APAF1 is a cytosolic NB-ARC/WD40 scaffold that couples mitochondrial cytochrome c release to initiator caspase activation. Cytochrome c and dATP/ATP binding relieve the autoinhibited ADP-bound APAF1 monomer and promote APAF1 oligomerization into the apoptosome, where APAF1 CARD domains recruit procaspase-9 CARDs and concentrate CASP9 for activation of the intrinsic apoptotic caspase cascade.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000166 nucleotide binding | TAS PMID:10383829 A soluble version of the receptor-like protein tyrosine phos... | MODIFY | Summary: The broad nucleotide-binding assertion is biologically sound for APAF1, but ATP binding is a better replacement for this row because the existing GOA already carries the ADP-binding child term and the original PMID is attached to an unrelated PTPRK paper. Reason: APAF1 is a nucleotide-controlled NB-ARC adaptor; the inactive protein is ADP-bound and cytochrome c plus dATP/ATP drive the nucleotide-dependent conformational cycle that builds the apoptosome. GO:0005524 captures the ATP side of the switch not otherwise present in GOA, whereas PMID:10383829 should not be used as APAF1 support. Proposed replacements: ATP binding Supporting Evidence: PMID:10393175 Apaf-1 requires dATP/ATP hydrolysis to interact with cytochrome c, self-associate and bind to procaspase-9 |
| GO:0001666 response to hypoxia | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The hypoxia row over-projects APAF1 apoptosome activity into a stimulus- or tissue-level outcome. Reason: Loss of APAF1 can alter developmental or stress-response cell death outcomes, but APAF1 does the direct work of cytochrome-c-dependent apoptosome assembly in intrinsic apoptotic signaling. The more specific stimulus and anatomy terms should not be the core flat APAF1 process annotations. |
| GO:0001822 kidney development | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The kidney development row over-projects APAF1 apoptosome activity into a stimulus- or tissue-level outcome. Reason: Loss of APAF1 can alter developmental or stress-response cell death outcomes, but APAF1 does the direct work of cytochrome-c-dependent apoptosome assembly in intrinsic apoptotic signaling. The more specific stimulus and anatomy terms should not be the core flat APAF1 process annotations. |
| GO:0005515 protein binding | IPI PMID:10206961 An APAF-1.cytochrome c multimeric complex is a functional ap... | MODIFY | Summary: The CASP9 interaction is a core CARD-CARD contact in the apoptosome and should be represented specifically as CARD domain binding. Reason: APAF1 recruits procaspase-9 through homotypic contacts between the APAF1 CARD and CASP9 CARD. GO:0050700 captures the molecular recognition event directly, whereas GO:0005515 discards the relevant domain-level specificity. Proposed replacements: CARD domain binding Supporting Evidence: PMID:10206961 Such a complex can be isolated using gel filtration chromatography and is by itself sufficient to recruit and activate procaspase-9 |
| GO:0005515 protein binding | IPI PMID:10206961 An APAF-1.cytochrome c multimeric complex is a functional ap... | REMOVE | Summary: Cytochrome c binding is central to APAF1 activation, but there is no precise GO binding term and generic protein binding adds no value. Reason: The APAF1-cytochrome-c interaction is biologically real and is captured by APAF1 intrinsic-signaling and apoptosome annotations. GO:0005515 should be removed on the APAF1 side rather than replaced with a caspase-activator term that does not describe the binding event itself. Supporting Evidence: PMID:10206961 Such a complex can be isolated using gel filtration chromatography and is by itself sufficient to recruit and activate procaspase-9 |
| GO:0005515 protein binding | IPI PMID:10376594 Structural basis of procaspase-9 recruitment by the apoptoti... | MODIFY | Summary: The CASP9 interaction is a core CARD-CARD contact in the apoptosome and should be represented specifically as CARD domain binding. Reason: APAF1 recruits procaspase-9 through homotypic contacts between the APAF1 CARD and CASP9 CARD. GO:0050700 captures the molecular recognition event directly, whereas GO:0005515 discards the relevant domain-level specificity. Proposed replacements: CARD domain binding Supporting Evidence: PMID:10376594 each molecule of Apaf-1 interacts with a molecule of procaspase-9 through two highly charged and complementary surfaces |
| GO:0005515 protein binding | IPI PMID:10949025 Aven, a novel inhibitor of caspase activation, binds Bcl-xL ... | REMOVE | Summary: AVEN binds APAF1 to inhibit apoptosome assembly; this is regulator action on APAF1, not a distinct APAF1 molecular function. Reason: The reported physical interaction can be biologically real, but GO:0005515 is an uninformative assertion on the APAF1 side and the cited work does not establish a more specific core molecular function for APAF1. Supporting Evidence: PMID:10949025 Aven interferes with the ability of Apaf-1 to self-associate |
