{"gene":"ANAPC5","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":1998,"finding":"ANAPC5 (APC5) was identified as one of four previously uncharacterized subunits of the anaphase-promoting complex (APC/C), an eight-subunit E3 ubiquitin ligase that targets cell cycle regulators for degradation; APC5 shares no similarity to proteins of known function but is a core structural component of the complex.","method":"Biochemical purification and cloning of human APC subunits","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 — original biochemical identification replicated across APC field","pmids":["9469815"],"is_preprint":false},{"year":2003,"finding":"APC5, together with APC1 and APC4, forms a scaffold subcomplex that connects the catalytic module (APC2/APC11) with the TPR subunits; this subcomplex can assemble multiubiquitin chains but cannot bind the co-activator CDH1 or ubiquitinate substrates alone.","method":"Biochemical fractionation and reconstitution of human APC subcomplexes; in vitro ubiquitination assays; CDH1 binding assays","journal":"Current Biology","confidence":"High","confidence_rationale":"Tier 1 — reconstitution and in vitro assay with multiple orthogonal methods","pmids":["12956947"],"is_preprint":false},{"year":2011,"finding":"Cryo-EM combined with mass spectrometry and crystallographic docking defined APC5 as a scaffolding subunit that, together with APC1 and APC4 (the platform subcomplex), coordinates juxtaposition of the catalytic module (APC2/APC11/APC10) and the TPR subcomplex (CDC16/CDC23/CDC27) within the APC/C.","method":"Electron microscopy, mass spectrometry, recombinant reconstitution of holo-APC/C, and docking of crystallographic coordinates","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — reconstitution + structure + MS, replicated in field","pmids":["21307936"],"is_preprint":false},{"year":2015,"finding":"Crystal structure of the N-terminal domain of human APC5 (Apc5N) was determined, revealing an α-helical fold; in the context of the APC/C cryo-EM map, Apc5N shows small conformational changes and regions of Apc4 disordered in crystal gain order through contacts with Apc5.","method":"X-ray crystallography of Apc5N and Apc4; fitting into 3.6-Å cryo-EM map of APC/C","journal":"Journal of Molecular Biology","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with cryo-EM validation","pmids":["26343760"],"is_preprint":false},{"year":2016,"finding":"APC5 is part of the platform subcomplex (Apc1/Apc4/Apc5/Apc15); deletion of the Apc1 WD40 domain locks the APC/C into an inactive conformation, implicating the platform in the coactivator-induced allosteric transition that allows UbcH10 binding and substrate ubiquitination initiation.","method":"Crystal structure of Apc1N, cryo-EM of mutant APC/C-Cdh1 complex lacking Apc1(WD40), in vitro ubiquitination assays","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 1 — structure + mutagenesis + in vitro assay","pmids":["27601667"],"is_preprint":false},{"year":2005,"finding":"APC5 and APC7 directly interact with the transcriptional co-activators CBP and p300 through evolutionarily conserved protein-protein interaction domains (shared with adenovirus E1A); this interaction stimulates CBP/p300 acetyltransferase activity and potentiates CBP/p300-dependent transcription. APC5 and APC7 suppress E1A-mediated transformation in a CBP/p300-dependent manner.","method":"Co-immunoprecipitation, GST pulldown, acetyltransferase activity assays, reporter gene assays, siRNA knockdown, focus formation assay","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP + enzymatic assay + functional rescue, single lab but multiple orthogonal methods","pmids":["16319895"],"is_preprint":false},{"year":2004,"finding":"APC5 (Apc5) binds poly(A) binding protein (PABP) and represses IRES-mediated translation of PDGF-2 mRNA; APC5 overexpression counteracts PABP-stimulated IRES activity, and APC5 is degraded upon megakaryocytic differentiation in correlation with IRES activation.","method":"Yeast three-hybrid screen, co-immunoprecipitation, sucrose gradient sedimentation with ribosomal fraction, IRES reporter assays, differentiation experiments","journal":"Molecular and Cellular Biology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods (3-hybrid, co-IP, functional assay) but single lab","pmids":["15082755"],"is_preprint":false},{"year":2013,"finding":"APC5 (AnapC5) interacts with both IL-17RA and IL-17RC receptor subunits and with the negative regulator A20 (TNFAIP3); siRNA silencing of AnapC5 enhanced IL-17-induced gene expression, identifying AnapC5 as an inhibitory adaptor in IL-17 signaling distinct from the Itch/TAXBP1 scaffold used in TNFα/IL-1 pathways.","method":"Yeast 2-hybrid screen, siRNA knockdown, co-immunoprecipitation, IL-17-responsive reporter gene assays","journal":"PLoS One","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP + functional KD assay, single lab","pmids":["23922952"],"is_preprint":false},{"year":2012,"finding":"APC5 binds E2F1 (identified by Co-IP in vivo and GST pulldown in vitro) and is essential for APC/C(Cdh1)-mediated K11-linked ubiquitination and proteasomal degradation of E2F1 after S phase.","method":"Co-immunoprecipitation, GST pulldown, ubiquitination assays with K11-specific ubiquitin, siRNA knockdown, proteasome inhibitor experiments","journal":"Cell Cycle","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal co-IP + in vitro pulldown + ubiquitination assay, single lab","pmids":["22580462"],"is_preprint":false},{"year":2010,"finding":"During HCMV infection of quiescent cells, APC5 and APC4 are degraded in a proteasome-dependent manner, temporally associated with APC/C disassembly; immediate early viral gene expression is not sufficient, implicating early viral gene products in APC5 degradation.","method":"Immunoblot, proteasome inhibitor treatment, mutant virus infection (ΔUL97), mass spectrometry analysis of Cdh1 phosphorylation","journal":"Journal of Virology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic/pharmacological dissection with multiple virus mutants","pmids":["20686030"],"is_preprint":false},{"year":2012,"finding":"HCMV protein pUL21a binds the APC/C and is necessary and sufficient for proteasome-dependent degradation of APC5 and APC4 subunits, causing APC/C disruption; residues P109-R110 of pUL21a are critical for APC binding and regulation.","method":"Proteomics/MS, Co-IP, siRNA knockdown, point mutant virus construction, ubiquitin ligase activity assays","journal":"PLoS Pathogens","confidence":"High","confidence_rationale":"Tier 2 — proteomics + co-IP + mutagenesis + viral genetics, multiple orthogonal methods","pmids":["22792066"],"is_preprint":false},{"year":2015,"finding":"A cellular mechanism exists whereby depletion of any one of APC1, APC4, APC5, or APC8 leads to co-dependent downmodulation of all three platform subunits (APC1, APC4, APC5); this inter-dependency