Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0007091 metaphase/anaphase transition of mitotic cell cycle	IBA GO_REF:0000033	ACCEPT	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. 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. Supporting Evidence: PMID:16364912 The anaphase-promoting complex/cyclosome (APC/C) is a ubiquitin ligase with essential functions in mitosis, meiosis, and G1 phase of the cell cycle. PMID:26083744 These structures define the architecture of all APC/C subunits, the position of the catalytic module
GO:0070979 protein K11-linked ubiquitination	IBA GO_REF:0000033	ACCEPT	Summary: APC/C-dependent K11-linked ubiquitin-chain assembly is a well-supported output of the ANAPC2-containing APC/C catalytic module. 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. Supporting Evidence: PMID:18485873 We find that the APC/C triggers substrate degradation by assembling K11-linked ubiquitin chains PMID:29033132 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. PMID:16364912 bound substrates are ubiquitinated by E2 enzymes that interact with a hetero-dimer of the RING subunit Apc11 and the cullin Apc2
GO:0005680 anaphase-promoting complex	IBA GO_REF:0000033	ACCEPT	Summary: ANAPC2 is a core subunit of the anaphase-promoting complex/cyclosome. 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. Supporting Evidence: PMID:16364912 These proteins are located on the same side of the asymmetric APC/C, implying that this is where substrates are ubiquitinated. PMID:26083744 These structures define the architecture of all APC/C subunits, the position of the catalytic module
GO:0010498 proteasomal protein catabolic process	IEA GO_REF:0000117	ACCEPT	Summary: APC/C ubiquitination of cell-cycle substrates leads to proteasome-mediated degradation. 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. Supporting Evidence: PMID:26083744 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. PMID:27120157 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.
GO:0031461 cullin-RING ubiquitin ligase complex	IEA GO_REF:0000117	MODIFY	Summary: ANAPC2 belongs to a cullin-like RING E3 module, but the specific complex is APC/C rather than a generic CRL complex. 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 replacements: anaphase-promoting complex Supporting Evidence: PMID:16364912 bound substrates are ubiquitinated by E2 enzymes that interact with a hetero-dimer of the RING subunit Apc11 and the cullin Apc2 PMID:26083744 the catalytic module comprising the RING subunit Apc11 and the C-terminal domain of Apc2 (Apc2CTD) file:human/ANAPC2/ANAPC2-uniprot.txt Belongs to the cullin family.
GO:0005515 protein binding	IPI PMID:23708001 Emi1 preferentially inhibits ubiquitin chain elongation by t...	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: PMID:23708001 the carboxy-terminal tail of Emi1 antagonizes chain elongation by Ube2S, by competitively preventing its binding to the APC cullin subunit
GO:0005515 protein binding	IPI PMID:26083744 Atomic structure of the APC/C and its mechanism of protein u...	MARK AS OVER ANNOTATED	Summary: The structural study supports APC/C subunit and E2/regulator interactions, but generic protein binding is not a useful core molecular-function annotation. 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. Supporting Evidence: PMID:26083744 These structures define the architecture of all APC/C subunits, the position of the catalytic module
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: This high-throughput binary interactome record is useful interaction context but not a core ANAPC2 function. Reason: The HuRI-style protein-binding annotation records physical interaction data without establishing a specific ANAPC2 molecular activity or pathway role. Supporting Evidence: PMID:32296183 HuRI provides an unbiased genome-scale scaffold with which to coordinate this information as it emerges.
GO:0010629 negative regulation of gene expression	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: file:human/ANAPC2/ANAPC2-uniprot.txt Together with the RING-H2 protein ANAPC11, constitutes the catalytic component of the anaphase promoting complex/cyclosome
GO:0031915 positive regulation of synaptic plasticity	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: file:human/ANAPC2/ANAPC2-uniprot.txt CDC20-APC/C-induced degradation of NEUROD2 drives presynaptic differentiation
GO:0045773 positive regulation of axon extension	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Positive regulation of axon extension is an over-specific orthology-transferred neuronal process annotation for ANAPC2. 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. Supporting Evidence: file:human/ANAPC2/ANAPC2-uniprot.txt CDC20-APC/C complex positively regulates the formation of synaptic vesicle clustering at active zone to the presynaptic membrane in postmitotic neurons
GO:0050775 positive regulation of dendrite morphogenesis	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Positive regulation of dendrite morphogenesis is an over-specific orthology-transferred neuronal process annotation for ANAPC2. 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. Supporting Evidence: file:human/ANAPC2/ANAPC2-uniprot.txt CDC20-APC/C complex positively regulates the formation of synaptic vesicle clustering at active zone to the presynaptic membrane in postmitotic neurons
GO:0090129 positive regulation of synapse maturation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Synapse maturation is retained as non-core orthology-derived context for CDC20-APC/C neuronal roles, not as ANAPC2's defining molecular function. 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. Supporting Evidence: file:human/ANAPC2/ANAPC2-uniprot.txt CDC20-APC/C-induced degradation of NEUROD2 drives presynaptic differentiation
GO:0016567 protein ubiquitination	IEA GO_REF:0000041	ACCEPT	Summary: Protein ubiquitination is a broad but correct process annotation for ANAPC2-containing APC/C. Reason: ANAPC2 is part of the APC/C E3 ubiquitin ligase catalytic module, and APC/C catalyzes substrate ubiquitination through E2 enzymes. Supporting Evidence: PMID:16364912 bound substrates are ubiquitinated by E2 enzymes that interact with a hetero-dimer of the RING subunit Apc11 and the cullin Apc2 PMID:26083744 the catalytic module comprising the RING subunit Apc11 and the C-terminal domain of Apc2 (Apc2CTD) PMID:26083744 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.
GO:0005680 anaphase-promoting complex	IPI PMID:27120157 Molecular mechanism of APC/C activation by mitotic phosphory...	ACCEPT	Summary: ANAPC2 is a core subunit of the anaphase-promoting complex/cyclosome. 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. Supporting Evidence: PMID:16364912 These proteins are located on the same side of the asymmetric APC/C, implying that this is where substrates are ubiquitinated. PMID:26083744 These structures define the architecture of all APC/C subunits, the position of the catalytic module
GO:0007346 regulation of mitotic cell cycle	NAS PMID:15678131 The anaphase-promoting complex: a key factor in the regulati...	ACCEPT	Summary: ANAPC2 supports mitotic cell-cycle regulation through APC/C-mediated ubiquitination and degradation of cell-cycle regulators. 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. Supporting Evidence: PMID:15678131 Two different ubiquitin ligases play an important role in the cell cycle: the SCF (Skp1/Cullin/F-box) and the anaphase-promoting complex (APC). PMID:26083744 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.
GO:0031145 anaphase-promoting complex-dependent catabolic process	NAS PMID:15678131 The anaphase-promoting complex: a key factor in the regulati...	ACCEPT	Summary: APC/C-dependent catabolic process is directly aligned with ANAPC2's role in APC/C substrate ubiquitination and proteasomal degradation. 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. Supporting Evidence: PMID:26083744 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. PMID:27120157 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. PMID:18485873 The anaphase-promoting complex (APC/C) orchestrates progression through mitosis by decorating cell-cycle regulators with ubiquitin chains.
GO:0051445 regulation of meiotic cell cycle	NAS PMID:15678131 The anaphase-promoting complex: a key factor in the regulati...	KEEP AS NON CORE	Summary: Regulation of meiotic cell cycle is plausible APC/C biology but is not the main context for this human ANAPC2 review. 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. Supporting Evidence: PMID:16364912 The anaphase-promoting complex/cyclosome (APC/C) is a ubiquitin ligase with essential functions in mitosis, meiosis, and G1 phase of the cell cycle.
GO:0005654 nucleoplasm	IDA GO_REF:0000052	KEEP AS NON CORE	Summary: Nucleoplasm is retained as APC/C reaction/localization context rather than a core molecular function. 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. Supporting Evidence: PMID:26083744 These structures define the architecture of all APC/C subunits, the position of the catalytic module
GO:0005680 anaphase-promoting complex	NAS PMID:27120157 Molecular mechanism of APC/C activation by mitotic phosphory...	ACCEPT	Summary: ANAPC2 is a core subunit of the anaphase-promoting complex/cyclosome. 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. Supporting Evidence: PMID:16364912 These proteins are located on the same side of the asymmetric APC/C, implying that this is where substrates are ubiquitinated. PMID:26083744 These structures define the architecture of all APC/C subunits, the position of the catalytic module
GO:0141198 protein branched polyubiquitination	IDA PMID:29033132 Assembly and Function of Heterotypic Ubiquitin Chains in Cel...	ACCEPT	Summary: Branched ubiquitin-chain assembly is supported for APC/C-dependent cell-cycle and protein-quality-control substrates. 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. Supporting Evidence: PMID:29033132 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. PMID:29033132 these conjugates promote rapid proteasomal clearance of aggregation-prone proteins. PMID:16364912 bound substrates are ubiquitinated by E2 enzymes that interact with a hetero-dimer of the RING subunit Apc11 and the cullin Apc2
GO:0031145 anaphase-promoting complex-dependent catabolic process	IDA PMID:29033132 Assembly and Function of Heterotypic Ubiquitin Chains in Cel...	ACCEPT	Summary: APC/C-dependent catabolic process is directly aligned with ANAPC2's role in APC/C substrate ubiquitination and proteasomal degradation. 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. Supporting Evidence: PMID:26083744 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. PMID:27120157 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. PMID:18485873 The anaphase-promoting complex (APC/C) orchestrates progression through mitosis by decorating cell-cycle regulators with ubiquitin chains.
GO:0070936 protein K48-linked ubiquitination	IDA PMID:29033132 Assembly and Function of Heterotypic Ubiquitin Chains in Cel...	ACCEPT	Summary: K48-linked ubiquitination is supported as part of APC/C-generated K11/K48 heterotypic chains and proteasomal clearance outputs. Reason: Although APC/C is especially associated with K11-linked chains, the cited evidence supports K11/K48 branched conjugates that promote proteasomal clearance. Supporting Evidence: PMID:29033132 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. PMID:29033132 these conjugates promote rapid proteasomal clearance of aggregation-prone proteins.
GO:0070979 protein K11-linked ubiquitination	IDA PMID:29033132 Assembly and Function of Heterotypic Ubiquitin Chains in Cel...	ACCEPT	Summary: APC/C-dependent K11-linked ubiquitin-chain assembly is a well-supported output of the ANAPC2-containing APC/C catalytic module. 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. Supporting Evidence: PMID:18485873 We find that the APC/C triggers substrate degradation by assembling K11-linked ubiquitin chains PMID:29033132 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. PMID:16364912 bound substrates are ubiquitinated by E2 enzymes that interact with a hetero-dimer of the RING subunit Apc11 and the cullin Apc2
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-174057	KEEP AS NON CORE	Summary: Nucleoplasm is retained as APC/C reaction/localization context rather than a core molecular function. 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. Supporting Evidence: Reactome:R-HSA-174057 Cdh1 is multiubiquitinated by the APC/C:Cdh1 complex prior to degradation by the 26S proteasome.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-174058	KEEP AS NON CORE	Summary: Nucleoplasm is retained as APC/C reaction/localization context rather than a core molecular function. 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. Supporting Evidence: Reactome:R-HSA-174058 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>
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-174079	KEEP AS NON CORE	Summary: Nucleoplasm is retained as APC/C reaction/localization context rather than a core molecular function. 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. Supporting Evidence: Reactome:R-HSA-174079 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.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-174119	KEEP AS NON CORE	Summary: Nucleoplasm is retained as APC/C reaction/localization context rather than a core molecular function. 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. Supporting Evidence: Reactome:R-HSA-174119 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.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-174132	KEEP AS NON CORE	Summary: Nucleoplasm is retained as APC/C reaction/localization context rather than a core molecular function. 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. Supporting Evidence: Reactome:R-HSA-174132 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.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-174139	KEEP AS NON CORE	Summary: Nucleoplasm is retained as APC/C reaction/localization context rather than a core molecular function. 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. Supporting Evidence: Reactome:R-HSA-174139 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.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-188191	KEEP AS NON CORE	Summary: Nucleoplasm is retained as APC/C reaction/localization context rather than a core molecular function. 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. Supporting Evidence: Reactome:R-HSA-188191 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).