| GO:0005515 protein binding | IPI PMID:11112785 A mutational epitope for cytochrome C binding to the apoptos... | REMOVE | Summary: The cytochrome-c mutational-epitope paper maps a core APAF1 activator contact, but generic protein binding is not a useful APAF1 molecular-function assertion. Reason: The binding evidence is sound, but no precise cytochrome-c binding GO term is available in this review. APAF1's response to cytochrome c is represented by intrinsic apoptotic signaling and apoptosome assembly instead of a flat GO:0005515 row. Supporting Evidence: PMID:11112785 Cytochrome c (Cc) binding to apoptosis protease activation factor-1 (Apaf-1) is a critical activation step |
| GO:0005515 protein binding | IPI PMID:11821383 CARD-8 protein, a new CARD family member that regulates casp... | UNDECIDED | Summary: The CARD8 paper is abstract-only locally and the abstract foregrounds CARD8-caspase-1 rather than a directly verifiable APAF1 interaction. Reason: A full-text assay could underlie this IPI row, but the cached abstract only states that CARD8 binds caspase-1 and regulates apoptosis. Leave curator review open rather than removing an experimental annotation from incomplete evidence. Supporting Evidence: PMID:11821383 We demonstrate that CARD-8 interacts physically with caspase-1 and negatively regulates caspase-1-dependent IL-1beta generation in the THP-1 monocytic cell line |
| GO:0005515 protein binding | IPI PMID:15735003 p53CSV, a novel p53-inducible gene involved in the p53-depen... | UNDECIDED | Summary: The p53CSV/TRIAP1 row should remain open because the abstract does not show a direct APAF1 interaction assay. Reason: The cached paper is abstract-only and states that p53CSV modulates apoptosis through interaction with Hsp70 that probably inhibits APAF1. Full text is needed to tell whether the original APAF1 IPI row reflects a direct TRIAP1-APAF1 interaction or an indirect HSP70-mediated regulatory mechanism. Supporting Evidence: PMID:15735003 p53CSV can modulate apoptotic pathways through interaction with Hsp70 that probably inhibits activity of apoptosis protease activating factor-1 |
| GO:0005515 protein binding | IPI PMID:17274640 A limited screen for protein interactions reveals new roles ... | REMOVE | Summary: The PP1 catalytic-subunit interaction came from an interaction screen and does not define a specific APAF1 activity. Reason: The reported physical interaction can be biologically real, but GO:0005515 is an uninformative assertion on the APAF1 side and the cited work does not establish a more specific core molecular function for APAF1. Supporting Evidence: PMID:17274640 We confirmed by co-immunoprecipitation that 9 of these proteins associate with PP1: APAF-1 |
| GO:0005515 protein binding | IPI PMID:19494828 The Apaf-1*procaspase-9 apoptosome complex functions as a pr... | MODIFY | Summary: The CASP9 interaction is a core CARD-CARD contact in the apoptosome and should be represented specifically as CARD domain binding. Reason: APAF1 recruits procaspase-9 through homotypic contacts between the APAF1 CARD and CASP9 CARD. GO:0050700 captures the molecular recognition event directly, whereas GO:0005515 discards the relevant domain-level specificity. Proposed replacements: CARD domain binding Supporting Evidence: PMID:19494828 procaspase-9 possessed higher affinity for the apoptosome and could displace the processed caspase-9 from the complex |
| GO:0005515 protein binding | IPI PMID:20462491 Structure of an apoptosome-procaspase-9 CARD complex. | MODIFY | Summary: The CASP9 interaction is a core CARD-CARD contact in the apoptosome and should be represented specifically as CARD domain binding. Reason: APAF1 recruits procaspase-9 through homotypic contacts between the APAF1 CARD and CASP9 CARD. GO:0050700 captures the molecular recognition event directly, whereas GO:0005515 discards the relevant domain-level specificity. Proposed replacements: CARD domain binding Supporting Evidence: PMID:20462491 During activation, each Apaf-1 CARD interacts with a pc-9 CARD |
| GO:0005515 protein binding | IPI PMID:21371431 Integrity of ATP binding site is essential for effective inh... | REMOVE | Summary: NAIP binds APAF1 to inhibit intrinsic apoptosis; this is regulator action on APAF1, not an APAF1 activity. Reason: The reported physical interaction can be biologically real, but GO:0005515 is an uninformative assertion on the APAF1 side and the cited work does not establish a more specific core molecular function for APAF1. Supporting Evidence: PMID:21371431 Pull down experiment showed direct interaction of the NOD domain of NAIP with the CARD-NOD domain of Apoptotic Protease Activating Factor 1 |
| GO:0005515 protein binding | IPI PMID:21827945 The holo-apoptosome: activation of procaspase-9 and interact... | MODIFY | Summary: The CASP9 interaction is a core CARD-CARD contact in the apoptosome and should be represented specifically as CARD domain binding. Reason: APAF1 recruits procaspase-9 through homotypic contacts between the APAF1 CARD and CASP9 CARD. GO:0050700 captures the molecular recognition event directly, whereas GO:0005515 discards the relevant domain-level specificity. Proposed replacements: CARD domain binding Supporting Evidence: PMID:21827945 caspase recruitment domains of pc-9 and Apaf-1 form a CARD-CARD disk |