was demonstrated in uninfected cells independent of viral infection.","method":"siRNA knockdown of individual APC subunits, immunoblot quantification of co-depletion","journal":"Journal of Virology","confidence":"Medium","confidence_rationale":"Tier 2 — systematic KD panel with consistent phenotype, single lab","pmids":["25903336"],"is_preprint":false},{"year":2002,"finding":"In Drosophila, IDA (the APC5 ortholog) is required for APC/C function in imaginal disc cell proliferation; ida mutants show high mitotic index, aneuploid chromosomes, and failure to degrade cyclin B, but some APC/C substrates controlling sister-chromatid separation are still turned over, suggesting APC5 controls specific regulatory subfunctions of the APC/C.","method":"Genetic cloning and characterization, immunofluorescence cytology, cyclin B immunostaining in mutant brains","journal":"Journal of Cell Science","confidence":"High","confidence_rationale":"Tier 2 — ortholog loss-of-function with specific substrate analysis, well-controlled genetic study","pmids":["11870214"],"is_preprint":false},{"year":2003,"finding":"In budding yeast, Mnd2 and Swm1 (novel APC subunits) interact directly with Apc5 (and Cdc23/Apc1) when coexpressed in vitro, placing Apc5 as a docking site for these peripheral APC subunits.","method":"Mass spectrometry of purified APC, in vitro transcription/translation co-immunoprecipitation, epitope-tagging co-purification","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 3 — in vitro co-expression pulldown + MS, single lab","pmids":["12609981"],"is_preprint":false},{"year":2009,"finding":"In fission yeast, transcription factor Atf1 physically binds the APC/C in vivo and addition of purified Atf1 to a cell-free system stimulates APC/C-dependent ubiquitylation of cyclin B and securin; Atf1 suppresses the mitotic arrest of the apc5-1 mutant in a bZIP-domain-independent manner.","method":"Genetic suppressor screen, co-immunoprecipitation, cell-free ubiquitination assay with purified Atf1","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro reconstitution assay + co-IP + genetic epistasis, single lab","pmids":["19584054"],"is_preprint":false},{"year":2002,"finding":"In yeast, APC5 (RMC1) is required for in vitro chromatin assembly; the rmc1/apc5 allele genetically interacts with apc9Δ, apc10Δ, and cdc26Δ, and confers UV sensitivity, plasmid loss, and G2/M accumulation, establishing APC5 as required for APC-dependent chromatin assembly and genomic stability.","method":"In vitro chromatin assembly screen, genetic interaction analysis, cell cycle FACS, UV survival assays","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro assay + multiple genetic interactions, single lab","pmids":["12399376"],"is_preprint":false},{"year":2013,"finding":"In yeast, Apc5 (used as two-hybrid bait) interacts with the lifespan determinant Fob1; Fob1 is unstable in G1 and stabilized in apc5(CA) and rpn10 (proteasome) mutants, and a putative L-box destruction motif in Fob1 is required for its modifications, placing Fob1 as an APC/C substrate that influences rDNA stability and replicative lifespan.","method":"Yeast two-hybrid, protein stability assays (cycloheximide chase), mutant analysis (apc5CA, rpn10), lifespan assays, rDNA recombination assays","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 — two-hybrid + stability assay + genetic epistasis, single lab","pmids":["24361936"],"is_preprint":false},{"year":2025,"finding":"ANAPC5 mediates ubiquitination of GPAA1 (a catalytic subunit of GPI transamidase); radiation inhibits the APC/C complex, reducing ANAPC5-mediated ubiquitination of GPAA1, leading to GPAA1 accumulation, enhanced GPI anchoring of CD24, increased surface CD24 expression, and tumor immune evasion.","method":"Co-immunoprecipitation, ubiquitination assays, GPAA1 and CD24 expression analysis in irradiated cells, GPAA1/CD24 ablation in preclinical tumor models, flow cytometry","journal":"Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP + ubiquitination assay + in vivo functional validation, single lab","pmids":["41512182"],"is_preprint":false},{"year":2025,"finding":"ANAPC5 overexpression inhibits M1 macrophage polarization and promotes M2 polarization in LPS-induced acute lung injury by inducing ubiquitination of EGFR, reducing EGFR activation and expression; EGFR knockdown reversed the inhibitory effects of ANAPC5 on inflammation, and EGFR suppressed CD24 expression downstream, placing ANAPC5 as a negative regulator of EGFR/CD24-axis-mediated macrophage polarization.","method":"ANAPC5 overexpression in vivo (ALI mouse model) and in vitro (macrophages), ubiquitination assays for EGFR, cytokine measurement, macrophage polarization markers, rescue experiments with EGFR","journal":"Cellular Immunology","confidence":"Medium","confidence_rationale":"Tier 2 — ubiquitination assay + in vivo model + genetic rescue, single lab","pmids":["40834712"],"is_preprint":false},{"year":2024,"finding":"In mouse and human cell line models, co-depletion of ANAPC5 (APC5) exacerbates mitotic arrest induced by KIF18A depletion, while co-depletion of ANAPC7 partially rescues it, revealing that ANAPC5 and ANAPC7 have opposing effects on APC/C activity during mitosis and modulate sensitivity to KIF18A loss.","method":"siRNA co-depletion experiments in cell lines, time-lapse mitotic progression assays, mouse genetic screen for loci modifying KIF18A-dependent germ cell depletion","journal":"Scientific Reports / bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — genetic modifier screen + cell line KD with mitotic phenotype readout, replicated in preprint and peer-reviewed publication","pmids":["40596695","39677807"],"is_preprint":false},{"year":2007,"finding":"In C. elegans, a mutation in the APC5-like component SUCH-1/APC5 delays anaphase onset in germline and early embryonic cells and acts as a suppressor of mdf-1/MAD1 (spindle assembly checkpoint) lethality by delaying mitotic progression with concomitant IFY-1/securin accumulation.","method":"EMS mutagenesis screen, time-lapse imaging of embryonic cells, IFY-1 immunostaining, genetic suppression analysis","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 — live imaging + genetic epistasis in C. elegans ortholog","pmids":["17237515"],"is_preprint":false},{"year":2010,"finding":"In C. elegans, the two APC5 paralogs SUCH-1 and GFI-3 are co-expressed in germline but have non-overlapping expression in other tissues; single depletion has no meiotic effect, but co-depletion causes meiotic arrest, demonstrating redundant APC5 function during meiotic divisions.","method":"RNAi co-depletion, meiotic phenotype scoring, expression pattern analysis","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 — RNAi epistasis with clear meiotic phenotype in ortholog, single lab","pmids":["20944012"],"is_preprint":false},{"year":2010,"finding":"In C. elegans, a novel allele of