CYCS encodes human cytochrome c, a small (105 aa, ~12 kDa) soluble heme-containing electron carrier protein of the mitochondrial intermembrane space. Cytochrome c has two well-established, evolutionarily conserved functions: (1) In the mitochondrial electron transport chain, it shuttles single electrons from Complex III (cytochrome bc1, via its cytochrome c1 subunit) to Complex IV (cytochrome c oxidase), accepting electrons via its covalently bound heme c group. (2) In apoptosis, upon mitochondrial outer membrane permeabilization (MOMP) triggered by pro-apoptotic Bcl-2 family members (BAX/BAK), cytochrome c is released into the cytosol where it binds Apaf-1 to form the apoptosome, activating caspase-9 and triggering the downstream caspase cascade. The heme c prosthetic group is covalently attached via thioether bonds to Cys14 and Cys17 (mature numbering Cys15 and Cys18 in UniProt), with His18 and Met80 as axial ligands to the iron atom. Gain-of-function mutations in CYCS (e.g., G42S) cause thrombocytopenia type 4 (THC4) by enhancing apoptotic activation in the megakaryocyte/platelet lineage. Cytochrome c is one of the most extensively studied proteins in biochemistry and a classic example of a dual-function (moonlighting) protein.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0009055 electron transfer activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for electron transfer activity. Cytochrome c is the canonical soluble single-electron carrier of the mitochondrial electron transport chain, accepting electrons from Complex III and donating them to Complex IV through reversible oxidation and reduction of its covalently bound heme c. Reason: Electron transfer is the primary respiratory molecular function of cytochrome c and is conserved across opisthokont and broader eukaryotic cytochrome-c orthologs. The PAINT assertion is therefore appropriate for human CYCS. Supporting Evidence: Reactome:R-HSA-164651 Complex III consumes two molecules of ubiquinol (QH2) and two molecules of oxidized cytochrome c Reactome:R-HSA-163214 Electron transfer from reduced cytochrome c to molecular oxygen |
| GO:0006122 mitochondrial electron transport, ubiquinol to cytochrome c | IBA GO_REF:0000033 | ACCEPT | Summary: Cytochrome c is the mobile electron acceptor in the Complex III Q-cycle reaction, receiving electrons after ubiquinol oxidation. Reason: Although CYCS is not an integral Complex III subunit, the process explicitly ends with reduction of cytochrome c. This is one half of the core respiratory role of the mature IMS protein. Supporting Evidence: Reactome:R-HSA-164651 Complex III transfers electrons from ubiquinol to cytochrome c |
| GO:0005758 mitochondrial intermembrane space | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for mitochondrial intermembrane space localization. Cytochrome c resides in the IMS, loosely associated with the inner membrane via electrostatic and hydrophobic interactions including cardiolipin binding. This is the site of its electron transfer function and is conserved across eukaryotes. UniProt confirms this localization: "Mitochondrion intermembrane space. Loosely associated with the inner membrane." The IBA is phylogenetically appropriate. Reason: Mitochondrial intermembrane space is the primary localization of cytochrome c during its electron transfer function. This is a core CC annotation, well established experimentally and phylogenetically sound. Supporting Evidence: PMID:9515723 It is released from its places on the outer surface of the inner mitochondrial membrane |
| GO:0006123 mitochondrial electron transport, cytochrome c to oxygen | IBA GO_REF:0000033 | ACCEPT | Summary: Cytochrome c is the electron donor to cytochrome c oxidase during the Complex IV reaction that reduces molecular oxygen to water. Reason: The IBA is biologically correct: reduced cytochrome c hands electrons to Complex IV as the second half of its respiratory electron-shuttle function. Supporting Evidence: Reactome:R-HSA-163214 Electron transfer from reduced cytochrome c to molecular oxygen |
| GO:0005758 mitochondrial intermembrane space | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation for mitochondrial intermembrane space based on UniProt subcellular location mapping. Consistent with the IBA annotation for the same term and with direct experimental evidence (IDA from PMID:19393246). Redundant but correct. Reason: Correct and consistent with IBA and IDA annotations for the same term. IEA mapping from UniProt subcellular location is accurate for this well-characterized localization. |
| GO:0006915 apoptotic process | IEA GO_REF:0000043 | MODIFY | Summary: UniProt keyword mapping correctly recognizes CYCS as an apoptosis factor, but the direct step is mitochondrial cytochrome-c release followed by APAF1 binding and apoptosome formation. Reason: The broad apoptotic-process row should be tightened to intrinsic apoptotic signaling pathway: cytosolic cytochrome c binds APAF1 and triggers the mitochondrial apoptosome branch rather than executing all apoptosis. Proposed replacements: intrinsic apoptotic signaling pathway Supporting Evidence: PMID:8689682 Cells undergoing apoptosis in vivo showed increased release of cytochrome c to their cytosol PMID:9267021 Cytochrome c binds to Apaf-1, an event that may trigger the activation of caspase-3, leading to apoptosis |