| GO:0005515 protein binding | IPI PMID:22246185 Rsk-mediated phosphorylation and 14-3-3Ι binding of Apaf-1 s... | REMOVE | Summary: YWHAE/14-3-3 binds phosphorylated APAF1 and suppresses apoptosome formation; this regulatory binding event does not need a flat APAF1 protein-binding row. Reason: The reported physical interaction can be biologically real, but GO:0005515 is an uninformative assertion on the APAF1 side and the cited work does not establish a more specific core molecular function for APAF1. Supporting Evidence: PMID:22246185 phosphorylated Ser268 impedes the ability of cytochrome c to nucleate apoptosome formation |
| GO:0005515 protein binding | IPI PMID:9267021 Apaf-1, a human protein homologous to C. elegans CED-4, part... | REMOVE | Summary: The original APAF1 paper established the cytochrome-c interaction, but generic protein binding should not be retained as a flat APAF1 activity. Reason: Cytochrome c binding triggers APAF1-dependent caspase activation and apoptosome formation; those pathway and complex annotations capture the useful function without preserving an uninformative GO:0005515 assertion. Supporting Evidence: PMID:9267021 Cytochrome c binds to Apaf-1, an event that may trigger the activation of caspase-3 |
| GO:0005515 protein binding | IPI PMID:9922454 Ordering the cytochrome c-initiated caspase cascade: hierarc... | MODIFY | Summary: The CASP9 interaction is a core CARD-CARD contact in the apoptosome and should be represented specifically as CARD domain binding. Reason: APAF1 recruits procaspase-9 through homotypic contacts between the APAF1 CARD and CASP9 CARD. GO:0050700 captures the molecular recognition event directly, whereas GO:0005515 discards the relevant domain-level specificity. Proposed replacements: CARD domain binding Supporting Evidence: PMID:9922454 In vitro association assays confirmed that caspase-9 selectively bound to Apaf-1 |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6798748 | TOO GENERAL | Summary: Extracellular region from the Reactome secretory-granule exocytosis reaction of the neutrophil degranulation model, which is not part of the established cytosolic APAF1 apoptosome biology; the term itself is entailed by the extracellular exosome annotation kept in this review. Reason: Extracellular region is entailed by the extracellular exosome annotation kept in this review (exosomes are part of the extracellular region), so the broad term is true of APAF1 only in that vesicle-cargo sense and adds nothing to it. The basis of this particular row, the Reactome neutrophil degranulation model that treats APAF1 as secreted granule cargo, is not supported: APAF1 is a cytosolic apoptosome scaffold and nothing shows it being released from granules. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6800434 | TOO GENERAL | Summary: Extracellular region from the Reactome ficolin-rich granule exocytosis reaction of the neutrophil degranulation model, which is not part of the established cytosolic APAF1 apoptosome biology; the term itself is entailed by the extracellular exosome annotation kept in this review. Reason: Extracellular region is entailed by the extracellular exosome annotation kept in this review (exosomes are part of the extracellular region), so the broad term is true of APAF1 only in that vesicle-cargo sense and adds nothing to it. The basis of this particular row, the Reactome neutrophil degranulation model that treats APAF1 as secreted granule cargo, is not supported: APAF1 is a cytosolic apoptosome scaffold and nothing shows it being released from granules. |
| GO:0005634 nucleus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The nucleus projection is not a core APAF1 location and is weakly supported compared with the cytosolic apoptosome role. Reason: APAF1 executes its core activity in the cytosol as the cytochrome-c-responsive apoptosome scaffold. A flat nuclear location projection from mouse is peripheral at best for human APAF1 curation. |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Cytoplasm is a correct but broad location for APAF1. Reason: The intrinsic apoptosome assembles in the cytosol after cytochrome c release, so cytoplasm is directionally correct but less precise than cytosol/apoptosome. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Cytosol is the physiological compartment where APAF1 responds to released cytochrome c and assembles the apoptosome. Reason: APAF1 was originally purified from cytosol as the factor required for cytochrome-c-dependent caspase-3 activation, and this is the compartment of apoptosome assembly. |
| GO:0005829 cytosol | IEA GO_REF:0000120 | ACCEPT | Summary: The automated cytosol assertion matches the established site of APAF1 apoptosome activity. Reason: APAF1 is an intracellular cytochrome-c-responsive scaffold that forms the apoptosome in the cytosol. |