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-188371	KEEP AS NON CORE	Summary: Nucleoplasm is retained as APC/C reaction/localization context rather than a core molecular function. 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. Supporting Evidence: Reactome:R-HSA-188371 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.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-3788705	KEEP AS NON CORE	Summary: Nucleoplasm is retained as APC/C reaction/localization context rather than a core molecular function. 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. Supporting Evidence: Reactome:R-HSA-3788705 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).
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-3788708	KEEP AS NON CORE	Summary: Nucleoplasm is retained as APC/C reaction/localization context rather than a core molecular function. 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. Supporting Evidence: Reactome:R-HSA-3788708 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).
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-3788724	KEEP AS NON CORE	Summary: Nucleoplasm is retained as APC/C reaction/localization context rather than a core molecular function. 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. Supporting Evidence: Reactome:R-HSA-3788724 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).
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-3788725	KEEP AS NON CORE	Summary: Nucleoplasm is retained as APC/C reaction/localization context rather than a core molecular function. 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. Supporting Evidence: Reactome:R-HSA-3788725 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).
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-68712	KEEP AS NON CORE	Summary: Nucleoplasm is retained as APC/C reaction/localization context rather than a core molecular function. 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. Supporting Evidence: Reactome:R-HSA-68712 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).
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9686969	KEEP AS NON CORE	Summary: Nucleoplasm is retained as APC/C reaction/localization context rather than a core molecular function. 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. Supporting Evidence: Reactome:R-HSA-9686969 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).
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9686980	KEEP AS NON CORE	Summary: Nucleoplasm is retained as APC/C reaction/localization context rather than a core molecular function. 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. Supporting Evidence: Reactome:R-HSA-9686980 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).
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9687377	KEEP AS NON CORE	Summary: Nucleoplasm is retained as APC/C reaction/localization context rather than a core molecular function. 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. Supporting Evidence: Reactome:R-HSA-9687377 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).
GO:0005829 cytosol	TAS Reactome:R-HSA-141423	KEEP AS NON CORE	Summary: Cytosol is retained as APC/C reaction/localization context rather than a core molecular function. Reason: Reactome places some APC/C reactions in cytosolic contexts. This supports localization context for ANAPC2-containing APC/C but not a defining activity. Supporting Evidence: Reactome:R-HSA-141423 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.
GO:0005829 cytosol	TAS Reactome:R-HSA-174070	KEEP AS NON CORE	Summary: Cytosol is retained as APC/C reaction/localization context rather than a core molecular function. Reason: Reactome places some APC/C reactions in cytosolic contexts. This supports localization context for ANAPC2-containing APC/C but not a defining activity. Supporting Evidence: Reactome:R-HSA-174070 Following its dephosphorylation in late mitosis, Cdh1 replaces Cdc20 as the APC/C activator.
GO:0005829 cytosol	TAS Reactome:R-HSA-174088	KEEP AS NON CORE	Summary: Cytosol is retained as APC/C reaction/localization context rather than a core molecular function. Reason: Reactome places some APC/C reactions in cytosolic contexts. This supports localization context for ANAPC2-containing APC/C but not a defining activity. Supporting Evidence: Reactome:R-HSA-174088 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).
GO:0005829 cytosol	TAS Reactome:R-HSA-174104	KEEP AS NON CORE	Summary: Cytosol is retained as APC/C reaction/localization context rather than a core molecular function. Reason: Reactome places some APC/C reactions in cytosolic contexts. This supports localization context for ANAPC2-containing APC/C but not a defining activity. Supporting Evidence: Reactome:R-HSA-174104 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.
GO:0005829 cytosol	TAS Reactome:R-HSA-174105	KEEP AS NON CORE	Summary: Cytosol is retained as APC/C reaction/localization context rather than a core molecular function. Reason: Reactome places some APC/C reactions in cytosolic contexts. This supports localization context for ANAPC2-containing APC/C but not a defining activity. Supporting Evidence: Reactome:R-HSA-174105 Cell cycle proteins mulitubiquitinated by the APC/C are targeted for degradation by the 26S proteasome.
GO:0005829 cytosol	TAS Reactome:R-HSA-174120	KEEP AS NON CORE	Summary: Cytosol is retained as APC/C reaction/localization context rather than a core molecular function. Reason: Reactome places some APC/C reactions in cytosolic contexts. This supports localization context for ANAPC2-containing APC/C but not a defining activity. Supporting Evidence: Reactome:R-HSA-174120 Cyclin B is believed to be recognized by the APC/C:Cdc20 complex through its D-box sequence.
GO:0005829 cytosol	TAS Reactome:R-HSA-174121	KEEP AS NON CORE	Summary: Cytosol is retained as APC/C reaction/localization context rather than a core molecular function. Reason: Reactome places some APC/C reactions in cytosolic contexts. This supports localization context for ANAPC2-containing APC/C but not a defining activity. Supporting Evidence: Reactome:R-HSA-174121 Securin is thought to be recognized by the APC/C:Cdc20 complex through its conserved D-box sequence.
GO:0005829 cytosol	TAS Reactome:R-HSA-174144	KEEP AS NON CORE	Summary: Cytosol is retained as APC/C reaction/localization context rather than a core molecular function. Reason: Reactome places some APC/C reactions in cytosolic contexts. This supports localization context for ANAPC2-containing APC/C but not a defining activity. Supporting Evidence: Reactome:R-HSA-174144 Securin is ubiquitinated by APC/C:Cdc20 (Hagting et al., 2002; Jin et al. 2008).
GO:0005829 cytosol	TAS Reactome:R-HSA-174157	KEEP AS NON CORE	Summary: Cytosol is retained as APC/C reaction/localization context rather than a core molecular function. Reason: Reactome places some APC/C reactions in cytosolic contexts. This supports localization context for ANAPC2-containing APC/C but not a defining activity. Supporting Evidence: Reactome:R-HSA-174157 Mulitubiquitinated Cyclin B is targeted for degradation by the 26S proteasome.
GO:0005829 cytosol	TAS Reactome:R-HSA-174171	KEEP AS NON CORE	Summary: Cytosol is retained as APC/C reaction/localization context rather than a core molecular function. Reason: Reactome places some APC/C reactions in cytosolic contexts. This supports localization context for ANAPC2-containing APC/C but not a defining activity. Supporting Evidence: Reactome:R-HSA-174171 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).
GO:0005829 cytosol	TAS Reactome:R-HSA-174195	KEEP AS NON CORE	Summary: Cytosol is retained as APC/C reaction/localization context rather than a core molecular function. Reason: Reactome places some APC/C reactions in cytosolic contexts. This supports localization context for ANAPC2-containing APC/C but not a defining activity. Supporting Evidence: Reactome:R-HSA-174195 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>
GO:0005829 cytosol	TAS Reactome:R-HSA-174202	KEEP AS NON CORE	Summary: Cytosol is retained as APC/C reaction/localization context rather than a core molecular function. Reason: Reactome places some APC/C reactions in cytosolic contexts. This supports localization context for ANAPC2-containing APC/C but not a defining activity. Supporting Evidence: Reactome:R-HSA-174202 Following ubiquitination, securin is degraded by the 26S proteasome.
GO:0005829 cytosol	TAS Reactome:R-HSA-174224	KEEP AS NON CORE	Summary: Cytosol is retained as APC/C reaction/localization context rather than a core molecular function. Reason: Reactome places some APC/C reactions in cytosolic contexts. This supports localization context for ANAPC2-containing APC/C but not a defining activity. Supporting Evidence: Reactome:R-HSA-174224 In late mitosis, Cdc20 dissociates from the APC/C and is replaced by the activator Cdh1 (Ballabeni et al. 2011).
GO:0005829 cytosol	TAS Reactome:R-HSA-174227	KEEP AS NON CORE	Summary: Cytosol is retained as APC/C reaction/localization context rather than a core molecular function. Reason: Reactome places some APC/C reactions in cytosolic contexts. This supports localization context for ANAPC2-containing APC/C but not a defining activity. Supporting Evidence: Reactome:R-HSA-174227 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>
GO:0005829 cytosol	TAS Reactome:R-HSA-174238	KEEP AS NON CORE	Summary: Cytosol is retained as APC/C reaction/localization context rather than a core molecular function. Reason: Reactome places some APC/C reactions in cytosolic contexts. This supports localization context for ANAPC2-containing APC/C but not a defining activity. Supporting Evidence: Reactome:R-HSA-174238 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.
GO:0005829 cytosol	TAS Reactome:R-HSA-174255	KEEP AS NON CORE	Summary: Cytosol is retained as APC/C reaction/localization context rather than a core molecular function. Reason: Reactome places some APC/C reactions in cytosolic contexts. This supports localization context for ANAPC2-containing APC/C but not a defining activity. Supporting Evidence: Reactome:R-HSA-174255 Following multiubiquitination, Cyclin A is targeted for destruction by the 26S proteasome.
GO:0005829 cytosol	TAS Reactome:R-HSA-179410	KEEP AS NON CORE	Summary: Cytosol is retained as APC/C reaction/localization context rather than a core molecular function. Reason: Reactome places some APC/C reactions in cytosolic contexts. This supports localization context for ANAPC2-containing APC/C but not a defining activity. Supporting Evidence: Reactome:R-HSA-179410 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).
GO:0005829 cytosol	TAS Reactome:R-HSA-179417	KEEP AS NON CORE	Summary: Cytosol is retained as APC/C reaction/localization context rather than a core molecular function. Reason: Reactome places some APC/C reactions in cytosolic contexts. This supports localization context for ANAPC2-containing APC/C but not a defining activity. Supporting Evidence: Reactome:R-HSA-179417 Nek2A is ubiquitinated by the APC/C-Cdc20 ubiquitin ligase.
GO:0005829 cytosol	TAS Reactome:R-HSA-179421	KEEP AS NON CORE	Summary: Cytosol is retained as APC/C reaction/localization context rather than a core molecular function. Reason: Reactome places some APC/C reactions in cytosolic contexts. This supports localization context for ANAPC2-containing APC/C but not a defining activity. Supporting Evidence: Reactome:R-HSA-179421 Nek2A is degraded by the 26S proteasome following ubiquitylation by the E3 ubiquitin ligase APC/C: Cdc20.
GO:0005829 cytosol	TAS Reactome:R-HSA-69015	KEEP AS NON CORE	Summary: Cytosol is retained as APC/C reaction/localization context rather than a core molecular function. Reason: Reactome places some APC/C reactions in cytosolic contexts. This supports localization context for ANAPC2-containing APC/C but not a defining activity. Supporting Evidence: Reactome:R-HSA-69015 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>
GO:0031915 positive regulation of synaptic plasticity	ISS GO_REF:0000024	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: file:human/ANAPC2/ANAPC2-uniprot.txt CDC20-APC/C-induced degradation of NEUROD2 drives presynaptic differentiation
GO:0090129 positive regulation of synapse maturation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Synapse maturation is retained as non-core orthology-derived context for CDC20-APC/C neuronal roles, not as ANAPC2's defining molecular function. 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. Supporting Evidence: file:human/ANAPC2/ANAPC2-uniprot.txt CDC20-APC/C-induced degradation of NEUROD2 drives presynaptic differentiation
GO:0005680 anaphase-promoting complex	IDA PMID:16364912 Localization of the coactivator Cdh1 and the cullin subunit ...	ACCEPT	Summary: ANAPC2 is a core subunit of the anaphase-promoting complex/cyclosome. 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. Supporting Evidence: PMID:16364912 These proteins are located on the same side of the asymmetric APC/C, implying that this is where substrates are ubiquitinated. PMID:26083744 These structures define the architecture of all APC/C subunits, the position of the catalytic module
GO:0070979 protein K11-linked ubiquitination	IDA PMID:18485873 Mechanism of ubiquitin-chain formation by the human anaphase...	ACCEPT	Summary: APC/C-dependent K11-linked ubiquitin-chain assembly is a well-supported output of the ANAPC2-containing APC/C catalytic module. 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. Supporting Evidence: PMID:18485873 We find that the APC/C triggers substrate degradation by assembling K11-linked ubiquitin chains PMID:29033132 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. PMID:16364912 bound substrates are ubiquitinated by E2 enzymes that interact with a hetero-dimer of the RING subunit Apc11 and the cullin Apc2
GO:0160072 ubiquitin ligase complex scaffold activity	IC PMID:26083744 Atomic structure of the APC/C and its mechanism of protein u...	NEW	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. 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. Supporting Evidence: PMID:16364912 bound substrates are ubiquitinated by E2 enzymes that interact with a hetero-dimer of the RING subunit Apc11 and the cullin Apc2 PMID:11739784 a heterodimeric complex of APC2 and APC11 is sufficient to catalyze the ubiquitination of human securin and cyclin B1 PMID:26083744 the catalytic module comprising the RING subunit Apc11 and the C-terminal domain of Apc2 (Apc2CTD) file:human/ANAPC2/ANAPC2-uniprot.txt Belongs to the cullin family. file:human/ANAPC2/ANAPC2-notes.md Conservative decision: ANAPC2 is not a canonical cullin like CUL1-CUL5, but the cached literature supports a cullin-like APC/C scaffold role.