| GO:0009055 electron transfer activity | IEA GO_REF:0000002 | ACCEPT | Summary: IEA annotation for electron transfer activity from InterPro domain mapping (IPR002327, IPR009056, IPR036909). The cytochrome c domain is a well-characterized electron transfer domain. Consistent with the IBA annotation for the same term. Reason: Correct and consistent with the IBA annotation. The cytochrome c domain family is defined by its electron transfer function. |
| GO:0020037 heme binding | IEA GO_REF:0000002 | ACCEPT | Summary: IEA annotation for heme binding from InterPro domain mapping. Cytochrome c contains a covalently bound heme c group attached via thioether bonds to Cys15 and Cys18 (PMID:23150584 per UniProt). This is a core structural feature essential for both electron transfer and the protein's redox properties. Consistent with the TAS annotation from PMID:9515723. Reason: Heme binding is a core molecular function of cytochrome c. The heme c group is covalently attached and is essential for electron transfer activity. |
| GO:0022904 respiratory electron transport chain | IEA GO_REF:0000043 | ACCEPT | Summary: IEA annotation for respiratory electron transport chain from UniProt keyword mapping (KW-0679, Respiratory chain). This is broader than the specific IBA annotations for GO:0006122 and GO:0006123 but is correct. Cytochrome c is a key component of the respiratory electron transport chain. Reason: Correct but general. The specific IBA annotations for Complex III-to-cyt c and cyt c-to-O2 processes are more informative, but this broader term is acceptable for IEA. |
| GO:0046872 metal ion binding | IEA GO_REF:0000043 | MODIFY | Summary: The only relevant metal ion is the iron held inside the covalent heme c prosthetic group. Reason: GO:0046872 is technically true but loses the defining chemistry. CYCS should be represented by heme binding, which captures both the iron and its tetrapyrrole context. Proposed replacements: heme binding |
| GO:0005515 protein binding | IPI PMID:10206961 An APAF-1.cytochrome c multimeric complex is a functional ap... | REMOVE | Summary: The APAF1 interaction is central to CYCS-dependent apoptosome assembly, but generic protein binding is not a useful molecular-function assertion for this well-defined apoptotic step. Reason: Cytochrome c binding to APAF1 is biologically real and is captured by the intrinsic apoptotic signaling and apoptosome annotations. There is no precise GO molecular-function term for the cytochrome-c/APAF1 contact in this review, so the uninformative GO:0005515 row should be removed rather than replaced by an ill-fitting caspase-activator term. Supporting Evidence: PMID:10206961 the binding of cytochrome c promote APAF-1 oligomerization |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Protein binding imported from a proteome-scale interactome dataset with no curated CYCS-specific mechanism. Reason: This may record a screening edge, but bare GO:0005515 carries no information about the respiratory electron-transfer or apoptosome functions of CYCS, and the row does not support a more precise replacement annotation. |
| GO:0005515 protein binding | IPI PMID:25595453 Respiratory complexes III and IV can each bind two molecules... | REMOVE | Summary: This focused heterologous study probed interaction of human cytochrome c with plant respiratory complexes III and IV, but the imported GO term is only generic protein binding. Reason: The underlying respiratory-chain contact is already represented by the electron-transfer molecular function and the Complex III-to-cytochrome-c and cytochrome-c-to-oxygen process rows. A flat GO:0005515 assertion to plant cytochrome c1 adds no specific human CYCS function. Supporting Evidence: PMID:25595453 Respiratory complexes III and IV can each bind two molecules of cytochrome c at low ionic strength |
| GO:0005515 protein binding | IPI PMID:25910212 Widespread macromolecular interaction perturbations in human... | REMOVE | Summary: Protein binding imported from a proteome-scale interactome dataset with no curated CYCS-specific mechanism. Reason: This may record a screening edge, but bare GO:0005515 carries no information about the respiratory electron-transfer or apoptosome functions of CYCS, and the row does not support a more precise replacement annotation. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: Protein binding imported from a proteome-scale interactome dataset with no curated CYCS-specific mechanism. Reason: This may record a screening edge, but bare GO:0005515 carries no information about the respiratory electron-transfer or apoptosome functions of CYCS, and the row does not support a more precise replacement annotation. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Protein binding imported from a proteome-scale interactome dataset with no curated CYCS-specific mechanism. Reason: This may record a screening edge, but bare GO:0005515 carries no information about the respiratory electron-transfer or apoptosome functions of CYCS, and the row does not support a more precise replacement annotation. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: This IPI row comes from Haenig et al. 2020, a yeast two-hybrid interactome map centered on neurodegenerative-disease proteins. The cached abstract establishes a large-scale network resource, but it does not provide a CYCS-specific respiratory or apoptotic mechanism for this partner. Reason: The IntAct edge may be a reported screen hit, but GO:0005515 is a generic protein-binding assertion and the source does not support a more informative CYCS molecular-function or process annotation for this partner. Remove the GO row without treating the physical interaction as disproven. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Protein binding imported from a proteome-scale interactome dataset with no curated CYCS-specific mechanism. Reason: This may record a screening edge, but bare GO:0005515 carries no information about the respiratory electron-transfer or apoptosome functions of CYCS, and the row does not support a more precise replacement annotation. |