| GO:0005829 cytosol | TAS PMID:9267021 Apaf-1, a human protein homologous to C. elegans CED-4, part... | ACCEPT | Summary: Cytosol is the physiological compartment where APAF1 responds to released cytochrome c and assembles the apoptosome. Reason: APAF1 was originally purified from cytosol as the factor required for cytochrome-c-dependent caspase-3 activation, and this is the compartment of apoptosome assembly. Supporting Evidence: PMID:9267021 a novel 130 kd protein from HeLa cell cytosol that participates in the cytochrome c-dependent activation of caspase-3 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-114252 | ACCEPT | Summary: The Reactome projection places APAF1 in the cytosol, the correct compartment for apoptosome assembly. Reason: These Reactome events use cytosolic APAF1 as the platform that binds cytochrome c, recruits procaspase-9, or is regulated before or after apoptosome formation; the location is correct even when the pathway event itself is regulatory. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-114254 | ACCEPT | Summary: The Reactome projection places APAF1 in the cytosol, the correct compartment for apoptosome assembly. Reason: These Reactome events use cytosolic APAF1 as the platform that binds cytochrome c, recruits procaspase-9, or is regulated before or after apoptosome formation; the location is correct even when the pathway event itself is regulatory. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-114256 | ACCEPT | Summary: The Reactome projection places APAF1 in the cytosol, the correct compartment for apoptosome assembly. Reason: These Reactome events use cytosolic APAF1 as the platform that binds cytochrome c, recruits procaspase-9, or is regulated before or after apoptosome formation; the location is correct even when the pathway event itself is regulatory. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-114259 | ACCEPT | Summary: The Reactome projection places APAF1 in the cytosol, the correct compartment for apoptosome assembly. Reason: These Reactome events use cytosolic APAF1 as the platform that binds cytochrome c, recruits procaspase-9, or is regulated before or after apoptosome formation; the location is correct even when the pathway event itself is regulatory. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-114261 | ACCEPT | Summary: The Reactome projection places APAF1 in the cytosol, the correct compartment for apoptosome assembly. Reason: These Reactome events use cytosolic APAF1 as the platform that binds cytochrome c, recruits procaspase-9, or is regulated before or after apoptosome formation; the location is correct even when the pathway event itself is regulatory. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-6791348 | ACCEPT | Summary: The Reactome projection places APAF1 in the cytosol, the correct compartment for apoptosome assembly. Reason: These Reactome events use cytosolic APAF1 as the platform that binds cytochrome c, recruits procaspase-9, or is regulated before or after apoptosome formation; the location is correct even when the pathway event itself is regulatory. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-6804596 | ACCEPT | Summary: The Reactome projection places APAF1 in the cytosol, the correct compartment for apoptosome assembly. Reason: These Reactome events use cytosolic APAF1 as the platform that binds cytochrome c, recruits procaspase-9, or is regulated before or after apoptosome formation; the location is correct even when the pathway event itself is regulatory. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-6805507 | ACCEPT | Summary: The Reactome projection places APAF1 in the cytosol, the correct compartment for apoptosome assembly. Reason: These Reactome events use cytosolic APAF1 as the platform that binds cytochrome c, recruits procaspase-9, or is regulated before or after apoptosome formation; the location is correct even when the pathway event itself is regulatory. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9007496 | ACCEPT | Summary: The Reactome projection places APAF1 in the cytosol, the correct compartment for apoptosome assembly. Reason: These Reactome events use cytosolic APAF1 as the platform that binds cytochrome c, recruits procaspase-9, or is regulated before or after apoptosome formation; the location is correct even when the pathway event itself is regulatory. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9627056 | ACCEPT | Summary: The Reactome projection places APAF1 in the cytosol, the correct compartment for apoptosome assembly. Reason: These Reactome events use cytosolic APAF1 as the platform that binds cytochrome c, recruits procaspase-9, or is regulated before or after apoptosome formation; the location is correct even when the pathway event itself is regulatory. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9627078 | ACCEPT | Summary: The Reactome projection places APAF1 in the cytosol, the correct compartment for apoptosome assembly. Reason: These Reactome events use cytosolic APAF1 as the platform that binds cytochrome c, recruits procaspase-9, or is regulated before or after apoptosome formation; the location is correct even when the pathway event itself is regulatory. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9627089 | ACCEPT | Summary: The Reactome projection places APAF1 in the cytosol, the correct compartment for apoptosome assembly. Reason: These Reactome events use cytosolic APAF1 as the platform that binds cytochrome c, recruits procaspase-9, or is regulated before or after apoptosome formation; the location is correct even when the pathway event itself is regulatory. |