SUCH-1/APC5 causes prolonged mitosis that is dependent on the spindle assembly checkpoint (SAC); inactivation of SAC components MDF-1/MAD1 or MDF-2/MAD2 rescues mitotic timing in APC/C-compromised embryos assembling monopolar spindles, indicating mutual antagonism between APC/C (via APC5) and the SAC.","method":"Genetic characterization of such-1(t1668) allele, SAC component RNAi, time-lapse imaging of mitotic duration","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis with live imaging, single lab","pmids":["20944014"],"is_preprint":false}],"current_model":"ANAPC5 (APC5) is a scaffolding subunit of the APC/C E3 ubiquitin ligase that, together with APC1 and APC4, forms the platform subcomplex bridging the catalytic module (APC2/APC11) to the TPR subunits; beyond its structural role, APC5 directly interacts with co-activators CBP/p300 to stimulate their acetyltransferase activity, binds E2F1 to facilitate its K11-linked ubiquitination and degradation, associates with poly(A)-binding protein to repress IRES-mediated translation, and mediates ubiquitination of substrates such as GPAA1 and EGFR to regulate GPI-anchored surface protein trafficking and macrophage polarization, while also modulating IL-17 signaling as an inhibitory adaptor through association with A20."},"narrative":{"teleology":[{"year":1998,"claim":"Identifying APC5 as a core APC/C subunit established that the complex contains previously uncharacterized components beyond the known CDC proteins, opening the question of what structural or catalytic role each subunit plays.","evidence":"Biochemical purification and cloning of human APC subunits from HeLa cells","pmids":["9469815"],"confidence":"High","gaps":["No structural or catalytic function assigned to APC5 specifically","Stoichiometry within the complex unknown"]},{"year":2002,"claim":"Genetic studies in Drosophila and yeast revealed that APC5 is essential for APC/C-dependent degradation of cyclin B and for chromatin assembly, but not all APC/C substrates depend equally on APC5, raising the question of whether APC5 controls substrate selectivity.","evidence":"Drosophila ida mutant analysis with substrate-specific immunostaining; yeast rmc1/apc5 allele with in vitro chromatin assembly, genetic interactions, and cell cycle phenotyping","pmids":["11870214","12399376"],"confidence":"High","gaps":["Mechanism by which APC5 contributes to substrate selectivity unclear","Whether chromatin assembly role is direct or indirect through substrate degradation"]},{"year":2003,"claim":"Biochemical reconstitution showed that APC5, APC1, and APC4 form a discrete platform subcomplex that supports multiubiquitin chain assembly but cannot bind co-activators or ubiquitinate substrates alone, defining a modular architecture for the APC/C.","evidence":"Biochemical fractionation of human APC subcomplexes, in vitro ubiquitination and CDH1 binding assays","pmids":["12956947","12609981"],"confidence":"High","gaps":["No atomic-resolution structure of APC5 or the platform","How the platform communicates with the TPR lobe to enable co-activator binding"]},{"year":2004,"claim":"The discovery that APC5 binds poly(A)-binding protein and represses IRES-mediated translation revealed an unexpected non-canonical role for an APC/C subunit in translational regulation, though whether this occurs as part of the holo-complex or independently remained unresolved.","evidence":"Yeast three-hybrid screen, co-immunoprecipitation, IRES reporter assays, megakaryocytic differentiation experiments","pmids":["15082755"],"confidence":"Medium","gaps":["Whether APC5 acts on translation as a free monomer or within the APC/C","Not independently replicated","Scope of mRNAs regulated unknown"]},{"year":2005,"claim":"Showing that APC5 (and APC7) directly bind and stimulate CBP/p300 acetyltransferase activity established a link between the APC/C and transcriptional co-activation, and explained how APC subunits suppress E1A-mediated transformation independently of ubiquitin ligase activity.","evidence":"Reciprocal co-IP, GST pulldown, acetyltransferase activity assays, reporter assays, siRNA knockdown, focus formation assay","pmids":["16319895"],"confidence":"High","gaps":["Whether stimulation of CBP/p300 occurs in the context of intact APC/C or free APC5","Physiological transcriptional targets of the APC5–CBP/p300 axis unknown"]},{"year":2007,"claim":"Genetic studies of APC5 orthologs in C. elegans demonstrated that partial loss of APC5 function delays anaphase onset in a spindle assembly checkpoint-dependent manner, establishing APC5 as a rate-limiting component for mitotic timing and revealing mutual antagonism between the APC/C and the SAC.","evidence":"EMS mutagenesis, time-lapse imaging of C. elegans embryos, SAC component RNAi epistasis","pmids":["17237515","20944014","20944012"],"confidence":"Medium","gaps":["Whether the SAC-dependent delay reflects direct APC5–SAC interaction or reduced APC/C catalytic capacity","Redundancy between APC5 paralogs complicates interpretation in non-mammalian systems"]},{"year":2010,"claim":"Discovery that HCMV infection induces proteasome-dependent degradation of APC5 and APC4 revealed that viruses exploit the co-dependent stability of platform subunits to dismantle the APC/C and reprogram the host cell cycle.","evidence":"Immunoblot of APC subunits during HCMV infection, proteasome inhibitor treatment, mutant virus analysis","pmids":["20686030","22792066"],"confidence":"High","gaps":["Ubiquitin ligase responsible for APC5 degradation during infection not identified at this stage"]},{"year":2011,"claim":"Cryo-EM and crystallographic studies resolved the spatial organization of APC5 within the holo-APC/C, confirming its position in the platform and showing that its N-terminal α-helical domain makes stabilizing contacts with APC4, providing the first structural framework for understanding how the platform bridges catalytic and TPR modules.","evidence":"Cryo-EM at sub-nanometer resolution, X-ray crystallography of Apc5N and Apc4, fitting into 3.6-Å APC/C map","pmids":["21307936","26343760"],"confidence":"High","gaps":["Full atomic model of APC5 C-terminus still lacking at the time","Conformational dynamics during catalytic cycle not resolved"]},{"year":2012,"claim":"Identification of APC5 as a direct binding partner of E2F1, required for APC/C(Cdh1)-mediated K11-linked ubiquitination and post-S-phase degradation of E2F1, connected the APC/C platform to cell cycle-dependent transcription factor turnover.","evidence":"Co-IP, GST pulldown, K11-specific ubiquitination assays, siRNA knockdown","pmids":["22580462"],"confidence":"Medium","gaps":["Whether APC5 acts as a substrate receptor or facilitates co-activator-mediated recognition","Not independently replicated"]},{"year":2013,"claim":"APC5 was found to interact with IL-17 receptor subunits and A20, functioning as an inhibitory adaptor that restrains IL-17 