| GO:0005515 protein binding | IPI PMID:9267021 Apaf-1, a human protein homologous to C. elegans CED-4, part... | REMOVE | Summary: The APAF1 interaction is central to CYCS-dependent apoptosome assembly, but generic protein binding is not a useful molecular-function assertion for this well-defined apoptotic step. Reason: Cytochrome c binding to APAF1 is biologically real and is captured by the intrinsic apoptotic signaling and apoptosome annotations. There is no precise GO molecular-function term for the cytochrome-c/APAF1 contact in this review, so the uninformative GO:0005515 row should be removed rather than replaced by an ill-fitting caspase-activator term. Supporting Evidence: PMID:9267021 Cytochrome c binds to Apaf-1, an event that may trigger the activation of caspase-3 |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: IDA annotation for mitochondrial localization from HPA immunofluorescence data curation. Cytochrome c is a well-established mitochondrial protein. The mitochondrial intermembrane space (GO:0005758) is the more specific localization, but the broader mitochondrion annotation is also correct. Reason: Correct localization supported by immunofluorescence. A broader term than GO:0005758 but still accurate. |
| GO:0097193 intrinsic apoptotic signaling pathway | NAS PMID:10206961 An APAF-1.cytochrome c multimeric complex is a functional ap... | ACCEPT | Summary: Zou et al. reconstituted the cytochrome-c/APAF1/procaspase-9 apoptosome from purified factors, directly placing CYCS in intrinsic apoptotic signaling. Reason: Cytosolic CYCS promotes APAF1 oligomerization into a procaspase-9-activating apoptosome, which is the core intrinsic apoptotic signaling role of CYCS. 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:0097190 apoptotic signaling pathway | ISS PMID:12107093 Microinjection of cathepsin d induces caspase-dependent apop... | MODIFY | Summary: The orthology-based row correctly follows cytochrome-c redistribution during mitochondrial apoptosis but stops at the parent apoptotic signaling term. Reason: Cytochrome-c redistribution from mitochondria to cytosol is the entry point to the intrinsic branch, so GO:0097193 is more informative than the generic apoptotic signaling parent. Proposed replacements: intrinsic apoptotic signaling pathway Supporting Evidence: PMID:12107093 changes in distribution of cytochrome c, cell shrinkage, activation of caspases |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: HTP annotation for mitochondrial localization from Morgenstern et al. 2021, a quantitative high-confidence human mitochondrial proteome study. Cytochrome c was identified in the mitochondrial proteome. Correct but less specific than GO:0005758. Reason: Correct. Cytochrome c is a well-established mitochondrial protein. Confirmed by this high-confidence proteomics study. |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-163214 | MODIFY | Summary: Reactome projects CYCS to the mitochondrial inner membrane for a reaction that occurs at that membrane, but mature CYCS is the soluble intermembrane space cytochrome that transiently contacts the membrane surface. Reason: The inner-membrane context is real for Complex III, Complex IV, superoxide, and HCCS reactions, but GO:0005758 is the cleaner localization for CYCS itself. CYCS is in the IMS rather than an inner-membrane component. Proposed replacements: mitochondrial intermembrane space |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-164651 | MODIFY | Summary: Reactome projects CYCS to the mitochondrial inner membrane for a reaction that occurs at that membrane, but mature CYCS is the soluble intermembrane space cytochrome that transiently contacts the membrane surface. Reason: The inner-membrane context is real for Complex III, Complex IV, superoxide, and HCCS reactions, but GO:0005758 is the cleaner localization for CYCS itself. CYCS is in the IMS rather than an inner-membrane component. Proposed replacements: mitochondrial intermembrane space |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-3341294 | MODIFY | Summary: Reactome projects CYCS to the mitochondrial inner membrane for a reaction that occurs at that membrane, but mature CYCS is the soluble intermembrane space cytochrome that transiently contacts the membrane surface. Reason: The inner-membrane context is real for Complex III, Complex IV, superoxide, and HCCS reactions, but GO:0005758 is the cleaner localization for CYCS itself. CYCS is in the IMS rather than an inner-membrane component. Proposed replacements: mitochondrial intermembrane space |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9866217 | MODIFY | Summary: Reactome projects CYCS to the mitochondrial inner membrane for a reaction that occurs at that membrane, but mature CYCS is the soluble intermembrane space cytochrome that transiently contacts the membrane surface. Reason: The inner-membrane context is real for Complex III, Complex IV, superoxide, and HCCS reactions, but GO:0005758 is the cleaner localization for CYCS itself. CYCS is in the IMS rather than an inner-membrane component. Proposed replacements: mitochondrial intermembrane space |
