11-linked ubiquitin chains that support substrate degradation.
- id: PMID:23708001
  title: Emi1 preferentially inhibits ubiquitin chain elongation by the anaphase-promoting 
    complex.
  findings:
  - statement: >-
      Emi1 inhibits APC/C chain elongation in part by blocking Ube2S binding to the APC cullin
      subunit.
  full_text_unavailable: true
- id: PMID:26083744
  title: 'Atomic structure of the APC/C and its mechanism of protein ubiquitination.'
  findings:
  - statement: >-
      Cryo-EM structures define the architecture of APC/C subunits and the catalytic module.
  - statement: >-
      The Apc2-Apc11 catalytic module provides structural support for a scaffold interpretation
      of ANAPC2.
- id: PMID:27120157
  title: Molecular mechanism of APC/C activation by mitotic phosphorylation.
  findings:
  - statement: >-
      APC/C regulates ubiquitin-dependent proteolysis of cell-cycle proteins during mitosis and
      G1 entry.
- id: PMID:29033132
  title: Assembly and Function of Heterotypic Ubiquitin Chains in Cell-Cycle and Protein 
    Quality Control.
  findings:
  - statement: >-
      K11/K48 branched ubiquitin chains occur on mitotic regulators and proteostasis substrates
      and promote rapid proteasomal clearance.
  full_text_unavailable: true
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings:
  - statement: >-
      HuRI provides high-throughput binary protein-interaction context; individual PPIs need functional
      interpretation.
- id: PMID:37735619
  title: Time-resolved cryo-EM (TR-EM) analysis of substrate polyubiquitination by the RING E3
    anaphase-promoting complex/cyclosome (APC/C).
  full_text_unavailable: true
  findings:
  - statement: >-
      Time-resolved cryo-EM of active human APC/C shows the priming E2 UBE2C is clasped by the
      ANAPC11 RING and the ANAPC2 (APC2) WHB region, while the elongation E2 UBE2S C-terminal peptide
      binds a groove formed by ANAPC2-ANAPC4, supporting a direct E2-docking role for ANAPC2.
  - statement: >-
      The ANAPC2-ANAPC11 catalytic arm samples autoinhibited "CRL down" and active "CRL up" states,
      and UBE2S allosterically stabilizes the "CRL up" state to potentiate processive substrate
      polyubiquitination.
- id: PMID:39567505
  title: 'Cryo-EM structures of apo-APC/C and APC/C(CDH1:EMI1) complexes provide insights into
    APC/C regulation.'
  full_text_unavailable: true
  findings:
  - statement: >-
      High-resolution cryo-EM identified a previously unreported zinc-binding module in ANAPC2 (APC2)
      that confers structural stability to the APC/C, with zinc ions confirmed experimentally.
  - statement: >-
      The structures resolve EMI1 inhibitor and CDH1 contacts on the APC/C catalytic platform that
      includes ANAPC2.
- id: PMID:36548081
  title: The UBE2C/CDH1/DEPTOR axis is an oncogene and tumor suppressor cascade in lung cancer
    cells.
  full_text_unavailable: true
  findings:
  - statement: >-
      APC/C-CDH1 with the E2 UBE2C ubiquitylates and degrades DEPTOR to activate mTORC signaling,
      and knockdown of APC2 or CDH1 increased DEPTOR protein, indicating ANAPC2-containing APC/C is
      required for DEPTOR turnover in lung cancer cells.