Core Functions

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.

Molecular Function:

ubiquitin ligase complex scaffold activity

Directly Involved In:

protein ubiquitination protein K11-linked ubiquitination anaphase-promoting complex-dependent catabolic process metaphase/anaphase transition of mitotic cell cycle

In Complex:

anaphase-promoting complex

Supporting Evidence:

PMID:16364912
bound substrates are ubiquitinated by E2 enzymes that interact with a hetero-dimer of the RING subunit Apc11 and the cullin Apc2
PMID:11739784
a heterodimeric complex of APC2 and APC11 is sufficient to catalyze the ubiquitination of human securin and cyclin B1
PMID:26083744
the catalytic module comprising the RING subunit Apc11 and the C-terminal domain of Apc2 (Apc2CTD)
PMID:18485873
We find that the APC/C triggers substrate degradation by assembling K11-linked ubiquitin chains
file:human/ANAPC2/ANAPC2-uniprot.txt
Together with the RING-H2 protein ANAPC11, constitutes the catalytic component of the anaphase promoting complex/cyclosome

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.

Directly Involved In:

protein branched polyubiquitination protein K48-linked ubiquitination proteasomal protein catabolic process

In Complex:

anaphase-promoting complex

Supporting Evidence:

PMID:29033132
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.
PMID:29033132
these conjugates promote rapid proteasomal clearance of aggregation-prone proteins.
PMID:26083744
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.

References

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000041

Gene Ontology annotation based on UniPathway vocabulary mapping

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

PMID:15678131

The anaphase-promoting complex: a key factor in the regulation of cell cycle.

PMID:16364912

Localization of the coactivator Cdh1 and the cullin subunit Apc2 in a cryo-electron microscopy model of vertebrate APC/C.

APC/C is a ubiquitin ligase with essential mitotic, meiotic, and G1 functions.
Apc2 and Apc11 form the cullin/RING side of APC/C where substrates are ubiquitinated.

PMID:11739784

APC2 Cullin protein and APC11 RING protein comprise the minimal ubiquitin ligase module of the anaphase-promoting complex.

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.

PMID:18485873

Mechanism of ubiquitin-chain formation by the human anaphase-promoting complex.

Human APC/C assembles K11-linked ubiquitin chains that support substrate degradation.

PMID:23708001

Emi1 preferentially inhibits ubiquitin chain elongation by the anaphase-promoting complex.

Emi1 inhibits APC/C chain elongation in part by blocking Ube2S binding to the APC cullin subunit.

PMID:26083744

Atomic structure of the APC/C and its mechanism of protein ubiquitination.

Cryo-EM structures define the architecture of APC/C subunits and the catalytic module.
The Apc2-Apc11 catalytic module provides structural support for a scaffold interpretation of ANAPC2.

PMID:27120157

Molecular mechanism of APC/C activation by mitotic phosphorylation.

APC/C regulates ubiquitin-dependent proteolysis of cell-cycle proteins during mitosis and G1 entry.

PMID:29033132

Assembly and Function of Heterotypic Ubiquitin Chains in Cell-Cycle and Protein Quality Control.

K11/K48 branched ubiquitin chains occur on mitotic regulators and proteostasis substrates and promote rapid proteasomal clearance.

PMID:32296183

A reference map of the human binary protein interactome.

HuRI provides high-throughput binary protein-interaction context; individual PPIs need functional interpretation.

PMID:37735619

Time-resolved cryo-EM (TR-EM) analysis of substrate polyubiquitination by the RING E3 anaphase-promoting complex/cyclosome (APC/C).

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.
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.

PMID:39567505

Cryo-EM structures of apo-APC/C and APC/C(CDH1:EMI1) complexes provide insights into APC/C regulation.

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.
The structures resolve EMI1 inhibitor and CDH1 contacts on the APC/C catalytic platform that includes ANAPC2.

PMID:36548081

The UBE2C/CDH1/DEPTOR axis is an oncogene and tumor suppressor cascade in lung cancer cells.

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.

Reactome:R-HSA-141423

Binding of the MCC complex to the APC/C complex

Reactome:R-HSA-174057

Multiubiquitination of APC/C-associated Cdh1

Reactome:R-HSA-174058

Degradation of multiubiquitinated Cdh1

Reactome:R-HSA-174070

Association of Cdh1 with the APC/C

Reactome:R-HSA-174079

Phosphorylation of Cdh1 by Cyclin A:Cdk2

Reactome:R-HSA-174088

Association of cell cycle proteins with the APC/C:Cdh1 complex

Reactome:R-HSA-174104

Ubiquitination of Cyclin A by APC/C:Cdc20 complex

Reactome:R-HSA-174105

Degradation of multiubiquitinated cell cycle proteins

Reactome:R-HSA-174119

Free APC/C phosphorylated by Plk1

Reactome:R-HSA-174120

Association of Cyclin B:Cdc2 with Cdc20:APC/C complex

Reactome:R-HSA-174121

Association of Securin with Cdc20:APC/C complex

Reactome:R-HSA-174132

Free APC/C phosphorylated by Cyclin B:Cdc2

Reactome:R-HSA-174139

Dissociation of phospho-Cdh1 from the APC/C complex

Reactome:R-HSA-174144

Ubiquitination of Securin by phospho-APC/C:Cdc20 complex

Reactome:R-HSA-174157

Degradation of multiubiquitinated Cyclin B

Reactome:R-HSA-174171

Association of Cyclin A with the APC/C

Reactome:R-HSA-174195

Ubiquitination of cell cycle proteins targeted by the APC/C:Cdh1complex

Reactome:R-HSA-174202

Degradation of multiubiquitinated Securin

Reactome:R-HSA-174224

Dissociation of Cdc20 from APC/C complex

Reactome:R-HSA-174227

Ubiquitination of Cyclin B by phospho-APC/C:Cdc20 complex

Reactome:R-HSA-174238

Activation of APC/C:Cdc20 by dissociation of Cdc20:phospho-APC/C from Cdc20:phospho-APC/C:Mad2:Bub3:BubR1

Reactome:R-HSA-174255

Degradation multiubiquitinated Cyclin A

Reactome:R-HSA-179410

Association of Nek2A with MCC:APC/C

Reactome:R-HSA-179417

Multiubiquitination of Nek2A

Reactome:R-HSA-179421

Degradation of multiubiquitinated Nek2A

Reactome:R-HSA-188191

APC/C:Cdh1-mediated degradation of Skp2

Reactome:R-HSA-188371

Association of Cyclin A:Cdk2 with Cdh1

Reactome:R-HSA-3788705

CDKN1A (p21) prevents phosphorylation of Cdh1 by Cyclin A:Cdk2

Reactome:R-HSA-3788708

CDKN1A (p21) prevents association of Cyclin A:Cdk2 with Cdh1

Reactome:R-HSA-3788724

Cdh1:APC/C ubiquitinates EHMT1 and EHMT2

Reactome:R-HSA-3788725

Cdh1:APC/C complex binds EHMT1:EHMT2

Reactome:R-HSA-68712

The geminin component of geminin:Cdt1 complexes is ubiquitinated, releasing Cdt1

Reactome:R-HSA-69015

Cytoplasmic phosphorylated Cdc6 is ubiquitinated by the anaphase-promoting complex

Reactome:R-HSA-9686969

APC/C:Cdh1 polyubiquitinates SKP2

Reactome:R-HSA-9686980

RB1 recruits APC/C:Cdh1 complex to SKP2

Reactome:R-HSA-9687377

Defective RB1 does not form a complex with SKP2 and FZR1

file:human/ANAPC2/ANAPC2-uniprot.txt

UniProtKB record for human ANAPC2

UniProt describes ANAPC2 as the cullin-family APC/C subunit that works with ANAPC11 in the APC/C catalytic component.

file:human/ANAPC2/ANAPC2-notes.md

ANAPC2 review notes and PN projection assessment

Falcon deep research timed out and the configured Perplexity fallback failed with quota error.
The PN scaffold projection was accepted only after gene-level review of ANAPC2 structural evidence.

file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv

PN projected gene-GO summary report

ANAPC2 already has exact APC/C complex coverage and entailed ubiquitin ligase complex coverage in GOA.

file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_candidate_additions.tsv

PN projected candidate additions report

ANAPC2 has a new-to-GOA PN candidate for GO:0160072 ubiquitin ligase complex scaffold activity.

Suggested Experiments

Experiment: 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.

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.

Type: mutational rescue and ubiquitination assay

Experiment: 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.

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.