| GO:0006915 apoptotic process | IEA GO_REF:0000117 | MODIFY | Summary: This broad apoptosis assertion should be tightened to APAF1's intrinsic apoptotic signaling role. Reason: APAF1 acts after mitochondrial cytochrome c release as the scaffold that nucleates procaspase-9 activation in the intrinsic pathway, not as a generic apoptotic-process or apoptotic-regulation factor. Proposed replacements: intrinsic apoptotic signaling pathway Supporting Evidence: PMID:10393175 Apaf-1 plays a critical role in apoptosis by binding to and activating procaspase-9 |
| GO:0006915 apoptotic process | TAS PMID:9753320 Apaf1 (CED-4 homolog) regulates programmed cell death in mam... | MODIFY | Summary: This broad apoptosis assertion should be tightened to APAF1's intrinsic apoptotic signaling role. Reason: APAF1 acts after mitochondrial cytochrome c release as the scaffold that nucleates procaspase-9 activation in the intrinsic pathway, not as a generic apoptotic-process or apoptotic-regulation factor. Proposed replacements: intrinsic apoptotic signaling pathway Supporting Evidence: PMID:10393175 Apaf-1 plays a critical role in apoptosis by binding to and activating procaspase-9 |
| GO:0007399 nervous system development | TAS PMID:9753320 Apaf1 (CED-4 homolog) regulates programmed cell death in mam... | MARK AS OVER ANNOTATED | Summary: The nervous system development row over-projects APAF1 apoptosome activity into a stimulus- or tissue-level outcome. Reason: Loss of APAF1 can alter developmental or stress-response cell death outcomes, but APAF1 does the direct work of cytochrome-c-dependent apoptosome assembly in intrinsic apoptotic signaling. The more specific stimulus and anatomy terms should not be the core flat APAF1 process annotations. |
| GO:0007584 response to nutrient | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The nutrient response row over-projects APAF1 apoptosome activity into a stimulus- or tissue-level outcome. Reason: Loss of APAF1 can alter developmental or stress-response cell death outcomes, but APAF1 does the direct work of cytochrome-c-dependent apoptosome assembly in intrinsic apoptotic signaling. The more specific stimulus and anatomy terms should not be the core flat APAF1 process annotations. |
| GO:0008656 cysteine-type endopeptidase activator activity involved in apoptotic process | IEA GO_REF:0000107 | MODIFY | Summary: APAF1 directly enables apoptotic cysteine-endopeptidase activation by assembling the procaspase-9-activating apoptosome. Reason: Although this row is orthology-projected, the same activity is extensively supported in human APAF1 biochemistry: cytochrome c and dATP/ATP convert APAF1 into an oligomer that binds and activates procaspase-9. Proposed replacements: cysteine-type endopeptidase activator activity Context of precomposed term: module intrinsic_apoptotic_signaling / apaf1_apaf1_apoptosome_scaffold in core functions Decomposed from the precomposed GO:0008656 (projects/INVOLVED_IN_PRECOMPOSITION.md) to its genus GO:0140608; the claim is unchanged and the apoptotic context is carried by the module intrinsic_apoptotic_signaling#apaf1_apaf1_apoptosome_scaffold and this review's core functions. Supporting Evidence: PMID:10393175 The product of this Apaf-1 cDNA activated procaspase-9 in a cytochrome c and dATP/ATP-dependent manner |
| GO:0010659 cardiac muscle cell apoptotic process | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The cardiac muscle cell apoptosis row over-projects APAF1 apoptosome activity into a stimulus- or tissue-level outcome. Reason: Loss of APAF1 can alter developmental or stress-response cell death outcomes, but APAF1 does the direct work of cytochrome-c-dependent apoptosome assembly in intrinsic apoptotic signaling. The more specific stimulus and anatomy terms should not be the core flat APAF1 process annotations. |
| GO:0030154 cell differentiation | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The cell differentiation row over-projects APAF1 apoptosome activity into a stimulus- or tissue-level outcome. Reason: Loss of APAF1 can alter developmental or stress-response cell death outcomes, but APAF1 does the direct work of cytochrome-c-dependent apoptosome assembly in intrinsic apoptotic signaling. The more specific stimulus and anatomy terms should not be the core flat APAF1 process annotations. |
| GO:0031072 heat shock protein binding | IEA GO_REF:0000107 | UNDECIDED | Summary: The orthology-projected heat-shock-protein-binding row is not established as a core human APAF1 activity in the cached APAF1 literature. Reason: APAF1 is regulated by chaperone-associated anti-apoptotic factors in some contexts, but this Ensembl projection has no direct PMID in the row and the human cached papers do not verify a specific APAF1 heat shock protein binding activity. |