- id: Reactome:R-HSA-141423
  title: Binding of the MCC complex to the APC/C complex
  findings: []
- id: Reactome:R-HSA-174057
  title: Multiubiquitination of APC/C-associated Cdh1
  findings: []
- id: Reactome:R-HSA-174058
  title: Degradation of multiubiquitinated Cdh1
  findings: []
- id: Reactome:R-HSA-174070
  title: Association of Cdh1 with the APC/C
  findings: []
- id: Reactome:R-HSA-174079
  title: Phosphorylation of Cdh1 by Cyclin A:Cdk2
  findings: []
- id: Reactome:R-HSA-174088
  title: Association of cell cycle proteins with the APC/C:Cdh1 complex
  findings: []
- id: Reactome:R-HSA-174104
  title: Ubiquitination of Cyclin A by APC/C:Cdc20 complex
  findings: []
- id: Reactome:R-HSA-174105
  title: Degradation of multiubiquitinated cell cycle proteins
  findings: []
- id: Reactome:R-HSA-174119
  title: Free APC/C phosphorylated by Plk1
  findings: []
- id: Reactome:R-HSA-174120
  title: Association of Cyclin B:Cdc2 with Cdc20:APC/C complex
  findings: []
- id: Reactome:R-HSA-174121
  title: Association of Securin with Cdc20:APC/C complex
  findings: []
- id: Reactome:R-HSA-174132
  title: Free APC/C phosphorylated by Cyclin B:Cdc2
  findings: []
- id: Reactome:R-HSA-174139
  title: Dissociation of phospho-Cdh1 from the APC/C complex
  findings: []
- id: Reactome:R-HSA-174144
  title: Ubiquitination of Securin by phospho-APC/C:Cdc20 complex
  findings: []
- id: Reactome:R-HSA-174157
  title: Degradation of multiubiquitinated Cyclin B
  findings: []
- id: Reactome:R-HSA-174171
  title: Association of Cyclin A with the APC/C
  findings: []
- id: Reactome:R-HSA-174195
  title: Ubiquitination of cell cycle proteins targeted by the APC/C:Cdh1complex
  findings: []
- id: Reactome:R-HSA-174202
  title: Degradation of multiubiquitinated Securin
  findings: []
- id: Reactome:R-HSA-174224
  title: Dissociation of Cdc20 from APC/C complex
  findings: []
- id: Reactome:R-HSA-174227
  title: Ubiquitination of Cyclin B by phospho-APC/C:Cdc20 complex
  findings: []
- id: Reactome:R-HSA-174238
  title: Activation of APC/C:Cdc20 by dissociation of Cdc20:phospho-APC/C from 
    Cdc20:phospho-APC/C:Mad2:Bub3:BubR1
  findings: []
- id: Reactome:R-HSA-174255
  title: Degradation multiubiquitinated Cyclin A
  findings: []
- id: Reactome:R-HSA-179410
  title: Association of Nek2A with MCC:APC/C
  findings: []
- id: Reactome:R-HSA-179417
  title: Multiubiquitination of Nek2A
  findings: []
- id: Reactome:R-HSA-179421
  title: Degradation of multiubiquitinated Nek2A
  findings: []
- id: Reactome:R-HSA-188191
  title: APC/C:Cdh1-mediated degradation of Skp2
  findings: []
- id: Reactome:R-HSA-188371
  title: Association of Cyclin A:Cdk2 with Cdh1
  findings: []
- id: Reactome:R-HSA-3788705
  title: CDKN1A (p21) prevents phosphorylation of Cdh1 by Cyclin A:Cdk2
  findings: []
- id: Reactome:R-HSA-3788708
  title: CDKN1A (p21) prevents association of Cyclin A:Cdk2 with Cdh1
  findings: []
- id: Reactome:R-HSA-3788724
  title: Cdh1:APC/C ubiquitinates EHMT1 and EHMT2
  findings: []
- id: Reactome:R-HSA-3788725
  title: Cdh1:APC/C complex binds EHMT1:EHMT2
  findings: []
- id: Reactome:R-HSA-68712
  title: The geminin component of geminin:Cdt1 complexes is ubiquitinated, releasing Cdt1
  findings: []
- id: Reactome:R-HSA-69015
  title: Cytoplasmic phosphorylated Cdc6 is ubiquitinated by the anaphase-promoting complex
  findings: []
- id: Reactome:R-HSA-9686969
  title: APC/C:Cdh1 polyubiquitinates SKP2
  findings: []
- id: Reactome:R-HSA-9686980
  title: RB1 recruits APC/C:Cdh1 complex to SKP2
  findings: []
- id: Reactome:R-HSA-9687377
  title: Defective RB1 does not form a complex with SKP2 and FZR1
  findings: []
- id: file:human/ANAPC2/ANAPC2-uniprot.txt
  title: UniProtKB record for human ANAPC2
  findings:
  - statement: >-
      UniProt describes ANAPC2 as the cullin-family APC/C subunit that works with ANAPC11 in the
      APC/C catalytic component.
- id: file:human/ANAPC2/ANAPC2-notes.md
  title: ANAPC2 review notes and PN projection assessment
  findings:
  - statement: >-
      Falcon deep research timed out and the configured Perplexity fallback failed with quota
      error.
  - statement: >-
      The PN scaffold projection was accepted only after gene-level review of ANAPC2 structural
      evidence.
- id: file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
  title: PN projected gene-GO summary report
  findings:
  - statement: >-
      ANAPC2 already has exact APC/C complex coverage and entailed ubiquitin ligase complex coverage
      in GOA.