| GO:0097194 execution phase of apoptosis | TAS PMID:9267021 Apaf-1, a human protein homologous to C. elegans CED-4, part... | MODIFY | Summary: The cited APAF1 discovery paper established cytochrome-c-dependent caspase-3 activation, but CYCS acts upstream of execution by forming the APAF1 apoptosome. Reason: The execution phase is carried out by effector caspases after apoptosome signaling. CYCS belongs on intrinsic apoptotic signaling pathway, which captures the mitochondrial cytochrome-c/APAF1 step. Proposed replacements: intrinsic apoptotic signaling pathway Supporting Evidence: PMID:9267021 Cytochrome c binds to Apaf-1, an event that may trigger the activation of caspase-3 |
| GO:0005739 mitochondrion | IDA PMID:12107093 Microinjection of cathepsin d induces caspase-dependent apop... | ACCEPT | Summary: IDA annotation for mitochondrial localization from Roberg et al. 2002 (PMID:12107093). This study on cathepsin D-induced apoptosis showed cytochrome c redistribution from mitochondria to cytosol, confirming its mitochondrial localization. Correct. Reason: The study directly observed cytochrome c distribution, confirming mitochondrial localization. Supporting Evidence: PMID:12107093 apoptosis, which was detected as changes in distribution of cytochrome c |
| GO:0005829 cytosol | IDA PMID:12107093 Microinjection of cathepsin d induces caspase-dependent apop... | ACCEPT | Summary: IDA annotation for cytosol localization from Roberg et al. 2002 (PMID:12107093). Cytochrome c was observed in the cytosol during apoptosis, having been released from mitochondria. This is a condition-specific localization (apoptosis) rather than a steady-state localization. However, it is functionally significant as cytosolic cytochrome c triggers the intrinsic apoptotic pathway. Reason: Cytosolic localization of cytochrome c is condition-specific (during apoptosis) but biologically significant. It is the site where cytochrome c exerts its apoptotic signaling function by binding Apaf-1. Supporting Evidence: PMID:12107093 changes in distribution of cytochrome c, cell shrinkage, activation of caspases |
| GO:0005758 mitochondrial intermembrane space | IDA PMID:19393246 Knockdown of human COX17 affects assembly and supramolecular... | ACCEPT | Summary: IDA annotation for mitochondrial intermembrane space from CAFA, citing Oswald et al. 2009 (PMID:19393246). This study focused on COX17 knockdown and its effects on cytochrome c oxidase assembly and supercomplex organization. While the study's primary focus is COX17, it involves cytochrome c in the context of respiratory supercomplexes in the IMS. Cytochrome c IMS localization is well established independently. Reason: Correct localization. The IMS is the established location of cytochrome c. While this particular study focuses on COX17, the IMS localization of cytochrome c is confirmed by many independent studies. Supporting Evidence: PMID:19393246 Assembly of cytochrome c oxidase, the terminal enzyme of the mitochondrial respiratory chain, requires a concerted activity of a number of chaperones and factors |
| GO:0005758 mitochondrial intermembrane space | TAS Reactome:R-HSA-5688294 | ACCEPT | Summary: TAS from Reactome R-HSA-5688294 (SIRT5 deacetylates Cytochrome C). This places cytochrome c in the IMS where SIRT5 deacetylation occurs. Correct localization. Reason: Correct. Cytochrome c resides in the IMS and is subject to post-translational modifications including deacetylation. |
| GO:0005634 nucleus | HDA PMID:21630459 Proteomic characterization of the human sperm nucleus. | MARK AS OVER ANNOTATED | Summary: HDA annotation for nuclear localization from de Mateo et al. 2011 (PMID:21630459), a proteomic characterization of the human sperm nucleus. Cytochrome c was identified among 403 proteins in isolated sperm nuclei. This is a high-throughput mass spectrometry detection and may represent contamination or a sperm-specific localization artifact. Sperm nuclei are extremely compact structures and the biological significance of cytochrome c in the nucleus is unclear and unlikely to represent a functional localization. Reason: Cytochrome c is a mitochondrial IMS protein. Its detection in sperm nuclei by mass spectrometry is likely due to contamination from the midpiece mitochondrial sheath, which is extremely close to the sperm nucleus. There is no established functional role for cytochrome c in the nucleus. This does not represent a meaningful localization. Supporting Evidence: PMID:21630459 sperm nuclei were obtained through CTAB treatment and isolated to over 99.9% purity without any tail fragments, acrosome or mitochondria |
| GO:0005739 mitochondrion | IDA PMID:20671748 Bcl-2 family interaction with the mitochondrial morphogenesi... | ACCEPT | Summary: IDA annotation for mitochondrial localization from Cleland et al. 2011 (PMID:20671748), a study on Bcl-2 family interaction with mitochondrial morphogenesis machinery. This study examined Bax/Bak-dependent mitochondrial dynamics and would have observed cytochrome c in mitochondrial contexts. Correct localization. Reason: Correct. Cytochrome c is a well-established mitochondrial protein. |