signaling — the first evidence placing an APC/C subunit in cytokine receptor signaling.","evidence":"Yeast two-hybrid, co-IP, siRNA knockdown with IL-17-responsive reporter assays","pmids":["23922952"],"confidence":"Medium","gaps":["Whether APC5 acts in this context as part of the holo-APC/C or independently","Mechanism of A20 recruitment through APC5 not detailed","Not independently replicated"]},{"year":2016,"claim":"Mutagenesis of APC1 within the platform showed that the platform subcomplex (including APC5) participates in a co-activator-induced allosteric transition required for UbcH10 engagement and substrate ubiquitination initiation, moving APC5 from a purely structural role to one involved in catalytic regulation.","evidence":"Crystal structure of Apc1N, cryo-EM of Apc1-WD40-deletion APC/C–Cdh1 complex, in vitro ubiquitination assays","pmids":["27601667"],"confidence":"High","gaps":["Direct contribution of APC5 residues to the allosteric mechanism not dissected","Whether APC5 undergoes conformational changes during catalysis"]},{"year":2025,"claim":"Two recent studies extended APC5's substrate repertoire to GPAA1 and EGFR, linking APC/C-mediated ubiquitination to GPI-anchored protein surface expression, tumor immune evasion, and macrophage polarization — expanding the functional scope of APC5 beyond canonical cell cycle control.","evidence":"Co-IP and ubiquitination assays for GPAA1 and EGFR, preclinical tumor models, macrophage polarization assays with genetic rescue","pmids":["41512182","40834712"],"confidence":"Medium","gaps":["Whether GPAA1 and EGFR are direct APC/C substrates recognized through canonical degron motifs","Each finding from a single lab and not yet independently replicated","Relative contribution of APC5 versus other APC/C subunits to these substrate interactions unknown"]},{"year":null,"claim":"It remains unresolved whether APC5's non-canonical functions (CBP/p300 stimulation, PABP binding, IL-17 signaling) occur within the context of the intact APC/C holoenzyme or reflect moonlighting activities of free APC5, and the structural basis for APC5's direct engagement of specific substrates has not been determined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No reconstitution separating holo-APC/C-dependent from APC5-autonomous activities","No structural model of APC5 bound to any non-canonical partner","Relative physiological importance of canonical versus non-canonical APC5 functions untested in genetic models"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,8,17,18]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,2,3,4]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,7]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,2,8]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,6]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,1,2,4,12,19,20,22]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,8,17,18]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7,18]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[9,10]}],"complexes":["APC/C","APC/C platform subcomplex (APC1/APC4/APC5)"],"partners":["ANAPC1","ANAPC4","ANAPC7","EP300","CREBBP","E2F1","PABPC1","TNFAIP3"],"other_free_text":[]},"mechanistic_narrative":"ANAPC5 (APC5) is a core scaffolding subunit of the anaphase-promoting complex/cyclosome (APC/C), the multi-subunit E3 ubiquitin ligase that drives cell cycle progression by targeting cyclins, securin, and other regulators for proteasomal degradation. Together with APC1 and APC4, APC5 forms the platform subcomplex that bridges the catalytic module (APC2/APC11) to the TPR lobe, and this platform undergoes co-activator-induced conformational changes required for substrate ubiquitination initiation [PMID:9469815, PMID:12956947, PMID:21307936, PMID:27601667]. Beyond its structural role in the APC/C, APC5 directly engages substrates and signaling partners: it binds E2F1 to promote K11-linked ubiquitination and degradation [PMID:22580462], interacts with CBP/p300 to stimulate acetyltransferase activity and suppress E1A-mediated transformation [PMID:16319895], associates with IL-17 receptor subunits and A20 to negatively regulate IL-17 signaling [PMID:23922952], and mediates ubiquitination of GPAA1 and EGFR linking APC/C activity to GPI-anchored protein trafficking and macrophage polarization [PMID:41512182, PMID:40834712]. During human cytomegalovirus infection, the viral protein pUL21a targets APC5 and APC4 for proteasome-dependent degradation, exploiting the co-dependent stability of platform subunits to dismantle the APC/C and override cell cycle control [PMID:22792066, PMID:25903336]."},"prefetch_data":{"uniprot":{"accession":"Q9UJX4","full_name":"Anaphase-promoting complex subunit 5","aliases":["Cyclosome subunit 5"],"length_aa":755,"mass_kda":85.1,"function":"Component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of the cell cycle (PubMed:18485873). The APC/C complex acts by mediating ubiquitination and subsequent degradation of target proteins: it mainly mediates the formation of 'Lys-11'-linked polyubiquitin chains and, to a lower extent, the formation of 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains (PubMed:18485873). The APC/C complex catalyzes assembly of branched 'Lys-11'-/'Lys-48'-linked branched ubiquitin chains on target proteins (PubMed:29033132)","subcellular_location":"Nucleus; Cytoplasm, cytoskeleton, spindle","url":"https://www.uniprot.org/uniprotkb/Q9UJX4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/ANAPC5","classification":"Common Essential","n_dependent_lines":1188,"n_total_lines":1208,"dependency_fraction":0.9834437086092715},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ANAPC16","stoichiometry":10.0},{"gene":"ANAPC4","stoichiometry":10.0},{"gene":"CDC16","stoichiometry":10.0},{"gene":"CDC23","stoichiometry":10.0},{"gene":"ANAPC2","stoichiometry":4.0},{"gene":"CDC26","stoichiometry":4.0},{"gene":"CDC27","stoichiometry":4.0},{"gene":"FKBP5","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"SRP9","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ANAPC5","total_profiled":1310},"omim":[{"mim_id":"606948","title":"ANAPHASE-PROMOTING COMPLEX, SUBUNIT 5; ANAPC5","url":"https://www.omim.org/entry/606948"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ANAPC5"},"hgnc":{"alias_symbol":["APC5"],"prev_symbol":[]},"alphafold":{"accession":"Q9UJX4","domains":[{"cath_id":"-","chopping":"31-171","consensus_level":"high","plddt":83.0122,"start":31,"end":171}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UJX4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UJX4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UJX4-F1-predicted_aligned_error_v6.png","plddt_mean":81.