Type: structure-guided mutagenesis with in vitro ubiquitination kinetics

Deep Research

Falcon

(ANAPC2-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 29 citations 2 artifacts 2026-06-07T04:32:13.616768

Edison artifact artifact-00 (text/markdown)

## Context ID: pqac-00000030 The requested panels illustrating the APC/C CRL up vs CRL down conformations and the UBE2S C-terminal peptide (CTP) binding groove (image/png)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Comprehensive research report: Human ANAPC2 (APC2; UniProt Q9UJX6) functional annotation

0) Target verification (required disambiguation)

The UniProt accession Q9UJX6 corresponds to Homo sapiens ANAPC2 (synonyms: APC2, KIAA1406) annotated as anaphase‑promoting complex subunit 2, also called cyclosome subunit 2. The literature retrieved here consistently uses “APC2/Apc2” to denote the cullin-family catalytic scaffold subunit of the human anaphase‑promoting complex/cyclosome (APC/C) E3 ubiquitin ligase, which matches the UniProt description and the expected cullin-like domain architecture. (watson2019posingtheapcc pages 1-3, alfieri2017visualizingthecomplex pages 2-3)

1) Key concepts and current understanding

1.1 What ANAPC2/APC2 is

ANAPC2 encodes APC2, a core subunit of the multi‑subunit E3 ubiquitin ligase APC/C (anaphase-promoting complex/cyclosome). APC2 is the cullin-like scaffold that pairs with the RING subunit APC11 to form the APC2–APC11 cullin–RING catalytic core (“CRL-like” module) responsible for recruiting and activating ubiquitin-loaded E2 enzymes for substrate ubiquitination. (watson2019posingtheapcc pages 1-3, alfieri2017visualizingthecomplex pages 2-3, bansal2019mechanismsforthe pages 1-2)

A central organizing principle is that APC/C function is achieved by:
- Catalytic module: APC2 (cullin-like) + APC11 (RING) that engages E2~Ub and catalyzes ubiquitin transfer. (watson2019posingtheapcc pages 1-3, alfieri2017visualizingthecomplex pages 2-3)
- Substrate recognition: coactivators CDC20 or CDH1 (FZR1), plus APC10/DOC1, which recognize substrate degrons (e.g., D‑box, KEN‑box, ABBA motifs) and position substrates for modification. (alfieri2017visualizingthecomplex pages 2-3, bansal2019mechanismsforthe pages 1-2, hofler2024cryoemstructuresof pages 1-3)

1.2 Molecular function: ubiquitin ligase “reaction” and substrate specificity

APC/C is a RING E3 ubiquitin ligase, meaning it does not form a covalent E3~Ub intermediate. Instead, APC2–APC11 recruits and activates an E2~Ub thioester and facilitates direct transfer of ubiquitin to lysine residues on substrates (or to ubiquitin to build chains). APC2 functions primarily as a structural/catalytic scaffold positioning the APC11 RING and providing key interaction surfaces (including the APC2 WHB region) needed for productive E2 engagement. (watson2019posingtheapcc pages 1-3, alfieri2017visualizingthecomplex pages 2-3, bodrug2023timeresolvedcryoem(trem) pages 2-3)

APC/C typically polyubiquitinates key cell‑cycle regulators (classically including securin and cyclins), using degron-guided substrate selection via CDC20/CDH1 and APC10. (curtis2020theanaphasepromoting pages 6-11, bansal2019mechanismsforthe pages 1-2)

1.3 E2 usage: division of labor

A widely accepted model is a two‑E2 system:
- Initiation/priming E2s: especially UBE2C (UBCH10) (and sometimes UBE2D/UBCH5 family) to install initial ubiquitin(s) and short chains. (zhou2016insightsintoapcc pages 1-2, yamano2019apcccurrentunderstanding pages 3-5)
- Elongation E2: UBE2S to extend K11-linked chains, generating a proteasome-recognized degradation signal. (zhou2016insightsintoapcc pages 1-2, bodrug2023timeresolvedcryoem(trem) pages 1-2)

2) Protein domains / structural features (with emphasis on 2023–2024)

2.1 Canonical APC2 features: cullin-like scaffold + WHB region

Structural work and reviews describe APC2 as the cullin within the APC/C catalytic module, with flexible tethering of the APC11 RING and the APC2 WHB region enabling catalytic conformational rearrangements. (alfieri2017visualizingthecomplex pages 2-3, alfieri2017visualizingthecomplex pages 4-4)

2.2 2024 high-resolution structures: APC2 zinc-binding module

A major 2024 advance is the report of high‑resolution cryo‑EM structures of human apo‑APC/C and APC/C^CDH1:EMI1 (2.9–3.2 Å), which identified a previously unreported zinc-binding module in APC2; zinc ions were experimentally confirmed and proposed to stabilize APC2. (Nature Communications, publication date Nov 2024; https://doi.org/10.1038/s41467-024-54398-5) (hofler2024cryoemstructuresof pages 1-3)

2.3 2023 time-resolved cryo-EM: APC2 participates in E2 docking via APC2–APC4 groove

Time-resolved cryo-EM (TR‑EM) of active human APC/C during substrate polyubiquitination revealed that the UBE2S C-terminal peptide (CTP) binds a groove formed by APC2–APC4, and that UBE2C is “clasped” by APC11 RING and the APC2 WHB region in active states. (Nature Structural & Molecular Biology, Sep 2023; https://doi.org/10.1038/s41594-023-01105-5) (bodrug2023timeresolvedcryoem(trem) pages 2-3)

Figure evidence: the CRL-up/CRL-down transitions and UBE2S CTP binding at the APC2–APC4 groove are shown in the cropped figure panels from Bodrug et al. 2023. (bodrug2023timeresolvedcryoem(trem) media b5724fab, bodrug2023timeresolvedcryoem(trem) media 4c971fd7, bodrug2023timeresolvedcryoem(trem) media 1866d704, bodrug2023timeresolvedcryoem(trem) media c7cbb8b1, bodrug2023timeresolvedcryoem(trem) media bafd06b8)

3) Mechanistic role of ANAPC2/APC2 in APC/C catalysis

3.1 Minimal catalytic module and biochemical sufficiency

APC2 and APC11 comprise the minimal CRL-like catalytic module of APC/C. A classic biochemical reconstitution showed that an APC2–APC11 heterodimer can be sufficient to catalyze ubiquitination of at least some APC/C substrates in conjunction with appropriate E2s (e.g., UbcH10/UBE2C). (hoflerUnknownyeardriversofcell pages 44-47)

3.2 Conformational activation: “CRL down” to “CRL up”

APC/C catalytic output depends on conformational transitions of the APC2–APC11 “CRL arm.” Coactivator binding (CDH1/CDC20) is linked to movement of the catalytic module from an autoinhibited “down” arrangement into an “up” state compatible with productive E2 engagement and ubiquitin transfer. (watson2019posingtheapcc pages 19-23)

The 2023 TR‑EM study quantified this landscape by cryoDRGN analysis, identifying dominant “CRL down” and “CRL up” states and measuring CRL movements (~15 Å and ~11 Å along principal components), supporting an energy landscape enabling thermally driven transitions. (bodrug2023timeresolvedcryoem(trem) pages 4-5)

3.3 Allosteric coupling between elongation and priming E2s via APC2

A key recent concept is that UBE2S (elongating E2) can allosterically promote UBE2C (priming E2) engagement by stabilizing a catalytically competent APC/C conformation. Specifically, a UBE2S CTP interaction at an APC2–APC4 groove stabilized a “CRL up” state and increased recruitment of UBE2C~Ub to APC/C^CDH1 and substrate in dose-dependent assays. (bodrug2023timeresolvedcryoem(trem) pages 6-7)

4) Pathways and regulation

4.1 Spindle assembly checkpoint (SAC) and MCC inhibition

During mitosis, the SAC restrains APC/C activation until proper kinetochore–microtubule attachment. Its key effector, the mitotic checkpoint complex (MCC) (CDC20, BUBR1, MAD2, BUB3), binds APC/C^CDC20 and inhibits substrate ubiquitination by blocking substrate engagement and/or E2 function. (curtis2020theanaphasepromoting pages 6-11, zhou2016insightsintoapcc pages 5-6)

4.2 EMI1 inhibition engages APC2 surfaces

EMI1 is a multi-domain inhibitor that acts as a pseudo-substrate and multivalent blocker. Structural analysis described EMI1 binding contacts including CDH1, APC10, APC11 RING, the APC2 WHB, and the APC2–APC4 groove, consistent with inhibition that directly targets APC2-centered catalytic and E2-binding interfaces. (watson2019posingtheapcc pages 19-23)

4.3 Phosphoregulation and coactivator exchange

APC/C activation and coactivator exchange are regulated by phosphorylation: CDK1 and PLK1 promote CDC20 binding/early mitotic activation, while CDK1 phosphorylation of CDH1 restrains CDH1 binding in early mitosis; CDH1 becomes effective later as CDK activity falls. (hoflerUnknownyeardriversofcell pages 44-47, zhou2016insightsintoapcc pages 5-6)

5) Subcellular localization

The evidence gathered here supports mechanistic spatial context (e.g., SAC signaling from unattached kinetochores) rather than a detailed catalog of APC/C steady-state localization (nucleus vs cytoplasm vs spindle/kinetochores). SAC/MCC signaling is described as initiated at unattached kinetochores, producing a diffusible MCC that inhibits APC/C^CDC20. (liu2020theinteractionprofile pages 44-47, zhou2016insightsintoapcc pages 5-6)

Direct, specific localization statements for APC2/ANAPC2 itself (e.g., immunofluorescence localizing APC2 to spindle poles/kinetochores) were not recovered in the retrieved text corpus; therefore, this report does not assert such localization beyond checkpoint-associated spatial signaling.

6) Recent developments (prioritizing 2023–2024)

6.1 2023: time-resolved cryo-EM reveals dynamic ubiquitination mechanism and quantitative conformational landscape

Bodrug et al. (2023) provided multiple advances relevant to functional annotation of APC2:
- Visualized native active complexes of human APC/C^CDH1 with UBE2C and UBE2S without crosslinking, showing APC2’s role in E2 engagement via APC2 WHB and APC2–APC4 groove. (bodrug2023timeresolvedcryoem(trem) pages 2-3)
- Quantified conformational distributions and relationships to coactivator occupancy (e.g., in the CRL-down state, ~80% of particles lacked CDH1). (bodrug2023timeresolvedcryoem(trem) pages 6-7)
- Provided quantitative EM and biochemical metrics (e.g., final particle images ~661k and ~775k; map resolutions 3.5–4.0 Å). (bodrug2023timeresolvedcryoem(trem) pages 4-5)
- Reported quantitative recruitment/affinity proxies and bead-rolling (METRIS) statistics supporting ubiquitin-enhanced processivity, including RP values (Ub–CycBN 0.21 ± 0.007 vs CycBN 0.15 ± 0.004). (bodrug2023timeresolvedcryoem(trem) pages 10-11)

6.2 2024: higher-resolution APC/C structures add new APC2 feature (zinc-binding module)

Höfler et al. (2024) achieved 2.9–3.2 Å structures that (i) clarified regulatory architecture in apo and inhibited states, and (ii) identified and experimentally confirmed a novel APC2 zinc-binding module, improving domain-level annotation for ANAPC2. (hofler2024cryoemstructuresof pages 1-3)

7) Current applications and real-world implementations

7.1 Cancer-relevant axis involving APC/C catalytic function: APC/C^CDH1–UBE2C–DEPTOR–mTOR signaling

A 2023 JCI study established a mechanistic axis in Kras-driven lung tumorigenesis in which UBE2C cooperates with APC/C^CDH1 to ubiquitylate and degrade DEPTOR, activating mTORC signaling. Importantly, knockdown of APC2 (and CDH1) increased DEPTOR protein, consistent with APC2-containing APC/C being required for DEPTOR ubiquitination. (Journal of Clinical Investigation, Feb 2023; https://doi.org/10.1172/JCI162434) (zhang2023theube2ccdh1deptoraxis pages 5-6, zhang2023theube2ccdh1deptoraxis pages 9-11)

This supports practical uses of APC/C pathway components as mechanistic biomarkers or therapeutic nodes, even if APC2 itself is not directly drugged.

7.2 Quantitative in vivo outcomes (disease-relevant statistics)

In the KrasG12D lung tumor model, Ube2c deletion produced quantitative disease modification: median survival increased from ~130 to ~150 days and delayed 100% mortality from day 175 to day 210 (P = 0.0241; n = 10/group). While this statistic is on the E2 component, the mechanism demonstrated requires APC/C function and includes APC2 dependence for DEPTOR regulation in vitro. (zhang2023theube2ccdh1deptoraxis pages 4-5, zhang2023theube2ccdh1deptoraxis pages 5-6)

7.3 Disease association resources

OpenTargets reports disease associations for ANAPC2 (evidence size 4 in the retrieved snapshot) including colorectal carcinoma and neurodegenerative disease, among others; these should be treated as hypothesis-generating and require deeper primary-evidence evaluation for causal claims. (OpenTargets; accessed via tool context) (OpenTargets Search: -ANAPC2)

8) Expert opinions / authoritative interpretations

Authoritative reviews frame APC2 as part of a cullin–RING E3 whose core challenge is coordinating long-range substrate recruitment with catalysis via conformational mobility of the APC2–APC11 module; coactivators provide both substrate recruitment and catalytic activation by promoting an “up” catalytic state. (watson2019posingtheapcc pages 1-3, watson2019posingtheapcc pages 19-23)

9) Summary of evidence (table)

The following table consolidates APC2/ANAPC2 functional annotation, emphasizing 2023–2024 advances and quantitative statistics.