| GO:0005739 mitochondrion | HDA PMID:20833797 Phosphoproteome analysis of functional mitochondria isolated... | ACCEPT | Summary: HDA annotation for mitochondrial localization from a phosphoproteome analysis of functional mitochondria isolated from resting human muscle (Zhao et al. 2011). Cytochrome c was identified in the mitochondrial proteome. Correct. Reason: Correct. Cytochrome c identified in purified mitochondrial preparations by mass spectrometry. |
| GO:0005758 mitochondrial intermembrane space | TAS Reactome:R-HSA-114284 | ACCEPT | Summary: TAS from Reactome R-HSA-114284 (Release of Cytochrome c from mitochondria). This Reactome entry describes the release of cytochrome c from the IMS during apoptosis. Correct localization for the starting point of the apoptotic release event. Reason: Correct. Cytochrome c resides in the IMS prior to release during apoptosis. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-114252 | ACCEPT | Summary: TAS from Reactome R-HSA-114252 (Cleavage of Procaspase-3 by the apoptosome). Cytochrome c is in the cytosol as part of the apoptosome during caspase-3 activation. Correct condition-specific localization during apoptosis. Reason: Correct. Cytochrome c is in the cytosol during apoptosis as part of the apoptosome complex. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-114254 | ACCEPT | Summary: TAS from Reactome R-HSA-114254 (CYCS binds to APAF1). Cytochrome c binds Apaf-1 in the cytosol to initiate apoptosome formation. Correct. Reason: Correct. The cytochrome c-Apaf-1 binding event occurs in the cytosol. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-114256 | ACCEPT | Summary: TAS from Reactome R-HSA-114256 (CYCS:APAF1 binds procaspase-9). Apoptosome formation in the cytosol. Correct. Reason: Correct. Apoptosome assembly occurs in the cytosol. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-114259 | ACCEPT | Summary: TAS from Reactome R-HSA-114259 (Cleavage of Procaspase-9 to caspase-9). Caspase-9 activation within the cytosolic apoptosome. Correct. Reason: Correct. Caspase-9 activation occurs in the cytosol within the apoptosome. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-114261 | ACCEPT | Summary: TAS from Reactome R-HSA-114261 (Cleavage of Procaspase-7 by the apoptosome). Apoptosome function in the cytosol. Correct. Reason: Correct. Effector caspase activation by the apoptosome occurs in the cytosol. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-114284 | ACCEPT | Summary: TAS from Reactome R-HSA-114284 (Release of Cytochrome c from mitochondria). This is the same Reactome entry used for the IMS annotation above. The cytosol annotation reflects where cytochrome c ends up after release. Correct. Reason: Correct. Cytochrome c is released into the cytosol during apoptosis. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1592231 | ACCEPT | Summary: True: entailed by apoptosome, kept in this review. Reason: The claim is true: apoptosome, kept in this review, entails this term. Other rows for this term are ACCEPTed. This row's reference does not establish it, but that concerns the evidence, not the claim, so it is not grounds for REMOVE. Supporting Evidence: PMID:12107093 changes in distribution of cytochrome c, cell shrinkage, activation of caspases |
| GO:0005829 cytosol | TAS Reactome:R-HSA-6804596 | ACCEPT | Summary: TAS from Reactome R-HSA-6804596 (APAF1:CYCS binds APIP). Describes APIP binding to the Apaf-1:cytochrome c complex in the cytosol. Correct. Reason: Correct. This interaction occurs in the cytosol during apoptotic signaling. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9627056 | ACCEPT | Summary: TAS from Reactome R-HSA-9627056 (Procaspase 9 forms dimer). Dimerization of procaspase-9 in the cytosol within the apoptosome context. Correct. Reason: Correct. Part of the apoptosome signaling cascade in the cytosol. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9627078 | ACCEPT | Summary: TAS from Reactome R-HSA-9627078 (XIAP binds CASP9). Regulation of caspase-9 by XIAP in the cytosol. Correct. Reason: Correct. Part of the apoptosis regulatory network in the cytosol. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9627089 | ACCEPT | Summary: TAS from Reactome R-HSA-9627089 (CASP9 is phosphorylated at T412). Post-translational modification of caspase-9 in the cytosol. Correct. Reason: Correct. Part of the apoptosis regulatory network in the cytosol. |
| GO:0005634 nucleus | IDA GO_REF:0000054 | MARK AS OVER ANNOTATED | Summary: IDA annotation from LIFEdb, based on curation of intracellular localizations of expressed fusion proteins in living cells. LIFEdb generates GFP-fusion proteins and observes their localization. Nuclear localization of a CYCS-GFP fusion is likely an artifact of the overexpression/fusion system. Cytochrome c is a small protein (12 kDa) that could diffuse through nuclear pores, especially when overexpressed as a GFP fusion. There is no established functional role for cytochrome c in the nucleus. Reason: LIFEdb GFP-fusion protein localization. Small proteins like cytochrome c (12 kDa) can passively diffuse through nuclear pores when overexpressed as fusion constructs. This is likely an artifact and does not represent a functional nuclear localization. The canonical localization of cytochrome c is the mitochondrial IMS. |