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ANAPC5","jax_strain_url":"https://www.jax.org/strain/search?query=ANAPC5"},"sequence":{"accession":"Q9UJX4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UJX4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UJX4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UJX4"}},"corpus_meta":[{"pmid":"21714072","id":"PMC_21714072","title":"Differential immune system DNA methylation and cytokine regulation in post-traumatic stress disorder.","date":"2011","source":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21714072","citation_count":259,"is_preprint":false},{"pmid":"9469815","id":"PMC_9469815","title":"Identification of a cullin homology region in a subunit of the anaphase-promoting complex.","date":"1998","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/9469815","citation_count":211,"is_preprint":false},{"pmid":"12956947","id":"PMC_12956947","title":"TPR subunits of the anaphase-promoting complex mediate binding to the activator protein CDH1.","date":"2003","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/12956947","citation_count":172,"is_preprint":false},{"pmid":"21307936","id":"PMC_21307936","title":"Structural basis for the subunit assembly of the anaphase-promoting 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APC5 shares no similarity to proteins of known function but is a core structural component of the complex.\",\n      \"method\": \"Biochemical purification and cloning of human APC subunits\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — original biochemical identification replicated across APC field\",\n      \"pmids\": [\"9469815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"APC5, together with APC1 and APC4, forms a scaffold subcomplex that connects the catalytic module (APC2/APC11) with the TPR subunits; this subcomplex can assemble multiubiquitin chains but cannot bind the co-activator CDH1 or ubiquitinate substrates alone.\",\n      \"method\": \"Biochemical fractionation and reconstitution of human APC subcomplexes; in vitro ubiquitination assays; CDH1 binding assays\",\n      \"journal\": \"Current Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution and in vitro assay with multiple orthogonal methods\",\n      \"pmids\": [\"12956947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Cryo-EM combined with mass spectrometry and crystallographic docking defined APC5 as a scaffolding subunit that, together with APC1 and APC4 (the platform subcomplex), coordinates juxtaposition of the catalytic module (APC2/APC11/APC10) and the TPR subcomplex (CDC16/CDC23/CDC27) within the APC/C.\",\n      \"method\": \"Electron microscopy, mass spectrometry, recombinant reconstitution of holo-APC/C, and docking of crystallographic coordinates\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution + structure + MS, replicated in field\",\n      \"pmids\": [\"21307936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structure of the N-terminal domain of human APC5 (Apc5N) was determined, revealing an α-helical fold; in the context of the APC/C cryo-EM map, Apc5N shows small conformational changes and regions of Apc4 disordered in crystal gain order through contacts with Apc5.\",\n      \"method\": \"X-ray crystallography of Apc5N and Apc4; fitting into 3.6-Å cryo-EM map of APC/C\",\n      \"journal\": \"Journal of Molecular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with cryo-EM validation\",\n      \"pmids\": [\"26343760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"APC5 is part of the platform subcomplex (Apc1/Apc4/Apc5/Apc15); deletion of the Apc1 WD40 domain locks the APC/C into an inactive conformation, implicating the platform in the coactivator-induced allosteric transition that allows UbcH10 binding and substrate ubiquitination initiation.\",\n      \"method\": \"Crystal structure of Apc1N, cryo-EM of mutant APC/C-Cdh1 complex lacking Apc1(WD40), in vitro ubiquitination assays\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structure + mutagenesis + in vitro assay\",\n      \"pmids\": [\"27601667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"APC5 and APC7 directly interact with the transcriptional co-activators CBP and p300 through evolutionarily conserved protein-protein interaction domains (shared with adenovirus E1A); this interaction stimulates CBP/p300 acetyltransferase activity and potentiates CBP/p300-dependent transcription. APC5 and APC7 suppress E1A-mediated transformation in a CBP/p300-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, acetyltransferase activity assays, reporter gene assays, siRNA knockdown, focus formation assay\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP + enzymatic assay + functional rescue, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"16319895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"APC5 (Apc5) binds poly(A) binding protein (PABP) and represses IRES-mediated translation of PDGF-2 mRNA; APC5 overexpression counteracts PABP-stimulated IRES activity, and APC5 is degraded upon megakaryocytic differentiation in correlation with IRES activation.\",\n      \"method\": \"Yeast three-hybrid screen, co-immunoprecipitation, sucrose gradient sedimentation with ribosomal fraction, IRES reporter assays, differentiation experiments\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods (3-hybrid, co-IP, functional assay) but single lab\",\n      \"pmids\": [\"15082755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"APC5 (AnapC5) interacts with both IL-17RA and IL-17RC receptor subunits and with the negative regulator A20 (TNFAIP3); siRNA silencing of AnapC5 enhanced IL-17-induced gene expression, identifying AnapC5 as an inhibitory adaptor in IL-17 signaling distinct from the Itch/TAXBP1 scaffold used in TNFα/IL-1 pathways.\",\n      \"method\": \"Yeast 2-hybrid screen, siRNA knockdown, co-immunoprecipitation, IL-17-responsive reporter gene assays\",\n      \"journal\": \"PLoS One\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP + functional KD assay, single lab\",\n      \"pmids\": [\"23922952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"APC5 binds E2F1 (identified by Co-IP in vivo and GST pulldown in vitro) and is essential for APC/C(Cdh1)-mediated K11-linked ubiquitination and proteasomal degradation of E2F1 after S phase.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, ubiquitination assays with K11-specific ubiquitin, siRNA knockdown, proteasome inhibitor experiments\",\n      \"journal\": \"Cell Cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP + in vitro pulldown + ubiquitination assay, single lab\",\n      \"pmids\": [\"22580462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"During HCMV infection of quiescent cells, APC5 and APC4 are degraded in a proteasome-dependent manner, temporally associated with APC/C disassembly; immediate early viral gene expression is not sufficient, implicating early viral gene products in APC5 degradation.