ANAPC2 (APC2) functional annotation: evidence summary	Key points	Recent (2023–2024) evidence	Foundational/consensus evidence	Practical implications/applications
Identity/domains	Human ANAPC2 encodes APC2, the cullin-family catalytic scaffold subunit of APC/C; literature matches UniProt Q9UJX6 and cullin-family/domain annotation. APC2 contains a cullin-like C-terminal region with a WHB subdomain; 2024 cryo-EM additionally identified a zinc-binding module stabilizing APC2.	High-resolution human APC/C structures identified a previously unreported APC2 zinc-binding module and confirmed APC2 as part of the catalytic module in 2.9–3.2 Å maps (hofler2024newstructuralfeatures pages 1-3, hofler2024cryoemstructuresof pages 1-3).	APC2 has long been defined as the cullin-like APC/C subunit, partnering APC11 in the catalytic core; structural reviews describe flexible APC2 CTD/WHB regions and cullin homology (alfieri2017visualizingthecomplex pages 2-3, alfieri2017visualizingthecomplex pages 4-4, curtis2020theanaphasepromoting pages 6-11).	Confirms the target is the human APC/C subunit rather than another APC2 symbol; domain knowledge supports functional annotation and variant interpretation in cell-cycle studies.
Catalytic role in APC/C	APC2 is the scaffold of the APC2–APC11 cullin–RING catalytic module, positioning APC11/RING and E2~Ub for ubiquitin transfer to APC/C substrates; APC2 itself is not the E2 or protease but a structural/catalytic organizer of the E3 ligase.	TR-EM directly visualized active APC/C with E2s and showed APC2 participates in E2/CTP engagement during substrate polyubiquitination (bodrug2023timeresolvedcryoem(trem) pages 2-3, bodrug2023timeresolvedcryoem(trem) pages 1-2).	Reconstitution showed APC2 plus APC11 is the minimal ubiquitin ligase module sufficient for ubiquitination with appropriate E2s; reviews consistently describe APC2 as the cullin scaffold of APC/C (hoflerUnknownyeardriversofcell pages 44-47, watson2019posingtheapcc pages 1-3, penas2012theapccubiquitin pages 1-2).	Central for interpreting APC/C-dependent proteolysis of cyclins, securin, and other cell-cycle substrates; useful when considering APC/C as a therapeutic vulnerability in proliferative disease.
E2/coactivator interactions	APC/C uses coactivators CDC20 or CDH1 for substrate recruitment and catalytic activation. APC2/APC11 engages initiating and elongating E2s, especially UBE2C/UBCH10 and UBE2S; APC10 and coactivators recognize degrons such as D-box/KEN/ABBA.	2023 TR-EM showed UBE2C clasped by APC11 RING and APC2 WHB, while the UBE2S C-terminal peptide binds a groove formed by APC2–APC4; both E2s can be engaged in active complexes (bodrug2023timeresolvedcryoem(trem) pages 6-7, bodrug2023timeresolvedcryoem(trem) pages 2-3, bodrug2023timeresolvedcryoem(trem) pages 8-9). 2024 structures reaffirmed that coactivators stimulate a catalytic-module change permitting UBE2C binding (hofler2024newstructuralfeatures pages 1-3, hofler2024cryoemstructuresof pages 1-3).	Reviews define APC/C substrate selection through CDC20/CDH1 plus APC10 and distinguish initiating E2s (UBE2C/UBCH10, sometimes UBE2D/UBCH5) from elongating UBE2S (curtis2020theanaphasepromoting pages 6-11, bansal2019mechanismsforthe pages 1-2, zhou2016insightsintoapcc pages 1-2, yamano2019apcccurrentunderstanding pages 3-5).	Explains substrate specificity and timing of mitotic exit; relevant to experimental design, degron engineering, and efforts to modulate APC/C signaling indirectly via E2s or coactivators.
Conformational regulation (CRL up/down)	APC2-containing catalytic module is mobile and switches between autoinhibited “CRL down” and active “CRL up” states; coactivators and UBE2S-linked interactions favor the active state and improve UBE2C recruitment/processivity.	CryoDRGN/TR-EM defined major CRL-down and CRL-up substates and showed UBE2S CTP allosterically stabilizes CRL-up, increasing UBE2C recruitment; APC2 CRL movements of ~15 Å and ~11 Å were quantified (bodrug2023timeresolvedcryoem(trem) pages 6-7, bodrug2023timeresolvedcryoem(trem) pages 4-5, bodrug2023timeresolvedcryoem(trem) media b5724fab).	Earlier structural work established that APC2 WHB and APC11 RING are flexibly tethered and undergo conformational changes required for catalysis (alfieri2017visualizingthecomplex pages 2-3, alfieri2017visualizingthecomplex pages 4-4, watson2019posingtheapcc pages 19-23).	Mechanistic basis for APC/C activity tuning; suggests allosteric control points for chemical probes or inhibitors and helps explain processive ubiquitin-chain assembly.
Inhibition/regulation (MCC, EMI1, phosphorylation)	APC/C is inhibited by the spindle assembly checkpoint via MCC (CDC20, BUBR1, MAD2, BUB3), which blocks substrate access and E2 function. EMI1 acts as a pseudosubstrate/multivalent inhibitor contacting CDH1, APC10, APC11, APC2 WHB, and the APC2–APC4 groove. Phosphorylation promotes CDC20 loading and regulates coactivator exchange, while CDK1 phosphorylation restrains CDH1 in early mitosis.	2024 structural work further clarified APC/C–CDH1:EMI1 organization and regulatory architecture (hofler2024cryoemstructuresof pages 1-3). 2024 Cdc20 functional analysis reinforced SAC dependence on proper APC/C–MCC interactions (hoflerUnknownyeardriversofcell pages 44-47).	Reviews consistently describe MCC-mediated inhibition, EMI1 blockade, and mitotic phosphorylation as core APC/C regulatory layers (hoflerUnknownyeardriversofcell pages 44-47, watson2019posingtheapcc pages 19-23, curtis2020theanaphasepromoting pages 6-11, zhou2016insightsintoapcc pages 5-6, yamano2019apcccurrentunderstanding pages 3-5).	Relevant to anti-mitotic strategies, checkpoint biology, and explaining how APC/C remains inactive until chromosomes are properly attached.
Disease relevance (lung cancer DEPTOR axis; OpenTargets associations)	Direct ANAPC2 disease literature is limited, but APC2 function is implicated through APC/C-dependent oncogenic signaling. In lung cancer, APC/C^CDH1 with UBE2C requires APC2 for DEPTOR degradation, activating mTOR signaling. OpenTargets lists ANAPC2 associations with colorectal carcinoma, neurodegenerative disease, aplastic anemia, and skeletal phenotypes, though evidence depth is limited.	In Kras-driven lung cancer, knockdown of APC2 or CDH1 increased DEPTOR protein, supporting DEPTOR as an APC/C^CDH1 substrate; Ube2c deletion suppressed tumorigenesis and survival defects in vivo, placing APC/C catalytic function in a disease-relevant pathway (zhang2023theube2ccdh1deptoraxis pages 5-6, zhang2023theube2ccdh1deptoraxis pages 9-11, zhang2023theube2ccdh1deptoraxis pages 4-5). OpenTargets reports several ANAPC2 disease associations with modest evidence sizes (OpenTargets Search: -ANAPC2).	APC/C dysregulation is broadly linked to tumorigenesis and genome instability in consensus reviews (alfieri2017visualizingthecomplex pages 2-3, zhou2016insightsintoapcc pages 1-2, hofler2024cryoemstructuresof pages 1-3).	Supports using APC/C pathway readouts as cancer biomarkers or mechanistic stratifiers; suggests indirect therapeutic opportunities by targeting APC/C partners (e.g., UBE2C, checkpoint regulators) rather than APC2 directly.
Quantitative statistics highlighted	Recent studies provide structural and functional numbers that strengthen annotation: cryo-EM resolutions, particle counts, conformational fractions, biochemical recruitment windows, and cancer survival outcomes.	TR-EM used ~25,380 and 25,900 movies, yielding ~661,289 and 774,933 particle images and 3.5–4.0 Å maps; CRL-down particles were largely CDH1-lacking (~80%); timepoints included 0.5, 1.5, 5, 15 min; UBE2S CTP titrations 0–1.25 µM increased UBE2C recruitment; METRIS RP values included Ub–CycBN 0.21 ± 0.007 versus CycBN 0.15 ± 0.004 and UbV competition ~0.13 ± 0.003 (bodrug2023timeresolvedcryoem(trem) pages 6-7, bodrug2023timeresolvedcryoem(trem) pages 2-3, bodrug2023timeresolvedcryoem(trem) pages 4-5, bodrug2023timeresolvedcryoem(trem) pages 10-11, bodrug2023timeresolvedcryoem(trem) pages 1-2). 2024 structures reached 2.9 and 3.2 Å (hofler2024newstructuralfeatures pages 1-3, hofler2024cryoemstructuresof pages 1-3). In KrasG12D lung cancer, Ube2c deletion extended median survival from ~130 to ~150 days and delayed 100% mortality from day 175 to day 210 (P = 0.0241; n = 10/group) (zhang2023theube2ccdh1deptoraxis pages 4-5).	Quantitative biochemical and structural measurements are consistent with long-standing APC/C models of dynamic catalytic activation and processive ubiquitination (watson2019posingtheapcc pages 1-3, alfieri2017visualizingthecomplex pages 2-3, zhou2016insightsintoapcc pages 1-2).	Useful for benchmarking structural quality, prioritizing recent evidence, and conveying effect sizes in translational or grant/reporting contexts.

Table: This table summarizes the strongest gathered evidence for human ANAPC2/APC2 function, mechanism, regulation, and disease relevance. It highlights both recent 2023–2024 structural advances and foundational consensus needed for functional annotation.

