CYCS

Existing Annotations Review

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 single-electron carrier of the mitochondrial ETC, shuttling electrons from Complex III to Complex IV via reversible oxidation/reduction of its heme c iron atom. This is one of the two core molecular functions of CYCS and is extremely well established. The IBA annotation is phylogenetically sound as this function is conserved across all eukaryotes (PMID:9515723). Reason: Electron transfer activity is the primary molecular function of cytochrome c in the respiratory chain. The protein shuttles single electrons between Complex III and Complex IV. This function is conserved across eukaryotes and is phylogenetically well supported by the IBA. 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 at early steps of apoptosis file:human/CYCS/CYCS-deep-research-falcon.md cytochrome c shuttles electrons from complex III (cytochrome bc1) to complex IV (cytochrome c oxidase) in the inner mitochondrial membrane cristae region, supporting oxidative phosphorylation
GO:0006122 mitochondrial electron transport, ubiquinol to cytochrome c	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for the biological process of electron transfer from ubiquinol to cytochrome c. This represents the Complex III (cytochrome bc1) reaction in which ubiquinol is oxidized and cytochrome c is reduced. Cytochrome c is the electron acceptor in this reaction, receiving electrons from the cytochrome c1 subunit of Complex III. While CYCS is not a subunit of Complex III, it is an essential participant in this process as the mobile electron carrier that accepts the electrons. The IBA annotation is appropriate as this function is conserved across eukaryotes. Reason: Cytochrome c is the direct electron acceptor from Complex III. The process of ubiquinol-to- cytochrome c electron transfer requires cytochrome c as the mobile carrier. This is a core biological process annotation that accurately describes one half of CYCS's ETC function. Supporting Evidence: file:human/CYCS/CYCS-deep-research-falcon.md cytochrome c shuttles electrons from complex III (cytochrome bc1) to complex IV (cytochrome c oxidase)
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: IBA annotation for the biological process of electron transfer from cytochrome c to oxygen. This represents the Complex IV (cytochrome c oxidase) reaction where cytochrome c donates electrons and molecular oxygen is reduced to water. Cytochrome c is the electron donor in this reaction. As with GO:0006122, CYCS is not a subunit of Complex IV but is an essential participant as the electron donor. The IBA annotation is appropriate. Reason: Cytochrome c is the direct electron donor to Complex IV. This process requires cytochrome c as the mobile carrier that delivers electrons from Complex III. This is a core biological process annotation for CYCS. Supporting Evidence: file:human/CYCS/CYCS-deep-research-falcon.md cytochrome c shuttles electrons from complex III (cytochrome bc1) to complex IV (cytochrome c oxidase) in the inner mitochondrial membrane cristae region
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	ACCEPT	Summary: IEA annotation for apoptotic process from UniProt keyword mapping (KW-0053, Apoptosis). Cytochrome c is indeed involved in apoptosis -- upon release from mitochondria it triggers the intrinsic apoptotic pathway. However, GO:0006915 (apoptotic process) is very broad. More specific terms such as GO:0097193 (intrinsic apoptotic signaling pathway) are also annotated. This broad IEA is acceptable alongside the more specific annotations. Reason: Correct but broad. The role of cytochrome c in apoptosis is well established (PMID:8689682, PMID:9267021, PMID:10206961). More specific child terms are also annotated. It is acceptable for IEA annotations to use broader terms.
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	ACCEPT	Summary: IEA annotation for metal ion binding from UniProt keyword mapping (KW-0479, Metal-binding). Cytochrome c contains a heme iron atom coordinated by His18 and Met80 (axial ligands). While technically correct, GO:0046872 is very broad. The more informative annotation is GO:0020037 (heme binding) which captures the specific nature of the metal coordination context. However, iron ion binding is part of the heme function and this IEA is not wrong. Reason: Technically correct -- cytochrome c binds iron as part of its heme prosthetic group. The more specific GO:0020037 (heme binding) is also annotated. It is acceptable for IEA annotations to use broader terms.
GO:0005515 protein binding	IPI PMID:10206961 An APAF-1.cytochrome c multimeric complex is a functional ap...	KEEP AS NON CORE	Summary: IPI annotation for protein binding with APAF1 (O14727) from Zou et al. 1999. This study reconstituted the apoptosome using purified cytochrome c, recombinant APAF-1, and recombinant procaspase-9, demonstrating direct physical interaction between cytochrome c and APAF-1 (PMID:10206961). This is one of the most biologically significant interactions of CYCS -- cytochrome c binding to Apaf-1 triggers apoptosome assembly and caspase-9 activation. While 'protein binding' is uninformative, the underlying interaction is a core function. A more informative term would be GO:0008656 (cysteine-type endopeptidase activator activity involved in apoptotic process) but that does not fully capture the binding aspect. Reason: The CYCS-APAF1 interaction is among the most biologically significant known protein-protein interactions, as it initiates apoptosome assembly. However, 'protein binding' is too vague to be informative. The functional significance is better captured by the BP annotation GO:0097193 (intrinsic apoptotic signaling pathway) and the CC annotation for apoptosome. Supporting Evidence: PMID:10206961 the binding of cytochrome c promote APAF-1 oligomerization, forming a large multimeric APAF-1.cytochrome c complex
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	KEEP AS NON CORE	Summary: IPI annotation for protein binding with KRT40 (Q6A162) from a proteome-scale human interactome study (Rolland et al. 2014). KRT40 is a keratin family member. The biological relevance of a CYCS-KRT40 interaction is unclear and likely represents a non-specific high-throughput detection. Reason: High-throughput interactome study. The CYCS-KRT40 interaction has no established biological significance. 'Protein binding' is uninformative.