\",\n      \"method\": \"Immunoblot, proteasome inhibitor treatment, mutant virus infection (ΔUL97), mass spectrometry analysis of Cdh1 phosphorylation\",\n      \"journal\": \"Journal of Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic/pharmacological dissection with multiple virus mutants\",\n      \"pmids\": [\"20686030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"HCMV protein pUL21a binds the APC/C and is necessary and sufficient for proteasome-dependent degradation of APC5 and APC4 subunits, causing APC/C disruption; residues P109-R110 of pUL21a are critical for APC binding and regulation.\",\n      \"method\": \"Proteomics/MS, Co-IP, siRNA knockdown, point mutant virus construction, ubiquitin ligase activity assays\",\n      \"journal\": \"PLoS Pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — proteomics + co-IP + mutagenesis + viral genetics, multiple orthogonal methods\",\n      \"pmids\": [\"22792066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A cellular mechanism exists whereby depletion of any one of APC1, APC4, APC5, or APC8 leads to co-dependent downmodulation of all three platform subunits (APC1, APC4, APC5); this inter-dependency was demonstrated in uninfected cells independent of viral infection.\",\n      \"method\": \"siRNA knockdown of individual APC subunits, immunoblot quantification of co-depletion\",\n      \"journal\": \"Journal of Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — systematic KD panel with consistent phenotype, single lab\",\n      \"pmids\": [\"25903336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"In Drosophila, IDA (the APC5 ortholog) is required for APC/C function in imaginal disc cell proliferation; ida mutants show high mitotic index, aneuploid chromosomes, and failure to degrade cyclin B, but some APC/C substrates controlling sister-chromatid separation are still turned over, suggesting APC5 controls specific regulatory subfunctions of the APC/C.\",\n      \"method\": \"Genetic cloning and characterization, immunofluorescence cytology, cyclin B immunostaining in mutant brains\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ortholog loss-of-function with specific substrate analysis, well-controlled genetic study\",\n      \"pmids\": [\"11870214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"In budding yeast, Mnd2 and Swm1 (novel APC subunits) interact directly with Apc5 (and Cdc23/Apc1) when coexpressed in vitro, placing Apc5 as a docking site for these peripheral APC subunits.\",\n      \"method\": \"Mass spectrometry of purified APC, in vitro transcription/translation co-immunoprecipitation, epitope-tagging co-purification\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — in vitro co-expression pulldown + MS, single lab\",\n      \"pmids\": [\"12609981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In fission yeast, transcription factor Atf1 physically binds the APC/C in vivo and addition of purified Atf1 to a cell-free system stimulates APC/C-dependent ubiquitylation of cyclin B and securin; Atf1 suppresses the mitotic arrest of the apc5-1 mutant in a bZIP-domain-independent manner.\",\n      \"method\": \"Genetic suppressor screen, co-immunoprecipitation, cell-free ubiquitination assay with purified Atf1\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro reconstitution assay + co-IP + genetic epistasis, single lab\",\n      \"pmids\": [\"19584054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"In yeast, APC5 (RMC1) is required for in vitro chromatin assembly; the rmc1/apc5 allele genetically interacts with apc9Δ, apc10Δ, and cdc26Δ, and confers UV sensitivity, plasmid loss, and G2/M accumulation, establishing APC5 as required for APC-dependent chromatin assembly and genomic stability.\",\n      \"method\": \"In vitro chromatin assembly screen, genetic interaction analysis, cell cycle FACS, UV survival assays\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro assay + multiple genetic interactions, single lab\",\n      \"pmids\": [\"12399376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In yeast, Apc5 (used as two-hybrid bait) interacts with the lifespan determinant Fob1; Fob1 is unstable in G1 and stabilized in apc5(CA) and rpn10 (proteasome) mutants, and a putative L-box destruction motif in Fob1 is required for its modifications, placing Fob1 as an APC/C substrate that influences rDNA stability and replicative lifespan.\",\n      \"method\": \"Yeast two-hybrid, protein stability assays (cycloheximide chase), mutant analysis (apc5CA, rpn10), lifespan assays, rDNA recombination assays\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — two-hybrid + stability assay + genetic epistasis, single lab\",\n      \"pmids\": [\"24361936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ANAPC5 mediates ubiquitination of GPAA1 (a catalytic subunit of GPI transamidase); radiation inhibits the APC/C complex, reducing ANAPC5-mediated ubiquitination of GPAA1, leading to GPAA1 accumulation, enhanced GPI anchoring of CD24, increased surface CD24 expression, and tumor immune evasion.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, GPAA1 and CD24 expression analysis in irradiated cells, GPAA1/CD24 ablation in preclinical tumor models, flow cytometry\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP + ubiquitination assay + in vivo functional validation, single lab\",\n      \"pmids\": [\"41512182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ANAPC5 overexpression inhibits M1 macrophage polarization and promotes M2 polarization in LPS-induced acute lung injury by inducing ubiquitination of EGFR, reducing EGFR activation and expression; EGFR knockdown reversed the inhibitory effects of ANAPC5 on inflammation, and EGFR suppressed CD24 expression downstream, placing ANAPC5 as a negative regulator of EGFR/CD24-axis-mediated macrophage polarization.\",\n      \"method\": \"ANAPC5 overexpression in vivo (ALI mouse model) and in vitro (macrophages), ubiquitination assays for EGFR, cytokine measurement, macrophage polarization markers, rescue experiments with EGFR\",\n      \"journal\": \"Cellular Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ubiquitination assay + in vivo model + genetic rescue, single lab\",\n      \"pmids\": [\"40834712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In mouse and human cell line models, co-depletion of ANAPC5 (APC5) exacerbates mitotic arrest induced by KIF18A depletion, while co-depletion of ANAPC7 partially rescues it, revealing that ANAPC5 and ANAPC7 have opposing effects on APC/C activity during mitosis and modulate sensitivity to KIF18A loss.\",\n      \"method\": \"siRNA co-depletion experiments in cell lines, time-lapse mitotic progression assays, mouse genetic screen for loci modifying KIF18A-dependent germ cell depletion\",\n      \"journal\": \"Scientific Reports / bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic modifier screen + cell line KD with mitotic phenotype readout, replicated in preprint and peer-reviewed publication\",\n      \"pmids\": [\"40596695\", \"39677807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In C. elegans, a mutation in the APC5-like component SUCH-1/APC5 delays anaphase onset in germline and early embryonic cells and acts as a suppressor of mdf-1/MAD1 (spindle assembly checkpoint) lethality by delaying mitotic progression with concomitant IFY-1/securin accumulation.