10) Key URLs and publication dates (most-cited/most-recent used here)

Bodrug et al., Nature Structural & Molecular Biology, Sep 2023. “Time-resolved cryo-EM analysis of substrate polyubiquitination by the APC/C.” https://doi.org/10.1038/s41594-023-01105-5 (bodrug2023timeresolvedcryoem(trem) pages 2-3)
Höfler et al., Nature Communications, Nov 2024. “Cryo-EM structures of apo-APC/C and APC/C^CDH1:EMI1…” https://doi.org/10.1038/s41467-024-54398-5 (hofler2024cryoemstructuresof pages 1-3)
Zhang et al., Journal of Clinical Investigation, Feb 2023. “The UBE2C/CDH1/DEPTOR axis…” https://doi.org/10.1172/jci162434 (zhang2023theube2ccdh1deptoraxis pages 1-2)
Watson et al., Trends in Cell Biology, Feb 2019. “Posing the APC/C E3 ubiquitin ligase to orchestrate cell division.” https://doi.org/10.1016/j.tcb.2018.09.007 (watson2019posingtheapcc pages 1-3)

11) Limitations of the current evidence set

APC/C subcellular localization: the retrieved evidence emphasizes checkpoint signaling and structural mechanism but does not provide strong primary localization statements for APC2/ANAPC2 itself (e.g., direct imaging to spindle/kinetochores). Accordingly, this report avoids over-claiming precise localization beyond the well-supported SAC context. (liu2020theinteractionprofile pages 44-47, zhou2016insightsintoapcc pages 5-6)

References

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(bodrug2023timeresolvedcryoem(trem) media b5724fab): Tatyana Bodrug, Kaeli A. Welsh, Derek L. Bolhuis, Ethan Paulаkonis, Raquel C. Martinez-Chacin, Bei Liu, Nicholas Pinkin, Thomas Bonacci, Liying Cui, Pengning Xu, Olivia Roscow, Sascha Josef Amann, Irina Grishkovskaya, Michael J. Emanuele, Joseph S. Harrison, Joshua P. Steimel, Klaus M. Hahn, Wei Zhang, Ellen D. Zhong, David Haselbach, and Nicholas G. Brown. Time-resolved cryo-em (tr-em) analysis of substrate polyubiquitination by the ring e3 anaphase-promoting complex/cyclosome (apc/c). Nature Structural & Molecular Biology, 30:1663-1674, Sep 2023. URL: https://doi.org/10.1038/s41594-023-01105-5, doi:10.1038/s41594-023-01105-5. This article has 21 citations and is from a highest quality peer-reviewed journal.
(bodrug2023timeresolvedcryoem(trem) media 4c971fd7): Tatyana Bodrug, Kaeli A. Welsh, Derek L. Bolhuis, Ethan Paulаkonis, Raquel C. Martinez-Chacin, Bei Liu, Nicholas Pinkin, Thomas Bonacci, Liying Cui, Pengning Xu, Olivia Roscow, Sascha Josef Amann, Irina Grishkovskaya, Michael J. Emanuele, Joseph S. Harrison, Joshua P. Steimel, Klaus M. Hahn, Wei Zhang, Ellen D. Zhong, David Haselbach, and Nicholas G. Brown. Time-resolved cryo-em (tr-em) analysis of substrate polyubiquitination by the ring e3 anaphase-promoting complex/cyclosome (apc/c). Nature Structural & Molecular Biology, 30:1663-1674, Sep 2023. URL: https://doi.org/10.1038/s41594-023-01105-5, doi:10.1038/s41594-023-01105-5. This article has 21 citations and is from a highest quality peer-reviewed journal.
(bodrug2023timeresolvedcryoem(trem) media 1866d704): Tatyana Bodrug, Kaeli A. Welsh, Derek L. Bolhuis, Ethan Paulаkonis, Raquel C. Martinez-Chacin, Bei Liu, Nicholas Pinkin, Thomas Bonacci, Liying Cui, Pengning Xu, Olivia Roscow, Sascha Josef Amann, Irina Grishkovskaya, Michael J. Emanuele, Joseph S. Harrison, Joshua P. Steimel, Klaus M. Hahn, Wei Zhang, Ellen D. Zhong, David Haselbach, and Nicholas G. Brown. Time-resolved cryo-em (tr-em) analysis of substrate polyubiquitination by the ring e3 anaphase-promoting complex/cyclosome (apc/c). Nature Structural & Molecular Biology, 30:1663-1674, Sep 2023. URL: https://doi.org/10.1038/s41594-023-01105-5, doi:10.1038/s41594-023-01105-5. This article has 21 citations and is from a highest quality peer-reviewed journal.
(bodrug2023timeresolvedcryoem(trem) media c7cbb8b1): Tatyana Bodrug, Kaeli A. Welsh, Derek L. Bolhuis, Ethan Paulаkonis, Raquel C. Martinez-Chacin, Bei Liu, Nicholas Pinkin, Thomas Bonacci, Liying Cui, Pengning Xu, Olivia Roscow, Sascha Josef Amann, Irina Grishkovskaya, Michael J. Emanuele, Joseph S. Harrison, Joshua P. Steimel, Klaus M. Hahn, Wei Zhang, Ellen D. Zhong, David Haselbach, and Nicholas G. Brown. Time-resolved cryo-em (tr-em) analysis of substrate polyubiquitination by the ring e3 anaphase-promoting complex/cyclosome (apc/c). Nature Structural & Molecular Biology, 30:1663-1674, Sep 2023. URL: https://doi.org/10.1038/s41594-023-01105-5, doi:10.1038/s41594-023-01105-5. This article has 21 citations and is from a highest quality peer-reviewed journal.
(bodrug2023timeresolvedcryoem(trem) media bafd06b8): Tatyana Bodrug, Kaeli A. Welsh, Derek L. Bolhuis, Ethan Paulаkonis, Raquel C. Martinez-Chacin, Bei Liu, Nicholas Pinkin, Thomas Bonacci, Liying Cui, Pengning Xu, Olivia Roscow, Sascha Josef Amann, Irina Grishkovskaya, Michael J. Emanuele, Joseph S. Harrison, Joshua P. Steimel, Klaus M. Hahn, Wei Zhang, Ellen D. Zhong, David Haselbach, and Nicholas G. Brown. Time-resolved cryo-em (tr-em) analysis of substrate polyubiquitination by the ring e3 anaphase-promoting complex/cyclosome (apc/c). Nature Structural & Molecular Biology, 30:1663-1674, Sep 2023. URL: https://doi.org/10.1038/s41594-023-01105-5, doi:10.1038/s41594-023-01105-5. This article has 21 citations and is from a highest quality peer-reviewed journal.
(hoflerUnknownyeardriversofcell pages 44-47): AK Höfler. Drivers of cell cycle progression: structures and functions of the e3 ubiquitin ligases trip12 and apc/c. Unknown journal, Unknown year.
(watson2019posingtheapcc pages 19-23): Edmond R. Watson, Nicholas G. Brown, Jan-Michael Peters, Holger Stark, and Brenda A. Schulman. Posing the apc/c e3 ubiquitin ligase to orchestrate cell division. Trends in cell biology, 29 2:117-134, Feb 2019. URL: https://doi.org/10.1016/j.tcb.2018.09.007, doi:10.1016/j.tcb.2018.09.007. This article has 149 citations and is from a domain leading peer-reviewed journal.
(bodrug2023timeresolvedcryoem(trem) pages 4-5): Tatyana Bodrug, Kaeli A. Welsh, Derek L. Bolhuis, Ethan Paulаkonis, Raquel C. Martinez-Chacin, Bei Liu, Nicholas Pinkin, Thomas Bonacci, Liying Cui, Pengning Xu, Olivia Roscow, Sascha Josef Amann, Irina Grishkovskaya, Michael J. Emanuele, Joseph S. Harrison, Joshua P. Steimel, Klaus M. Hahn, Wei Zhang, Ellen D. Zhong, David Haselbach, and Nicholas G. Brown. Time-resolved cryo-em (tr-em) analysis of substrate polyubiquitination by the ring e3 anaphase-promoting complex/cyclosome (apc/c). Nature Structural & Molecular Biology, 30:1663-1674, Sep 2023. URL: https://doi.org/10.1038/s41594-023-01105-5, doi:10.1038/s41594-023-01105-5. This article has 21 citations and is from a highest quality peer-reviewed journal.
(bodrug2023timeresolvedcryoem(trem) pages 6-7): Tatyana Bodrug, Kaeli A. Welsh, Derek L. Bolhuis, Ethan Paulаkonis, Raquel C. Martinez-Chacin, Bei Liu, Nicholas Pinkin, Thomas Bonacci, Liying Cui, Pengning Xu, Olivia Roscow, Sascha Josef Amann, Irina Grishkovskaya, Michael J. Emanuele, Joseph S. Harrison, Joshua P. Steimel, Klaus M. Hahn, Wei Zhang, Ellen D. Zhong, David Haselbach, and Nicholas G. Brown. Time-resolved cryo-em (tr-em) analysis of substrate polyubiquitination by the ring e3 anaphase-promoting complex/cyclosome (apc/c). Nature Structural & Molecular Biology, 30:1663-1674, Sep 2023. URL: https://doi.org/10.1038/s41594-023-01105-5, doi:10.1038/s41594-023-01105-5. This article has 21 citations and is from a highest quality peer-reviewed journal.
(zhou2016insightsintoapcc pages 5-6): Zhuan Zhou, Mingjing He, Anil A. Shah, and Yong Wan. Insights into apc/c: from cellular function to diseases and therapeutics. Cell Division, Mar 2016. URL: https://doi.org/10.1186/s13008-016-0021-6, doi:10.1186/s13008-016-0021-6. This article has 173 citations and is from a peer-reviewed journal.
(liu2020theinteractionprofile pages 44-47): Y Liu. The interaction profile between cdc20 and the components of the anaphase promoting complex or cyclosome (apc/c) in human hela cells. Unknown journal, 2020.
(bodrug2023timeresolvedcryoem(trem) pages 10-11): Tatyana Bodrug, Kaeli A. Welsh, Derek L. Bolhuis, Ethan Paulаkonis, Raquel C. Martinez-Chacin, Bei Liu, Nicholas Pinkin, Thomas Bonacci, Liying Cui, Pengning Xu, Olivia Roscow, Sascha Josef Amann, Irina Grishkovskaya, Michael J. Emanuele, Joseph S. Harrison, Joshua P. Steimel, Klaus M. Hahn, Wei Zhang, Ellen D. Zhong, David Haselbach, and Nicholas G. Brown. Time-resolved cryo-em (tr-em) analysis of substrate polyubiquitination by the ring e3 anaphase-promoting complex/cyclosome (apc/c). Nature Structural & Molecular Biology, 30:1663-1674, Sep 2023. URL: https://doi.org/10.1038/s41594-023-01105-5, doi:10.1038/s41594-023-01105-5. This article has 21 citations and is from a highest quality peer-reviewed journal.
(zhang2023theube2ccdh1deptoraxis pages 5-6): Shizhen Zhang, Xiahong You, Yawen Zheng, Yanwen Shen, Xiufang Xiong, and Yi Sun. The ube2c/cdh1/deptor axis is an oncogene and tumor suppressor cascade in lung cancer cells. Journal of Clinical Investigation, Feb 2023. URL: https://doi.org/10.1172/jci162434, doi:10.1172/jci162434. This article has 79 citations and is from a highest quality peer-reviewed journal.
(zhang2023theube2ccdh1deptoraxis pages 9-11): Shizhen Zhang, Xiahong You, Yawen Zheng, Yanwen Shen, Xiufang Xiong, and Yi Sun. The ube2c/cdh1/deptor axis is an oncogene and tumor suppressor cascade in lung cancer cells. Journal of Clinical Investigation, Feb 2023. URL: https://doi.org/10.1172/jci162434, doi:10.1172/jci162434. This article has 79 citations and is from a highest quality peer-reviewed journal.
(zhang2023theube2ccdh1deptoraxis pages 4-5): Shizhen Zhang, Xiahong You, Yawen Zheng, Yanwen Shen, Xiufang Xiong, and Yi Sun. The ube2c/cdh1/deptor axis is an oncogene and tumor suppressor cascade in lung cancer cells. Journal of Clinical Investigation, Feb 2023. URL: https://doi.org/10.1172/jci162434, doi:10.1172/jci162434. This article has 79 citations and is from a highest quality peer-reviewed journal.
(OpenTargets Search: -ANAPC2): Open Targets Query (-ANAPC2, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(hofler2024newstructuralfeatures pages 1-3): Anna Höfler, Jun Yu, Jing Yang, Ziguo Zhang, Leifu Chang, Stephen H. McLaughlin, Geoffrey W. Grime, Elspeth F. Garman, Andreas Boland, and David Barford. New structural features of the apc/c from high-resolution cryo-em structures of apo-apc/c and apc/ccdh1:emi1 complexes. bioRxiv, Nov 2024. URL: https://doi.org/10.1101/2023.08.31.555674, doi:10.1101/2023.08.31.555674. This article has 2 citations.
(penas2012theapccubiquitin pages 1-2): Clara Penas, Vimal Ramachandran, and Nagi George Ayad. The apc/c ubiquitin ligase: from cell biology to tumorigenesis. Frontiers in Oncology, Jan 2012. URL: https://doi.org/10.3389/fonc.2011.00060, doi:10.3389/fonc.2011.00060. This article has 66 citations.
(bodrug2023timeresolvedcryoem(trem) pages 8-9): Tatyana Bodrug, Kaeli A. Welsh, Derek L. Bolhuis, Ethan Paulаkonis, Raquel C. Martinez-Chacin, Bei Liu, Nicholas Pinkin, Thomas Bonacci, Liying Cui, Pengning Xu, Olivia Roscow, Sascha Josef Amann, Irina Grishkovskaya, Michael J. Emanuele, Joseph S. Harrison, Joshua P. Steimel, Klaus M. Hahn, Wei Zhang, Ellen D. Zhong, David Haselbach, and Nicholas G. Brown. Time-resolved cryo-em (tr-em) analysis of substrate polyubiquitination by the ring e3 anaphase-promoting complex/cyclosome (apc/c). Nature Structural & Molecular Biology, 30:1663-1674, Sep 2023. URL: https://doi.org/10.1038/s41594-023-01105-5, doi:10.1038/s41594-023-01105-5. This article has 21 citations and is from a highest quality peer-reviewed journal.
(zhang2023theube2ccdh1deptoraxis pages 1-2): Shizhen Zhang, Xiahong You, Yawen Zheng, Yanwen Shen, Xiufang Xiong, and Yi Sun. The ube2c/cdh1/deptor axis is an oncogene and tumor suppressor cascade in lung cancer cells. Journal of Clinical Investigation, Feb 2023. URL: https://doi.org/10.1172/jci162434, doi:10.1172/jci162434. This article has 79 citations and is from a highest quality peer-reviewed journal.