| GO:0032991 protein-containing complex | IDA PMID:11821383 CARD-8 protein, a new CARD family member that regulates casp... | UNDECIDED | Summary: The local CARD8 abstract does not expose enough APAF1-specific evidence to verify this broad protein-containing-complex row. Reason: The cached abstract focuses on CARD8 binding to caspase-1 and regulating IL-1 beta generation. Because the full text may include the curator-visible APAF1/CASP9 complex experiment, leave this row undecided. Supporting Evidence: PMID:11821383 We demonstrate that CARD-8 interacts physically with caspase-1 and negatively regulates caspase-1-dependent IL-1beta generation in the THP-1 monocytic cell line |
| GO:0034774 secretory granule lumen | TAS Reactome:R-HSA-6798748 | REMOVE | Summary: The Reactome secretory granule lumen projection is not part of the established cytosolic APAF1 apoptosome biology. Reason: APAF1 is a cytosolic apoptosome scaffold and the cited neutrophil degranulation Reactome events do not provide curated evidence for APAF1 as a lumenal secretory-granule component. |
| GO:0042802 identical protein binding | IEA GO_REF:0000120 | ACCEPT | Summary: Identical protein binding is an appropriate molecular-function abstraction for APAF1 self-oligomerization during apoptosome assembly. Reason: Cytochrome c and nucleotide hydrolysis drive APAF1 self-association into an oligomeric apoptosome scaffold, so the orthology-projected identical-protein-binding row matches a direct step in APAF1 activation. Supporting Evidence: PMID:10364241 full-length Apaf-1 exists as a monomer that can be transformed to an oligomeric complex made of at least eight subunits after binding to cytochrome c and dATP |
| GO:0042981 regulation of apoptotic process | IEA GO_REF:0000002 | MODIFY | Summary: This broad apoptosis assertion should be tightened to APAF1's intrinsic apoptotic signaling role. Reason: APAF1 acts after mitochondrial cytochrome c release as the scaffold that nucleates procaspase-9 activation in the intrinsic pathway, not as a generic apoptotic-process or apoptotic-regulation factor. Proposed replacements: intrinsic apoptotic signaling pathway Supporting Evidence: PMID:10393175 Apaf-1 plays a critical role in apoptosis by binding to and activating procaspase-9 |
| GO:0042981 regulation of apoptotic process | TAS PMID:10441496 Three new types of Apaf-1 in mammalian cells. | MODIFY | Summary: This broad apoptosis assertion should be tightened to APAF1's intrinsic apoptotic signaling role. Reason: APAF1 acts after mitochondrial cytochrome c release as the scaffold that nucleates procaspase-9 activation in the intrinsic pathway, not as a generic apoptotic-process or apoptotic-regulation factor. Proposed replacements: intrinsic apoptotic signaling pathway Supporting Evidence: PMID:10393175 Apaf-1 plays a critical role in apoptosis by binding to and activating procaspase-9 |
| GO:0043065 positive regulation of apoptotic process | IDA PMID:21827945 The holo-apoptosome: activation of procaspase-9 and interact... | MODIFY | Summary: This broad apoptosis assertion should be tightened to APAF1's intrinsic apoptotic signaling role. Reason: APAF1 acts after mitochondrial cytochrome c release as the scaffold that nucleates procaspase-9 activation in the intrinsic pathway, not as a generic apoptotic-process or apoptotic-regulation factor. Proposed replacements: intrinsic apoptotic signaling pathway Supporting Evidence: PMID:10393175 Apaf-1 plays a critical role in apoptosis by binding to and activating procaspase-9 |
| GO:0043065 positive regulation of apoptotic process | IDA PMID:9267021 Apaf-1, a human protein homologous to C. elegans CED-4, part... | MODIFY | Summary: This broad apoptosis assertion should be tightened to APAF1's intrinsic apoptotic signaling role. Reason: APAF1 acts after mitochondrial cytochrome c release as the scaffold that nucleates procaspase-9 activation in the intrinsic pathway, not as a generic apoptotic-process or apoptotic-regulation factor. Proposed replacements: intrinsic apoptotic signaling pathway Supporting Evidence: PMID:10393175 Apaf-1 plays a critical role in apoptosis by binding to and activating procaspase-9 |
| GO:0043065 positive regulation of apoptotic process | TAS PMID:18309324 No death without life: vital functions of apoptotic effector... | UNDECIDED | Summary: The term is plausible for APAF1, but the locally cached review abstract is too broad to verify this exact UniProt TAS assertion. Reason: PMID:18309324 is cached only as a short review abstract about non-apoptotic functions of apoptotic proteins and C. elegans ced-4. Without the full review text, this row should not be tightened or accepted against an unverifiable statement. Supporting Evidence: PMID:18309324 mammalian orthologs of these C. elegans proteins (i.e. caspases, Apaf-1 and multidomain proteins of the Bcl-2 family) participate in cell death-unrelated processes |
| GO:0043293 apoptosome | IDA PMID:21827945 The holo-apoptosome: activation of procaspase-9 and interact... | ACCEPT | Summary: APAF1 is a bona fide apoptosome component. Reason: Cytochrome c and nucleotide binding convert APAF1 into the oligomeric apoptosome, whose APAF1 hub recruits and activates procaspase-9. Supporting Evidence: PMID:20462491 Apaf-1 coassembles with cytochrome c to form the apoptosome, which then binds and activates procaspase-9 |