\",\n      \"method\": \"EMS mutagenesis screen, time-lapse imaging of embryonic cells, IFY-1 immunostaining, genetic suppression analysis\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — live imaging + genetic epistasis in C. elegans ortholog\",\n      \"pmids\": [\"17237515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In C. elegans, the two APC5 paralogs SUCH-1 and GFI-3 are co-expressed in germline but have non-overlapping expression in other tissues; single depletion has no meiotic effect, but co-depletion causes meiotic arrest, demonstrating redundant APC5 function during meiotic divisions.\",\n      \"method\": \"RNAi co-depletion, meiotic phenotype scoring, expression pattern analysis\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RNAi epistasis with clear meiotic phenotype in ortholog, single lab\",\n      \"pmids\": [\"20944012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In C. elegans, a novel allele of SUCH-1/APC5 causes prolonged mitosis that is dependent on the spindle assembly checkpoint (SAC); inactivation of SAC components MDF-1/MAD1 or MDF-2/MAD2 rescues mitotic timing in APC/C-compromised embryos assembling monopolar spindles, indicating mutual antagonism between APC/C (via APC5) and the SAC.\",\n      \"method\": \"Genetic characterization of such-1(t1668) allele, SAC component RNAi, time-lapse imaging of mitotic duration\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with live imaging, single lab\",\n      \"pmids\": [\"20944014\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ANAPC5 (APC5) is a scaffolding subunit of the APC/C E3 ubiquitin ligase that, together with APC1 and APC4, forms the platform subcomplex bridging the catalytic module (APC2/APC11) to the TPR subunits; beyond its structural role, APC5 directly interacts with co-activators CBP/p300 to stimulate their acetyltransferase activity, binds E2F1 to facilitate its K11-linked ubiquitination and degradation, associates with poly(A)-binding protein to repress IRES-mediated translation, and mediates ubiquitination of substrates such as GPAA1 and EGFR to regulate GPI-anchored surface protein trafficking and macrophage polarization, while also modulating IL-17 signaling as an inhibitory adaptor through association with A20.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ANAPC5 (APC5) is a core scaffolding subunit of the anaphase-promoting complex/cyclosome (APC/C), the multi-subunit E3 ubiquitin ligase that drives cell cycle progression by targeting cyclins, securin, and other regulators for proteasomal degradation. Together with APC1 and APC4, APC5 forms the platform subcomplex that bridges the catalytic module (APC2/APC11) to the TPR lobe, and this platform undergoes co-activator-induced conformational changes required for substrate ubiquitination initiation [PMID:9469815, PMID:12956947, PMID:21307936, PMID:27601667]. Beyond its structural role in the APC/C, APC5 directly engages substrates and signaling partners: it binds E2F1 to promote K11-linked ubiquitination and degradation [PMID:22580462], interacts with CBP/p300 to stimulate acetyltransferase activity and suppress E1A-mediated transformation [PMID:16319895], associates with IL-17 receptor subunits and A20 to negatively regulate IL-17 signaling [PMID:23922952], and mediates ubiquitination of GPAA1 and EGFR linking APC/C activity to GPI-anchored protein trafficking and macrophage polarization [PMID:41512182, PMID:40834712]. During human cytomegalovirus infection, the viral protein pUL21a targets APC5 and APC4 for proteasome-dependent degradation, exploiting the co-dependent stability of platform subunits to dismantle the APC/C and override cell cycle control [PMID:22792066, PMID:25903336].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Identifying APC5 as a core APC/C subunit established that the complex contains previously uncharacterized components beyond the known CDC proteins, opening the question of what structural or catalytic role each subunit plays.\",\n      \"evidence\": \"Biochemical purification and cloning of human APC subunits from HeLa cells\",\n      \"pmids\": [\"9469815\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural or catalytic function assigned to APC5 specifically\", \"Stoichiometry within the complex unknown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Genetic studies in Drosophila and yeast revealed that APC5 is essential for APC/C-dependent degradation of cyclin B and for chromatin assembly, but not all APC/C substrates depend equally on APC5, raising the question of whether APC5 controls substrate selectivity.\",\n      \"evidence\": \"Drosophila ida mutant analysis with substrate-specific immunostaining; yeast rmc1/apc5 allele with in vitro chromatin assembly, genetic interactions, and cell cycle phenotyping\",\n      \"pmids\": [\"11870214\", \"12399376\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which APC5 contributes to substrate selectivity unclear\", \"Whether chromatin assembly role is direct or indirect through substrate degradation\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Biochemical reconstitution showed that APC5, APC1, and APC4 form a discrete platform subcomplex that supports multiubiquitin chain assembly but cannot bind co-activators or ubiquitinate substrates alone, defining a modular architecture for the APC/C.\",\n      \"evidence\": \"Biochemical fractionation of human APC subcomplexes, in vitro ubiquitination and CDH1 binding assays\",\n      \"pmids\": [\"12956947\", \"12609981\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No atomic-resolution structure of APC5 or the platform\", \"How the platform communicates with the TPR lobe to enable co-activator binding\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"The discovery that APC5 binds poly(A)-binding protein and represses IRES-mediated translation revealed an unexpected non-canonical role for an APC/C subunit in translational regulation, though whether this occurs as part of the holo-complex or independently remained unresolved.\",\n      \"evidence\": \"Yeast three-hybrid screen, co-immunoprecipitation, IRES reporter assays, megakaryocytic differentiation experiments\",\n      \"pmids\": [\"15082755\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether APC5 acts on translation as a free monomer or within the APC/C\", \"Not independently replicated\", \"Scope of mRNAs regulated unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showing that APC5 (and APC7) directly bind and stimulate CBP/p300 acetyltransferase activity established a link between the APC/C and transcriptional co-activation, and explained how APC subunits suppress E1A-mediated transformation independently of ubiquitin ligase activity.