- id: file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_candidate_additions.tsv
  title: PN projected candidate additions report
  findings:
  - statement: >-
      ANAPC2 has a new-to-GOA PN candidate for GO:0160072 ubiquitin ligase complex scaffold activity.
core_functions:
- molecular_function:
    id: GO:0160072
    label: ubiquitin ligase complex scaffold activity
  contributes_to_molecular_function:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  description: >-
    ANAPC2 is the cullin-like scaffold subunit of the APC/C catalytic module. Together with ANAPC11,
    it positions the RING/E2 ubiquitination machinery in the anaphase-promoting complex, enabling
    substrate ubiquitination and ordered proteasome-mediated turnover of cell-cycle regulators.
  directly_involved_in:
  - id: GO:0016567
    label: protein ubiquitination
  - id: GO:0070979
    label: protein K11-linked ubiquitination
  - id: GO:0031145
    label: anaphase-promoting complex-dependent catabolic process
  - id: GO:0007091
    label: metaphase/anaphase transition of mitotic cell cycle
  in_complex:
    id: GO:0005680
    label: anaphase-promoting complex
  supported_by:
  - reference_id: PMID:16364912
    supporting_text: >-
      bound substrates are ubiquitinated by E2 enzymes that interact with a hetero-dimer of the
      RING subunit Apc11 and the cullin Apc2
  - reference_id: PMID:11739784
    supporting_text: >-
      a heterodimeric complex of APC2 and APC11 is sufficient to catalyze the ubiquitination of
      human securin and cyclin B1
  - reference_id: PMID:26083744
    supporting_text: >-
      the catalytic module comprising the RING subunit Apc11 and the C-terminal domain of Apc2
      (Apc2CTD)
  - reference_id: PMID:18485873
    supporting_text: >-
      We find that the APC/C triggers substrate degradation by assembling K11-linked ubiquitin
      chains
  - reference_id: file:human/ANAPC2/ANAPC2-uniprot.txt
    supporting_text: >-
      Together with the RING-H2 protein ANAPC11, constitutes the catalytic component of the anaphase
      promoting complex/cyclosome
- description: >-
    ANAPC2-containing APC/C also supports K11/K48 branched ubiquitin chains that connect cell-cycle
    substrate turnover with proteasomal quality-control outputs. This proteostasis link is a downstream
    consequence of APC/C ubiquitin chain assembly, not a separate chaperone or proteasome-subunit
    function.
  contributes_to_molecular_function:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  directly_involved_in:
  - id: GO:0141198
    label: protein branched polyubiquitination
  - id: GO:0070936
    label: protein K48-linked ubiquitination
  - id: GO:0010498
    label: proteasomal protein catabolic process
  in_complex:
    id: GO:0005680
    label: anaphase-promoting complex
  supported_by:
  - reference_id: PMID:29033132
    supporting_text: >-
      engineered a bispecific antibody to detect K11/K48-linked chains and identified mitotic
      regulators, misfolded nascent polypeptides, and pathological Huntingtin variants as their
      endogenous substrates.
  - reference_id: PMID:29033132
    supporting_text: >-
      these conjugates promote rapid proteasomal clearance of aggregation-prone proteins.
  - reference_id: PMID:26083744
    supporting_text: >-
      Two cullin-RING E3 ubiquitin ligases, the APC/C and SCF, catalyze the ubiquitination of
      multiple cell cycle proteins to regulate their proteasome-mediated proteolysis.
proposed_new_terms: []
suggested_questions:
- question: >-
    Should GO model ANAPC2/APC2 as a cullin-like scaffold activity for APC/C separately from canonical
    cullin-RING ligase scaffolds, or is GO:0160072 sufficiently broad for degenerate APC/C cullin
    subunits?
- question: >-
    Which human contexts justify retaining neuronal CDC20-APC/C process annotations on ANAPC2
    versus restricting them to experimentally studied mammalian orthologs or pathway-level APC/C
    annotations?
- question: >-
    Should the newly described ANAPC2 E2-docking surfaces (the WHB region that clasps UBE2C and the
    ANAPC2-ANAPC4 groove that binds the UBE2S C-terminal peptide) and the APC2 zinc-binding module
    be captured by more specific molecular-function or domain annotations beyond GO:0160072?
suggested_experiments:
- hypothesis: >-
    ANAPC2 scaffold surfaces that contact ANAPC11 and APC/C E2 enzymes are required for APC/C
    ubiquitin-chain initiation and elongation in human cells.
  description: >-
    Use rescue of ANAPC2-depleted human cells with interface mutants in the Apc2CTD/Apc11 region,
    then measure APC/C substrate ubiquitination, K11/K48 chain formation, and mitotic exit timing.
  experiment_type: mutational rescue and ubiquitination assay
- hypothesis: >-
    The ANAPC2 WHB region and the ANAPC2-ANAPC4 groove are required, respectively, for UBE2C-mediated
    ubiquitin priming and UBE2S-mediated K11 chain elongation, and UBE2S allosterically promotes
    UBE2C engagement via stabilization of the "CRL up" state.
  description: >-
    Reconstitute human APC/C with structure-guided point mutations in the ANAPC2 WHB and the
    ANAPC2-ANAPC4 groove and assay UBE2C priming versus UBE2S elongation in vitro, testing whether
    UBE2S titration rescues UBE2C recruitment and processive polyubiquitination on a model substrate.
  experiment_type: structure-guided mutagenesis with in vitro ubiquitination kinetics