| GO:0043293 apoptosome | IEA GO_REF:0000120 | ACCEPT | Summary: APAF1 is a bona fide apoptosome component. Reason: Cytochrome c and nucleotide binding convert APAF1 into the oligomeric apoptosome, whose APAF1 hub recruits and activates procaspase-9. Supporting Evidence: PMID:20462491 Apaf-1 coassembles with cytochrome c to form the apoptosome, which then binds and activates procaspase-9 |
| GO:0043293 apoptosome | IPI PMID:10206961 An APAF-1.cytochrome c multimeric complex is a functional ap... | ACCEPT | Summary: APAF1 is a bona fide apoptosome component. Reason: Cytochrome c and nucleotide binding convert APAF1 into the oligomeric apoptosome, whose APAF1 hub recruits and activates procaspase-9. Supporting Evidence: PMID:20462491 Apaf-1 coassembles with cytochrome c to form the apoptosome, which then binds and activates procaspase-9 |
| GO:0043293 apoptosome | TAS PMID:18309324 No death without life: vital functions of apoptotic effector... | UNDECIDED | Summary: The term is plausible for APAF1, but the locally cached review abstract is too broad to verify this exact UniProt TAS assertion. Reason: PMID:18309324 is cached only as a short review abstract about non-apoptotic functions of apoptotic proteins and C. elegans ced-4. Without the full review text, this row should not be tightened or accepted against an unverifiable statement. Supporting Evidence: PMID:18309324 mammalian orthologs of these C. elegans proteins (i.e. caspases, Apaf-1 and multidomain proteins of the Bcl-2 family) participate in cell death-unrelated processes |
| GO:0043531 ADP binding | IEA GO_REF:0000002 | ACCEPT | Summary: ADP binding is part of the autoinhibited APAF1 nucleotide switch that is released during cytochrome-c-driven apoptosome assembly. Reason: APAF1 is an NB-ARC/NOD ATPase-family scaffold; Reactome models the inactive monomer as ADP-bound, and primary biochemical work showed that dATP/ATP hydrolysis is required for cytochrome c interaction, self-association, and procaspase-9 binding. Supporting Evidence: file:human/APAF1/APAF1-uniprot.txt The monomeric form is autoinhibited in a closed conformation through a bound ADP at the nucleotide binding site PMID:10393175 Apaf-1 requires dATP/ATP hydrolysis to interact with cytochrome c, self-associate and bind to procaspase-9 |
| GO:0048731 system development | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: The system development row over-projects APAF1 apoptosome activity into a stimulus- or tissue-level outcome. Reason: Loss of APAF1 can alter developmental or stress-response cell death outcomes, but APAF1 does the direct work of cytochrome-c-dependent apoptosome assembly in intrinsic apoptotic signaling. The more specific stimulus and anatomy terms should not be the core flat APAF1 process annotations. |
| GO:0070059 intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The ER-stress-triggered intrinsic apoptosis row over-projects APAF1 apoptosome activity into a stimulus- or tissue-level outcome. Reason: Loss of APAF1 can alter developmental or stress-response cell death outcomes, but APAF1 does the direct work of cytochrome-c-dependent apoptosome assembly in intrinsic apoptotic signaling. The more specific stimulus and anatomy terms should not be the core flat APAF1 process annotations. |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: Detected in an extracellular-vesicle proteome. The protein is plausible EV content, but this is not where it functions. Reason: Cytoplasmic apoptosome scaffold. Cytosolic protein (UniProt); cytosolic proteins, including abundant enzymes and cytoskeletal proteins, are expected and often promiscuous EV contents (MISEV2018 (PMID:30637094) category 2b). True, but not its core location. (Manual re-review for OMICS_EVIDENCE, 2026-10-10; previous action: MARK_AS_OVER_ANNOTATED.) |
| GO:0071560 cellular response to transforming growth factor beta stimulus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The TGF-beta response row over-projects APAF1 apoptosome activity into a stimulus- or tissue-level outcome. Reason: Loss of APAF1 can alter developmental or stress-response cell death outcomes, but APAF1 does the direct work of cytochrome-c-dependent apoptosome assembly in intrinsic apoptotic signaling. The more specific stimulus and anatomy terms should not be the core flat APAF1 process annotations. |
| GO:0072432 response to G1 DNA damage checkpoint signaling | TAS PMID:18309324 No death without life: vital functions of apoptotic effector... | UNDECIDED | Summary: The abstract mentions a C. elegans ced-4 DNA-damage checkpoint phenotype but does not establish a human APAF1 G1-checkpoint response. Reason: A review full text may contain additional APAF1 material visible to the UniProt curator, but the local abstract only states that ced-4 affects DNA-damaged germline cells. Leave the human APAF1 response-to-G1-DNA-damage-checkpoint row for curator follow-up. Supporting Evidence: PMID:18309324 loss-of-function mutations of ced-4 compromise the mitotic arrest of DNA-damaged germline cells from adult nematodes |
| GO:0097190 apoptotic signaling pathway | IEA GO_REF:0000002 | MODIFY | Summary: This broad apoptosis assertion should be tightened to APAF1's intrinsic apoptotic signaling role. Reason: APAF1 acts after mitochondrial cytochrome c release as the scaffold that nucleates procaspase-9 activation in the intrinsic pathway, not as a generic apoptotic-process or apoptotic-regulation factor. Proposed replacements: intrinsic apoptotic signaling pathway Supporting Evidence: PMID:10393175 Apaf-1 plays a critical role in apoptosis by binding to and activating procaspase-9 |