\",\n      \"evidence\": \"Reciprocal co-IP, GST pulldown, acetyltransferase activity assays, reporter assays, siRNA knockdown, focus formation assay\",\n      \"pmids\": [\"16319895\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether stimulation of CBP/p300 occurs in the context of intact APC/C or free APC5\", \"Physiological transcriptional targets of the APC5–CBP/p300 axis unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Genetic studies of APC5 orthologs in C. elegans demonstrated that partial loss of APC5 function delays anaphase onset in a spindle assembly checkpoint-dependent manner, establishing APC5 as a rate-limiting component for mitotic timing and revealing mutual antagonism between the APC/C and the SAC.\",\n      \"evidence\": \"EMS mutagenesis, time-lapse imaging of C. elegans embryos, SAC component RNAi epistasis\",\n      \"pmids\": [\"17237515\", \"20944014\", \"20944012\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the SAC-dependent delay reflects direct APC5–SAC interaction or reduced APC/C catalytic capacity\", \"Redundancy between APC5 paralogs complicates interpretation in non-mammalian systems\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Discovery that HCMV infection induces proteasome-dependent degradation of APC5 and APC4 revealed that viruses exploit the co-dependent stability of platform subunits to dismantle the APC/C and reprogram the host cell cycle.\",\n      \"evidence\": \"Immunoblot of APC subunits during HCMV infection, proteasome inhibitor treatment, mutant virus analysis\",\n      \"pmids\": [\"20686030\", \"22792066\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin ligase responsible for APC5 degradation during infection not identified at this stage\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Cryo-EM and crystallographic studies resolved the spatial organization of APC5 within the holo-APC/C, confirming its position in the platform and showing that its N-terminal α-helical domain makes stabilizing contacts with APC4, providing the first structural framework for understanding how the platform bridges catalytic and TPR modules.\",\n      \"evidence\": \"Cryo-EM at sub-nanometer resolution, X-ray crystallography of Apc5N and Apc4, fitting into 3.6-Å APC/C map\",\n      \"pmids\": [\"21307936\", \"26343760\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full atomic model of APC5 C-terminus still lacking at the time\", \"Conformational dynamics during catalytic cycle not resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of APC5 as a direct binding partner of E2F1, required for APC/C(Cdh1)-mediated K11-linked ubiquitination and post-S-phase degradation of E2F1, connected the APC/C platform to cell cycle-dependent transcription factor turnover.\",\n      \"evidence\": \"Co-IP, GST pulldown, K11-specific ubiquitination assays, siRNA knockdown\",\n      \"pmids\": [\"22580462\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether APC5 acts as a substrate receptor or facilitates co-activator-mediated recognition\", \"Not independently replicated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"APC5 was found to interact with IL-17 receptor subunits and A20, functioning as an inhibitory adaptor that restrains IL-17 signaling — the first evidence placing an APC/C subunit in cytokine receptor signaling.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, siRNA knockdown with IL-17-responsive reporter assays\",\n      \"pmids\": [\"23922952\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether APC5 acts in this context as part of the holo-APC/C or independently\", \"Mechanism of A20 recruitment through APC5 not detailed\", \"Not independently replicated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Mutagenesis of APC1 within the platform showed that the platform subcomplex (including APC5) participates in a co-activator-induced allosteric transition required for UbcH10 engagement and substrate ubiquitination initiation, moving APC5 from a purely structural role to one involved in catalytic regulation.\",\n      \"evidence\": \"Crystal structure of Apc1N, cryo-EM of Apc1-WD40-deletion APC/C–Cdh1 complex, in vitro ubiquitination assays\",\n      \"pmids\": [\"27601667\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct contribution of APC5 residues to the allosteric mechanism not dissected\", \"Whether APC5 undergoes conformational changes during catalysis\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Two recent studies extended APC5's substrate repertoire to GPAA1 and EGFR, linking APC/C-mediated ubiquitination to GPI-anchored protein surface expression, tumor immune evasion, and macrophage polarization — expanding the functional scope of APC5 beyond canonical cell cycle control.\",\n      \"evidence\": \"Co-IP and ubiquitination assays for GPAA1 and EGFR, preclinical tumor models, macrophage polarization assays with genetic rescue\",\n      \"pmids\": [\"41512182\", \"40834712\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether GPAA1 and EGFR are direct APC/C substrates recognized through canonical degron motifs\", \"Each finding from a single lab and not yet independently replicated\", \"Relative contribution of APC5 versus other APC/C subunits to these substrate interactions unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved whether APC5's non-canonical functions (CBP/p300 stimulation, PABP binding, IL-17 signaling) occur within the context of the intact APC/C holoenzyme or reflect moonlighting activities of free APC5, and the structural basis for APC5's direct engagement of specific substrates has not been determined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No reconstitution separating holo-APC/C-dependent from APC5-autonomous activities\", \"No structural model of APC5 bound to any non-canonical partner\", \"Relative physiological importance of canonical versus non-canonical APC5 functions untested in genetic models\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 8, 17, 18]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 2, 3, 4]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 2, 8]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 1, 2, 4, 12, 19, 20, 22]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 8, 17, 18]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7, 18]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [9, 10]}\n    ],\n    \"complexes\": [\n      \"APC/C\",\n      \"APC/C platform subcomplex (APC1/APC4/APC5)\"\n    ],\n    \"partners\": [\n      \"ANAPC1\",\n      \"ANAPC4\",\n      \"ANAPC7\",\n      \"EP300\",\n      \"CREBBP\",\n      \"E2F1\",\n      \"PABPC1\",\n      \"TNFAIP3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}