Artifacts

Edison artifact artifact-00

Citations

hofler2024cryoemstructuresof pages 1-3
watson2019posingtheapcc pages 19-23
watson2019posingtheapcc pages 1-3
alfieri2017visualizingthecomplex pages 2-3
bansal2019mechanismsforthe pages 1-2
curtis2020theanaphasepromoting pages 6-11
zhou2016insightsintoapcc pages 1-2
yamano2019apcccurrentunderstanding pages 3-5
alfieri2017visualizingthecomplex pages 4-4
zhou2016insightsintoapcc pages 5-6
liu2020theinteractionprofile pages 44-47
hofler2024newstructuralfeatures pages 1-3
penas2012theapccubiquitin pages 1-2
https://doi.org/10.1038/s41467-024-54398-5
https://doi.org/10.1038/s41594-023-01105-5
https://doi.org/10.1172/JCI162434
https://doi.org/10.1172/jci162434
https://doi.org/10.1016/j.tcb.2018.09.007
https://doi.org/10.1016/j.tcb.2018.09.007,
https://doi.org/10.1098/rsob.170204,
https://doi.org/10.1186/s13008-019-0057-5,
https://doi.org/10.1038/s41467-024-54398-5,
https://doi.org/10.1038/s41594-023-01105-5,
https://doi.org/10.1007/978-3-030-28151-9_18,
https://doi.org/10.1186/s13008-016-0021-6,
https://doi.org/10.12688/f1000research.18582.1,
https://doi.org/10.1172/jci162434,
https://doi.org/10.1101/2023.08.31.555674,
https://doi.org/10.3389/fonc.2011.00060,

📚 Additional Documentation

Notes

(ANAPC2-notes.md)

ANAPC2 notes

Deep research status

Requested Falcon deep research was attempted with fallback:

just deep-research-falcon human ANAPC2 --fallback perplexity-lite

The Falcon provider timed out after the wrapper's 600 second timeout. The configured
perplexity-lite fallback then failed with a Perplexity API 401 quota error. No
ANAPC2-deep-research-falcon.md or fallback deep-research report was produced, so
this review uses the fetched UniProt record, cached publications, Reactome cache,
PANTHER family metadata, and project-local PN projection reports.

PN projection evaluation

The PN projection report lists three ANAPC2 gene-GO projections:

GO:0005680 anaphase-promoting complex: already_in_goa_exact, so no new
annotation is needed [projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv].
GO:0000151 ubiquitin ligase complex: entailed_by_goa_closure from existing
GO:0005680 anaphase-promoting complex and GO:0031461 cullin-RING ubiquitin ligase complex, so no new direct annotation is needed [projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv].
GO:0160072 ubiquitin ligase complex scaffold activity: new_to_goa from the
PN code Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cullin|degenerate, APC sununit [projects/PROTEOSTASIS/reports/pn_projection/pn_projected_candidate_additions.tsv].

Conservative decision: ANAPC2 is not a canonical cullin like CUL1-CUL5, but the
cached literature supports a cullin-like APC/C scaffold role. UniProt describes
ANAPC2 as belonging to the cullin family and states that ANAPC2 with ANAPC11
constitutes the catalytic APC/C component [genes/human/ANAPC2/ANAPC2-uniprot.txt].
The structural papers describe the catalytic module as Apc2-Apc11 and the
cullin Apc2/RING Apc11 pair as the site where substrates are ubiquitinated
[PMID:16364912; PMID:26083744]. The biochemical reconstitution paper shows that
human APC2 with APC11 forms a minimal ligase module sufficient to ubiquitinate
securin and cyclin B1 with Ubc4 or UbcH10, while lacking substrate specificity
alone PMID:11739784. I therefore added GO:0160072 as a proposed NEW
annotation rather than automatically changing existing GOA.

Annotation review summary

Core ANAPC2 function is as the cullin-like scaffold subunit of the APC/C
E3 ubiquitin ligase catalytic module. It works with ANAPC11 and E2 enzymes to
ubiquitinate APC/C substrates, especially in mitotic cell-cycle transitions and
APC/C-dependent proteasomal degradation [PMID:16364912; PMID:18485873;
PMID:26083744; PMID:29033132].

Neuron-development annotations transferred from mammalian orthology were kept
as non-core only where they directly match the UniProt CDC20-APC/C
presynaptic-differentiation context. Broader or more specific axon, dendrite,
and synaptic-plasticity terms were marked as over-annotated because the local
support does not establish those exact process labels for human ANAPC2. Generic
protein binding annotations were not treated as core because they primarily
record individual physical interactions and are less informative than the APC/C
scaffold and ubiquitin ligase module interpretation.

Falcon deep research findings (2026-06-07)

A Falcon (Edison Scientific) deep research report was generated successfully on
2026-06-07 (the earlier timeout noted above has now been superseded). Synthesis of
KEY findings, flagged as CONFIRMS / NEW / PROVISIONAL relative to the existing
review:

CONFIRMS: ANAPC2/APC2 is the cullin-family catalytic scaffold subunit of the
APC/C, pairing with the RING subunit ANAPC11 to form the Apc2-Apc11 cullin-RING
catalytic core that recruits and activates ubiquitin-loaded E2 enzymes; APC/C is
a RING E3 that does not form a covalent E3~Ub intermediate. This matches the
existing core_functions and ACCEPT annotations [PMID:30449648 Watson 2019
"Posing the APC/C E3 ubiquitin ligase"; PMID:11739784 minimal Apc2-Apc11 module].
NEW (structural detail, mechanism): Time-resolved cryo-EM of active human APC/C
during substrate polyubiquitination shows a two-E2 division of labor where the
priming E2 UBE2C/UBCH10 is "clasped" by the APC11 RING and the APC2 WHB region,
while the elongation E2 UBE2S C-terminal peptide (CTP) binds a groove formed by
APC2-APC4; UBE2S CTP allosterically stabilizes a catalytically active "CRL up"
state and increases UBE2C recruitment. APC2 thus directly contributes E2-docking
surfaces (WHB; APC2-APC4 groove) and a mobile "CRL up/down" catalytic arm
[PMID:37735619 Bodrug 2023 "Time-resolved cryo-EM (TR-EM) analysis of substrate
polyubiquitination by the RING E3 APC/C", doi:10.1038/s41594-023-01105-5]. This
enriches but does not contradict the existing K11-ubiquitination / scaffold
annotations.
NEW (structural feature): High-resolution (2.9-3.2 A) cryo-EM of apo-APC/C and
APC/C^CDH1:EMI1 identified a previously unreported zinc-binding module in APC2
that confers structural stability, with zinc ions experimentally confirmed; the
same structures resolve EMI1 contacts and CDH1 N-terminal helix
[PMID:39567505 Hofler 2024, Nat Commun, doi:10.1038/s41467-024-54398-5]. NEW
domain-level detail for ANAPC2 not previously in the review.
NEW (disease link / substrate axis): In KrasG12D-driven lung tumorigenesis,
APC/C^CDH1 cooperates with UBE2C to ubiquitylate and degrade DEPTOR, activating
mTORC signaling; knockdown of APC2 (or CDH1) increased DEPTOR protein,
indicating APC2-containing APC/C is required for DEPTOR turnover. This adds a
specific human substrate (DEPTOR) and an oncogenic-pathway context (mTOR)
[PMID:36548081 Zhang 2023 "The UBE2C/CDH1/DEPTOR axis...", doi:10.1172/JCI162434].
Treated as substrate/pathway context, not a new core MF.
CONFIRMS/CONTEXT: APC/C is restrained by the spindle assembly checkpoint via the
mitotic checkpoint complex (MCC: CDC20, BUBR1, MAD2, BUB3) and by the EMI1
pseudo-substrate inhibitor, which contacts CDH1, APC10, APC11 RING, the APC2 WHB,
and the APC2-APC4 groove; phosphoregulation (CDK1, PLK1) controls coactivator
exchange. Consistent with existing Reactome-derived KEEP_AS_NON_CORE
localization/regulation annotations and PMID:23708001 (Emi1).
PROVISIONAL / low-confidence (NOT used to change annotations): OpenTargets lists
ANAPC2 disease associations (colorectal carcinoma, neurodegenerative disease,
aplastic anemia, skeletal phenotypes) with limited evidence depth; hypothesis-
generating only. Also note the report cites a bioRxiv preprint version of the
Hofler work (hofler2024newstructuralfeatures, doi:10.1101/2023.08.31.555674) —
the peer-reviewed Nat Commun version (PMID:39567505) is used instead.

Curation decision: incorporated the three peer-reviewed primary papers
(PMID:37735619, PMID:39567505, PMID:36548081) as statement-only references and
added one suggested question and one suggested experiment around the newly
described APC2 E2-docking surfaces and zinc-binding module. No existing annotation
action was changed, since all new findings enrich rather than contradict the
existing cullin-like scaffold / catalytic-module interpretation.