| GO:0020037 heme binding | TAS PMID:9515723 Cytochrome c in the apoptotic and antioxidant cascades. | ACCEPT | Summary: TAS annotation for heme binding from Skulachev 1998 (PMID:9515723), a review on cytochrome c in apoptotic and antioxidant cascades. The heme c group is covalently bound to Cys15 and Cys18 via thioether bonds, with His18 and Met80 as axial iron ligands. This is a core molecular function of CYCS essential for electron transfer activity. Reason: Heme binding is a defining structural and functional feature of cytochrome c. The covalent heme attachment is essential for its electron carrier function. Well supported by structural and biochemical evidence. Supporting Evidence: PMID:9515723 cytochrome c is a pro-apoptotic factor. It is released from its places on the outer surface of the inner mitochondrial membrane |
| GO:0005758 mitochondrial intermembrane space | TAS PMID:8689682 Induction of apoptotic program in cell-free extracts: requir... | ACCEPT | Summary: TAS annotation for mitochondrial IMS localization from Liu et al. 1996 (PMID:8689682), the landmark paper demonstrating that cytochrome c is required for in vitro apoptosis. The study showed that cells undergoing apoptosis release cytochrome c from mitochondria to the cytosol, establishing its starting location in the IMS. Reason: This landmark paper established the role of cytochrome c in apoptosis and confirmed its mitochondrial localization prior to release during apoptosis. Supporting Evidence: PMID:8689682 Cells undergoing apoptosis in vivo showed increased release of cytochrome c to their cytosol, suggesting that mitochondria may function in apoptosis by releasing cytochrome c |
| GO:0005829 cytosol | IMP PMID:8689682 Induction of apoptotic program in cell-free extracts: requir... | ACCEPT | Summary: IMP annotation for cytosol localization from Liu et al. 1996 (PMID:8689682). The study demonstrated that addition of cytochrome c to cytosol activates the apoptotic program, and that cells undergoing apoptosis release cytochrome c to their cytosol. The IMP evidence is appropriate because the mutant phenotype (apoptosis) requires cytochrome c presence in the cytosol. Reason: Landmark experimental demonstration that cytochrome c in the cytosol activates apoptosis. The cytosolic localization is condition-specific but functionally essential for the apoptotic signaling role. Supporting Evidence: PMID:8689682 Cells undergoing apoptosis in vivo showed increased release of cytochrome c to their cytosol |
| GO:0045333 cellular respiration | TAS PMID:10383829 A soluble version of the receptor-like protein tyrosine phos... | MODIFY | Summary: The GO term is biologically compatible with CYCS respiration, but the original PMID resolves to an unrelated receptor-like protein tyrosine phosphatase kappa neurite-outgrowth paper. Reason: CYCS participates in cellular respiration specifically as the mobile carrier for electron transfer from Complex III to Complex IV. Replace the broad cellular-respiration assertion with those two specific mitochondrial electron-transport processes and flag the PMID as a wrong identifier. Proposed replacements: mitochondrial electron transport, ubiquinol to cytochrome c mitochondrial electron transport, cytochrome c to oxygen Supporting Evidence: Reactome:R-HSA-164651 Complex III transfers electrons from ubiquinol to cytochrome c Reactome:R-HSA-163214 Electron transfer from reduced cytochrome c to molecular oxygen |
| GO:0043293 apoptosome | IPI PMID:10206961 An APAF-1.cytochrome c multimeric complex is a functional ap... | NEW | Summary: Cytochrome c is a structural constituent of the APAF1 apoptosome assembled after mitochondrial outer-membrane permeabilization. Reason: UniProt/ComplexPortal already records CYCS as part of the apoptosome, and the purified APAF1-CYCS-procaspase-9 reconstitution showed that cytochrome c coassembles with APAF1 into the active procaspase-9-recruiting complex. Supporting Evidence: PMID:10206961 forming a large multimeric APAF-1.cytochrome c complex |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: This IPI row comes from Haenig et al. 2020, a yeast two-hybrid interactome map centered on neurodegenerative-disease proteins. The cached abstract establishes a large-scale network resource, but it does not provide a CYCS-specific respiratory or apoptotic mechanism for this partner. Reason: The IntAct edge may be a reported screen hit, but GO:0005515 is a generic protein-binding assertion and the source does not support a more informative CYCS molecular-function or process annotation for this partner. Remove the GO row without treating the physical interaction as disproven. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: This IPI row comes from Haenig et al. 2020, a yeast two-hybrid interactome map centered on neurodegenerative-disease proteins. The cached abstract establishes a large-scale network resource, but it does not provide a CYCS-specific respiratory or apoptotic mechanism for this partner. Reason: The IntAct edge may be a reported screen hit, but GO:0005515 is a generic protein-binding assertion and the source does not support a more informative CYCS molecular-function or process annotation for this partner. Remove the GO row without treating the physical interaction as disproven. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: This IPI row comes from Haenig et al. 2020, a yeast two-hybrid interactome map centered on neurodegenerative-disease proteins. The cached abstract establishes a large-scale network resource, but it does not provide a CYCS-specific respiratory or apoptotic mechanism for this partner. Reason: The IntAct edge may be a reported screen hit, but GO:0005515 is a generic protein-binding assertion and the source does not support a more informative CYCS molecular-function or process annotation for this partner. Remove the GO row without treating the physical interaction as disproven. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: This IPI row comes from Haenig et al. 2020, a yeast two-hybrid interactome map centered on neurodegenerative-disease proteins. The cached abstract establishes a large-scale network resource, but it does not provide a CYCS-specific respiratory or apoptotic mechanism for this partner. Reason: The IntAct edge may be a reported screen hit, but GO:0005515 is a generic protein-binding assertion and the source does not support a more informative CYCS molecular-function or process annotation for this partner. Remove the GO row without treating the physical interaction as disproven. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: This IPI row comes from Haenig et al. 2020, a yeast two-hybrid interactome map centered on neurodegenerative-disease proteins. The cached abstract establishes a large-scale network resource, but it does not provide a CYCS-specific respiratory or apoptotic mechanism for this partner. Reason: The IntAct edge may be a reported screen hit, but GO:0005515 is a generic protein-binding assertion and the source does not support a more informative CYCS molecular-function or process annotation for this partner. Remove the GO row without treating the physical interaction as disproven. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: This IPI row comes from Haenig et al. 2020, a yeast two-hybrid interactome map centered on neurodegenerative-disease proteins. The cached abstract establishes a large-scale network resource, but it does not provide a CYCS-specific respiratory or apoptotic mechanism for this partner. Reason: The IntAct edge may be a reported screen hit, but GO:0005515 is a generic protein-binding assertion and the source does not support a more informative CYCS molecular-function or process annotation for this partner. Remove the GO row without treating the physical interaction as disproven. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: This IPI row comes from Haenig et al. 2020, a yeast two-hybrid interactome map centered on neurodegenerative-disease proteins. The cached abstract establishes a large-scale network resource, but it does not provide a CYCS-specific respiratory or apoptotic mechanism for this partner. Reason: The IntAct edge may be a reported screen hit, but GO:0005515 is a generic protein-binding assertion and the source does not support a more informative CYCS molecular-function or process annotation for this partner. Remove the GO row without treating the physical interaction as disproven. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: This IPI row comes from Haenig et al. 2020, a yeast two-hybrid interactome map centered on neurodegenerative-disease proteins. The cached abstract establishes a large-scale network resource, but it does not provide a CYCS-specific respiratory or apoptotic mechanism for this partner. Reason: The IntAct edge may be a reported screen hit, but GO:0005515 is a generic protein-binding assertion and the source does not support a more informative CYCS molecular-function or process annotation for this partner. Remove the GO row without treating the physical interaction as disproven. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: This IPI row comes from Haenig et al. 2020, a yeast two-hybrid interactome map centered on neurodegenerative-disease proteins. The cached abstract establishes a large-scale network resource, but it does not provide a CYCS-specific respiratory or apoptotic mechanism for this partner. Reason: The IntAct edge may be a reported screen hit, but GO:0005515 is a generic protein-binding assertion and the source does not support a more informative CYCS molecular-function or process annotation for this partner. Remove the GO row without treating the physical interaction as disproven. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: This IPI row comes from Haenig et al. 2020, a yeast two-hybrid interactome map centered on neurodegenerative-disease proteins. The cached abstract establishes a large-scale network resource, but it does not provide a CYCS-specific respiratory or apoptotic mechanism for this partner. Reason: The IntAct edge may be a reported screen hit, but GO:0005515 is a generic protein-binding assertion and the source does not support a more informative CYCS molecular-function or process annotation for this partner. Remove the GO row without treating the physical interaction as disproven. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: This IPI row comes from Haenig et al. 2020, a yeast two-hybrid interactome map centered on neurodegenerative-disease proteins. The cached abstract establishes a large-scale network resource, but it does not provide a CYCS-specific respiratory or apoptotic mechanism for this partner. Reason: The IntAct edge may be a reported screen hit, but GO:0005515 is a generic protein-binding assertion and the source does not support a more informative CYCS molecular-function or process annotation for this partner. Remove the GO row without treating the physical interaction as disproven. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: This IPI row comes from Haenig et al. 2020, a yeast two-hybrid interactome map centered on neurodegenerative-disease proteins. The cached abstract establishes a large-scale network resource, but it does not provide a CYCS-specific respiratory or apoptotic mechanism for this partner. Reason: The IntAct edge may be a reported screen hit, but GO:0005515 is a generic protein-binding assertion and the source does not support a more informative CYCS molecular-function or process annotation for this partner. Remove the GO row without treating the physical interaction as disproven. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: This IPI row comes from Haenig et al. 2020, a yeast two-hybrid interactome map centered on neurodegenerative-disease proteins. The cached abstract establishes a large-scale network resource, but it does not provide a CYCS-specific respiratory or apoptotic mechanism for this partner. Reason: The IntAct edge may be a reported screen hit, but GO:0005515 is a generic protein-binding assertion and the source does not support a more informative CYCS molecular-function or process annotation for this partner. Remove the GO row without treating the physical interaction as disproven. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: This IPI row comes from Haenig et al. 2020, a yeast two-hybrid interactome map centered on neurodegenerative-disease proteins. The cached abstract establishes a large-scale network resource, but it does not provide a CYCS-specific respiratory or apoptotic mechanism for this partner. Reason: The IntAct edge may be a reported screen hit, but GO:0005515 is a generic protein-binding assertion and the source does not support a more informative CYCS molecular-function or process annotation for this partner. Remove the GO row without treating the physical interaction as disproven. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: This IPI row comes from Haenig et al. 2020, a yeast two-hybrid interactome map centered on neurodegenerative-disease proteins. The cached abstract establishes a large-scale network resource, but it does not provide a CYCS-specific respiratory or apoptotic mechanism for this partner. Reason: The IntAct edge may be a reported screen hit, but GO:0005515 is a generic protein-binding assertion and the source does not support a more informative CYCS molecular-function or process annotation for this partner. Remove the GO row without treating the physical interaction as disproven. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: This IPI row comes from Haenig et al. 2020, a yeast two-hybrid interactome map centered on neurodegenerative-disease proteins. The cached abstract establishes a large-scale network resource, but it does not provide a CYCS-specific respiratory or apoptotic mechanism for this partner. Reason: The IntAct edge may be a reported screen hit, but GO:0005515 is a generic protein-binding assertion and the source does not support a more informative CYCS molecular-function or process annotation for this partner. Remove the GO row without treating the physical interaction as disproven. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: This IPI row comes from Haenig et al. 2020, a yeast two-hybrid interactome map centered on neurodegenerative-disease proteins. The cached abstract establishes a large-scale network resource, but it does not provide a CYCS-specific respiratory or apoptotic mechanism for this partner. Reason: The IntAct edge may be a reported screen hit, but GO:0005515 is a generic protein-binding assertion and the source does not support a more informative CYCS molecular-function or process annotation for this partner. Remove the GO row without treating the physical interaction as disproven. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: This IPI row comes from Haenig et al. 2020, a yeast two-hybrid interactome map centered on neurodegenerative-disease proteins. The cached abstract establishes a large-scale network resource, but it does not provide a CYCS-specific respiratory or apoptotic mechanism for this partner. Reason: The IntAct edge may be a reported screen hit, but GO:0005515 is a generic protein-binding assertion and the source does not support a more informative CYCS molecular-function or process annotation for this partner. Remove the GO row without treating the physical interaction as disproven. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: This IPI row comes from Haenig et al. 2020, a yeast two-hybrid interactome map centered on neurodegenerative-disease proteins. The cached abstract establishes a large-scale network resource, but it does not provide a CYCS-specific respiratory or apoptotic mechanism for this partner. Reason: The IntAct edge may be a reported screen hit, but GO:0005515 is a generic protein-binding assertion and the source does not support a more informative CYCS molecular-function or process annotation for this partner. Remove the GO row without treating the physical interaction as disproven. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: This IPI row comes from Haenig et al. 2020, a yeast two-hybrid interactome map centered on neurodegenerative-disease proteins. The cached abstract establishes a large-scale network resource, but it does not provide a CYCS-specific respiratory or apoptotic mechanism for this partner. Reason: The IntAct edge may be a reported screen hit, but GO:0005515 is a generic protein-binding assertion and the source does not support a more informative CYCS molecular-function or process annotation for this partner. Remove the GO row without treating the physical interaction as disproven. |
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