| GO:0097193 intrinsic apoptotic signaling pathway | NAS PMID:10206961 An APAF-1.cytochrome c multimeric complex is a functional ap... | ACCEPT | Summary: The Zou et al. apoptosome reconstitution paper directly supports APAF1 in intrinsic apoptotic signaling. Reason: APAF1 binds cytochrome c, oligomerizes, and recruits procaspase-9 to build the caspase-activating apoptosome downstream of mitochondrial outer-membrane permeabilization. Supporting Evidence: PMID:10206961 We report here the reconstitution of the de novo procaspase-9 activation pathway using highly purified cytochrome c, recombinant APAF-1, and recombinant procaspase-9 |
| GO:0097193 intrinsic apoptotic signaling pathway | TAS PMID:18309324 No death without life: vital functions of apoptotic effector... | UNDECIDED | Summary: The term is plausible for APAF1, but the locally cached review abstract is too broad to verify this exact UniProt TAS assertion. Reason: PMID:18309324 is cached only as a short review abstract about non-apoptotic functions of apoptotic proteins and C. elegans ced-4. Without the full review text, this row should not be tightened or accepted against an unverifiable statement. Supporting Evidence: PMID:18309324 mammalian orthologs of these C. elegans proteins (i.e. caspases, Apaf-1 and multidomain proteins of the Bcl-2 family) participate in cell death-unrelated processes |
| GO:0140608 cysteine-type endopeptidase activator activity | NAS PMID:15009102 Analysis of APAF-1 expression in human cutaneous melanoma pr... | ACCEPT | Summary: APAF1 directly activates cysteine-type endopeptidases (caspases). The genus term is correct as it stands; the apoptotic context is carried by the module and core functions, not by a precomposed term. Reason: The genus GO:0140608 is the right term. An earlier pass proposed MODIFY to the precomposed GO:0008656; per projects/INVOLVED_IN_PRECOMPOSITION.md that adds only the apoptotic context, which is carried by the module intrinsic_apoptotic_signaling#apaf1_apaf1_apoptosome_scaffold and the core functions. Superseded reasoning (it argued for the precomposed term), retained only for its evidence: The melanoma expression paper only cites APAF1 as a pivotal factor that favors caspase-9 activation, but the assertion itself is a core molecular activity of APAF1 and should be represented by GO:0008656. Supporting Evidence: PMID:15009102 APAF-1 plays a pivotal role in mitochondria-dependent apoptosis, binding to cytochrome c and favoring activation of caspase-9 |
| GO:0140608 cysteine-type endopeptidase activator activity | TAS PMID:9267021 Apaf-1, a human protein homologous to C. elegans CED-4, part... | ACCEPT | Summary: APAF1 directly activates cysteine-type endopeptidases (caspases). The genus term is correct as it stands; the apoptotic context is carried by the module and core functions, not by a precomposed term. This row rests on the original APAF1 purification paper (caspase activation downstream of cytochrome c). Reason: The genus GO:0140608 is the right term. An earlier pass proposed MODIFY to the precomposed GO:0008656; per projects/INVOLVED_IN_PRECOMPOSITION.md that adds only the apoptotic context, which is carried by the module intrinsic_apoptotic_signaling#apaf1_apaf1_apoptosome_scaffold and the core functions. Superseded reasoning (it argued for the precomposed term), retained only for its evidence: GO:0140608 is a true but avoidably broad parent for APAF1. The curated function is activation of a cysteine-type endopeptidase in the apoptotic pathway. Supporting Evidence: PMID:9267021 Cytochrome c binds to Apaf-1, an event that may trigger the activation of caspase-3 |
| GO:0160108 animal gross anatomical part developmental process | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: The gross-anatomy development row over-projects APAF1 apoptosome activity into a stimulus- or tissue-level outcome. Reason: Loss of APAF1 can alter developmental or stress-response cell death outcomes, but APAF1 does the direct work of cytochrome-c-dependent apoptosome assembly in intrinsic apoptotic signaling. The more specific stimulus and anatomy terms should not be the core flat APAF1 process annotations. |
| GO:1904813 ficolin-1-rich granule lumen | TAS Reactome:R-HSA-6800434 | REMOVE | Summary: The Reactome ficolin-1-rich granule lumen projection is not part of the established cytosolic APAF1 apoptosome biology. Reason: APAF1 is a cytosolic apoptosome scaffold and the cited neutrophil degranulation Reactome events do not provide curated evidence for APAF1 as a lumenal secretory-granule component. |
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Q: Should regulatory interactions in which AVEN, NAIP, TRIAP1/HSP70, or phosphorylated 14-3-3-bound APAF1 inhibit apoptosome formation be modeled only on the inhibitor side, or should any yield specific non-core APAF1 binding terms?
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