Pn Notes

(ANAPC2-pn-notes.md)

ANAPC2 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q9UJX6
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-03 (PR 1367)
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/ANAPC2/ANAPC2-ai-review.yaml
AIGR review HTML: present - genes/human/ANAPC2/ANAPC2-ai-review.html
Gene notes: present - genes/human/ANAPC2/ANAPC2-notes.md
GOA TSV: present - genes/human/ANAPC2/ANAPC2-goa.tsv
UniProt record: present - genes/human/ANAPC2/ANAPC2-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/ANAPC2.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/ANAPC2.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

genes/human/ANAPC2/ANAPC2-deep-research-falcon.md

AIGR Review Snapshot

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.
Existing/core annotation action counts: ACCEPT: 15; KEEP_AS_NON_CORE: 40; MARK_AS_OVER_ANNOTATED: 8; MODIFY: 1; NEW: 1

PN Consistency Summary

Consistency: Fully consistent. DR ↔ notes ↔ YAML ↔ PN all converge: ANAPC2 is the cullin-like scaffold subunit of the APC/C catalytic module (Apc2-Apc11). No contradiction.
PN story / NEW pressure: PN projects three terms; review handles each correctly. GO:0005680 already_in_goa → ACCEPT (IBA). GO:0000151 entailed via GO:0005680/GO:0031461 → correctly NOT added. GO:0160072 ubiquitin ligase complex scaffold activity (verified real, new_to_goa): review ADDS as action: NEW (IC, PMID:26083744) only after gene-level scrutiny of structural literature (Apc2-Apc11 catalytic module; PMID:11739784 minimal module, 16364912). Defensible — APC2 is a degenerate cullin scaffold. Conclude: ADD (GO:0160072), others already captured/entailed.
Evidence alignment: PN cites PMID:16763193, 21107322, 29167309, 27259151, 31350353. Review uses overlapping structural set (16364912, 26083744, 11739784, 18485873, 29033132) plus DR additions PMID:37735619 (TR cryo-EM E2 docking), 39567505 (APC2 Zn module), 36548081 (DEPTOR substrate) as statement-only. Good overlap on APC/C catalytic-module structure; review enriches with newer cryo-EM.
Verdict: Consistent; GO:0160072 NEW warranted and matches PN (new_to_goa). GO:0005680 ACCEPT, GO:0000151 correctly entailed. No over-reach.

Full Consistency Review

UniProt: Q9UJX6 (APC2) · batch: proteostasis-batch-2026-06-03 (Falcon DR 2026-06-07) · review status: COMPLETE
PN placement: 3 rows, UPS. (1) …Cullin|degenerate, APC sununit; (2) …idiosyncratic RING complex|Anaphase Promoting Complex|catalytic / core; (3) …Ubiquitin and UBL binding|E3 ligase complex component|APC / catalytic subunit. PN-node mapping: Cullin group=mapped→GO:0160072 scaffold activity (new_to_goa); APC type=mapped→GO:0005680 anaphase-promoting complex (already_in_goa_exact); RING-complex/E3-component groups=mapped→GO:0000151 ubiquitin ligase complex (entailed_by_goa_closure).
Consistency: Fully consistent. DR ↔ notes ↔ YAML ↔ PN all converge: ANAPC2 is the cullin-like scaffold subunit of the APC/C catalytic module (Apc2-Apc11). No contradiction.
PN story / NEW pressure: PN projects three terms; review handles each correctly. GO:0005680 already_in_goa → ACCEPT (IBA). GO:0000151 entailed via GO:0005680/GO:0031461 → correctly NOT added. GO:0160072 ubiquitin ligase complex scaffold activity (verified real, new_to_goa): review ADDS as action: NEW (IC, PMID:26083744) only after gene-level scrutiny of structural literature (Apc2-Apc11 catalytic module; PMID:11739784 minimal module, 16364912). Defensible — APC2 is a degenerate cullin scaffold. Conclude: ADD (GO:0160072), others already captured/entailed.
Mapping strategy: ANAPC2 supports, rather than changes, the node mappings. The Cullin-group scaffold projection is precisely the term gene-level review accepts; APC and ligase-complex memberships are appropriately already-in/entailed. Scopes (ok_for_propagation) correct; no broader/narrower mismatch.
Evidence alignment: PN cites PMID:16763193, 21107322, 29167309, 27259151, 31350353. Review uses overlapping structural set (16364912, 26083744, 11739784, 18485873, 29033132) plus DR additions PMID:37735619 (TR cryo-EM E2 docking), 39567505 (APC2 Zn module), 36548081 (DEPTOR substrate) as statement-only. Good overlap on APC/C catalytic-module structure; review enriches with newer cryo-EM.
Verdict: Consistent; GO:0160072 NEW warranted and matches PN (new_to_goa). GO:0005680 ACCEPT, GO:0000151 correctly entailed. No over-reach.
Recommended edits: none to ANAPC2-ai-review.yaml; PN mappings sound as-is.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-03
review_yaml: genes/human/ANAPC2/ANAPC2-ai-review.yaml
PN workbook rows: 3

PN row 1: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | Cullin | degenerate, APC sununit

UniProt: Q9UJX6
In branches: UPS
Signature domains: IPR001373, IPR059120
Auxiliary domains: (none)
PN references (titles):
- 16763193
- 21107322
PN-node mapping records (path + ancestors):
- [type] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cullin|degenerate, APC sununit
  status=no_mapping scope= GO=[]
  rationale: Reviewed manually as a UPS source node. No single GO term is appropriate for direct propagation from this PN label without narrower context or gene-level evidence.
- [group] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cullin
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0160072 ubiquitin ligase complex scaffold activity]
  rationale: This PN group captures cullin or cullin-associated scaffold roles in ubiquitin ligase complexes. The shared GO molecular-function target is ubiquitin ligase complex scaffold activity.
- [class] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases
  status=context_only scope=too_broad_to_propagate GO=[GO:0061630 ubiquitin protein ligase activity]
  rationale: This class is a genuine E3-ligase context, but its descendants include catalytic ligases, cullin scaffolds, substrate receptors, adaptors, cofactors, regulators, and UBL modifier systems. A class-level propagation would over-annotate.
- [branch] Ubiquitin Proteasome System
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

PN row 2: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | idiosyncratic RING complex | Anaphase Promoting Complex | catalytic / core

UniProt: Q9UJX6
In branches: UPS
Signature domains: (none)
Auxiliary domains: IPR059120
PN references (titles):
- 29167309
- 16763193
PN-node mapping records (path + ancestors):
- [subtype] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|idiosyncratic RING complex|Anaphase Promoting Complex|catalytic / core
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a narrower E3-ligase architecture, component, or domain subdivision already covered by the curated parent E3 mapping. No additional direct GO mapping is needed at this node.
- [type] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|idiosyncratic RING complex|Anaphase Promoting Complex
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0005680 anaphase-promoting complex]
  rationale: In 4.3.11, APC/C is nested under the idiosyncratic RING-complex branch rather than appearing as a direct group. The GO cellular-component term anaphase-promoting complex remains the appropriate propagation target.
- [group] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|idiosyncratic RING complex
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0000151 ubiquitin ligase complex]
  rationale: This PN group is an E3 ligase complex bucket. The safest shared GO target is ubiquitin ligase complex membership rather than assigning catalytic activity to every subunit.
- [class] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases
  status=context_only scope=too_broad_to_propagate GO=[GO:0061630 ubiquitin protein ligase activity]
  rationale: This class is a genuine E3-ligase context, but its descendants include catalytic ligases, cullin scaffolds, substrate receptors, adaptors, cofactors, regulators, and UBL modifier systems. A class-level propagation would over-annotate.
- [branch] Ubiquitin Proteasome System
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

PN row 3: Ubiquitin Proteasome System | Ubiquitin and UBL binding | E3 ligase complex component | APC / catalytic subunit | idiosyncratic Ub binding / other

UniProt: Q9UJX6
In branches: UPS
Signature domains: PMID: 27259151, PMID: 31350353
Auxiliary domains: IPR059120
PN references (titles):
- 27259151
- 31350353
PN-node mapping records (path + ancestors):
- [subtype] Ubiquitin Proteasome System|Ubiquitin and UBL binding|E3 ligase complex component|APC / catalytic subunit|idiosyncratic Ub binding / other
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a narrower enzyme-family, domain, or architecture subdivision already covered by a curated parent enzyme mapping. No additional direct GO mapping is needed at this node.
- [type] Ubiquitin Proteasome System|Ubiquitin and UBL binding|E3 ligase complex component|APC / catalytic subunit
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a narrower enzyme-family, domain, or architecture subdivision already covered by a curated parent enzyme mapping. No additional direct GO mapping is needed at this node.
- [group] Ubiquitin Proteasome System|Ubiquitin and UBL binding|E3 ligase complex component
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0000151 ubiquitin ligase complex]
  rationale: This PN group captures E3 ligase complex components. The safe shared GO target is ubiquitin ligase complex membership.
- [class] Ubiquitin Proteasome System|Ubiquitin and UBL binding
  status=context_only scope=too_broad_to_propagate GO=[GO:0140036 ubiquitin-modified protein reader activity]
  rationale: This class records ubiquitin/UBL-reader context, but the subtree mixes ubiquitin, SUMO, UBL-domain, domain-architecture, catalytic, signaling, trafficking, and nucleic-acid process buckets. It is useful context, not a safe direct propagation.
- [branch] Ubiquitin Proteasome System
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

Projected GO annotations (4)

GO:0160072 ubiquitin ligase complex scaffold activity | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cullin
GO:0000151 ubiquitin ligase complex | scope=ok_for_propagation_to_go | goa_status=entailed_by_goa_closure | from=Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|idiosyncratic RING complex
GO:0005680 anaphase-promoting complex | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|idiosyncratic RING complex|Anaphase Promoting Complex
GO:0000151 ubiquitin ligase complex | scope=ok_for_propagation_to_go | goa_status=entailed_by_goa_closure | from=Ubiquitin Proteasome System|Ubiquitin and UBL binding|E3 ligase complex component

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

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

ANAPC2

Gene Description

Existing Annotations Review

Core Functions

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.

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.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Comprehensive research report: Human ANAPC2 (APC2; UniProt Q9UJX6) functional annotation

0) Target verification (required disambiguation)

1) Key concepts and current understanding

1.1 What ANAPC2/APC2 is

1.2 Molecular function: ubiquitin ligase “reaction” and substrate specificity

1.3 E2 usage: division of labor

2) Protein domains / structural features (with emphasis on 2023–2024)

2.1 Canonical APC2 features: cullin-like scaffold + WHB region

2.2 2024 high-resolution structures: APC2 zinc-binding module

2.3 2023 time-resolved cryo-EM: APC2 participates in E2 docking via APC2–APC4 groove

3) Mechanistic role of ANAPC2/APC2 in APC/C catalysis

3.1 Minimal catalytic module and biochemical sufficiency

3.2 Conformational activation: “CRL down” to “CRL up”

3.3 Allosteric coupling between elongation and priming E2s via APC2

4) Pathways and regulation

4.1 Spindle assembly checkpoint (SAC) and MCC inhibition

4.2 EMI1 inhibition engages APC2 surfaces

4.3 Phosphoregulation and coactivator exchange

5) Subcellular localization

6) Recent developments (prioritizing 2023–2024)

6.1 2023: time-resolved cryo-EM reveals dynamic ubiquitination mechanism and quantitative conformational landscape

6.2 2024: higher-resolution APC/C structures add new APC2 feature (zinc-binding module)

7) Current applications and real-world implementations

7.1 Cancer-relevant axis involving APC/C catalytic function: APC/C^CDH1–UBE2C–DEPTOR–mTOR signaling

7.2 Quantitative in vivo outcomes (disease-relevant statistics)

7.3 Disease association resources

8) Expert opinions / authoritative interpretations

9) Summary of evidence (table)

10) Key URLs and publication dates (most-cited/most-recent used here)

11) Limitations of the current evidence set

Artifacts

Citations

📚 Additional Documentation

Notes

ANAPC2 notes

Deep research status

PN projection evaluation

Annotation review summary

Falcon deep research findings (2026-06-07)

Pn Notes

ANAPC2 PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

PN row 1: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | Cullin | degenerate, APC sununit

PN row 2: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | idiosyncratic RING complex | Anaphase Promoting Complex | catalytic / core

PN row 3: Ubiquitin Proteasome System | Ubiquitin and UBL binding | E3 ligase complex component | APC / catalytic subunit | idiosyncratic Ub binding / other

Projected GO annotations (4)

Note

📄 View Raw YAML