GO:0005515 protein binding	IPI PMID:25595453 Respiratory complexes III and IV can each bind two molecules...	KEEP AS NON CORE	Summary: IPI annotation for protein binding with plant cytochrome c1 (Q9FKS5) from Moreno-Beltran et al. 2015. This study investigated the transient interactions of human cytochrome c with respiratory complexes III and IV using cross-species proteins. The study showed that two molecules of cytochrome c can bind to each complex at low ionic strength, supporting the electron transfer shuttle function (PMID:25595453). This is a functionally relevant interaction, though with a heterologous system. Reason: Heterologous system study (human cyt c with plant cyt c1). Demonstrates the conserved interaction between cytochrome c and its respiratory chain partners. 'Protein binding' is uninformative but the underlying biology is sound. Supporting Evidence: PMID:25595453 two cytochrome c molecules per adduct - at low ionic strength. We conclude that such extra binding sites at the surfaces of complexes III and IV can facilitate the turnover and sliding of cytochrome c molecules
GO:0005515 protein binding	IPI PMID:25910212 Widespread macromolecular interaction perturbations in human...	KEEP AS NON CORE	Summary: IPI annotation for protein binding with KRT40 (Q6A162) from Sahni et al. 2015, a study on macromolecular interaction perturbations in human genetic disorders. Second detection of CYCS-KRT40 interaction. Biological significance remains unclear. Reason: High-throughput interaction study. Repeated CYCS-KRT40 detection but no established biological significance.
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	KEEP AS NON CORE	Summary: IPI annotation for protein binding with LRG1 (P02750) from Huttlin et al. 2017, the architecture of the human interactome study. LRG1 is a leucine-rich alpha-2-glycoprotein involved in TGF-beta signaling. The biological relevance of this interaction is unclear. Reason: High-throughput interactome study. CYCS-LRG1 interaction has no established biological significance. 'Protein binding' is uninformative.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	KEEP AS NON CORE	Summary: IPI annotation for protein binding with MEOX2 (Q6FHY5) from Luck et al. 2020, a reference map of the human binary protein interactome. MEOX2 is a homeobox transcription factor. The biological relevance of this interaction is unclear. Reason: High-throughput interactome study. CYCS-MEOX2 interaction has no established biological significance. 'Protein binding' is uninformative.
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	KEEP AS NON CORE	Summary: IPI annotation for protein binding from Haenig et al. 2020, an interactome mapping study focused on neurodegenerative disease proteins. This PMID generates multiple GOA entries with different interactors including APP (P05067), SNCA (P37840), FYN (P06241), COA7 (Q96BR5), and many others. The APP and SNCA interactions are biologically interesting given that cytochrome c release and caspase activation are implicated in neurodegeneration. However, most of these are high-throughput detections and 'protein binding' is uninformative. Reason: Large-scale neurodegenerative disease interactome study with many interactors. Some interactions (APP, SNCA) are potentially biologically interesting but the evidence is from high-throughput screening. 'Protein binding' is uninformative.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	KEEP AS NON CORE	Summary: IPI annotation for protein binding with LRG1 (P02750) from Huttlin et al. 2021, dual proteome-scale networks study. Second detection of CYCS-LRG1 interaction. Reason: High-throughput interactome study. Repeated CYCS-LRG1 detection but no established biological significance.
GO:0005515 protein binding	IPI PMID:9267021 Apaf-1, a human protein homologous to C. elegans CED-4, part...	KEEP AS NON CORE	Summary: IPI annotation for protein binding with APAF1 (O14727) from Zou et al. 1997. This is the landmark paper identifying Apaf-1 as the cytochrome c-binding partner that mediates caspase activation. The study showed that "Cytochrome c binds to Apaf-1, an event that may trigger the activation of caspase-3, leading to apoptosis" (PMID:9267021). This is one of the most important protein interactions discovered for CYCS. Reason: Landmark paper establishing the CYCS-APAF1 interaction. The biological significance is enormous but 'protein binding' is uninformative. The functional context is captured by GO:0097193 and GO:0097194 annotations. Supporting Evidence: PMID:9267021 Cytochrome c binds to Apaf-1, an event that may trigger the activation of caspase-3, leading to apoptosis
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: NAS annotation from ComplexPortal for the intrinsic apoptotic signaling pathway. Zou et al. 1999 (PMID:10206961) reconstituted the apoptosome from purified cytochrome c, APAF-1, and procaspase-9, directly demonstrating that cytochrome c is a key activator of the intrinsic apoptotic pathway. This is a core biological process for CYCS. Reason: The intrinsic apoptotic signaling pathway is one of the two core biological processes for CYCS. Cytochrome c triggers apoptosome assembly by binding APAF-1, which leads to caspase-9 activation. This is extensively supported by multiple landmark studies. Supporting Evidence: PMID:10206961 the binding of cytochrome c promote APAF-1 oligomerization, forming a large multimeric APAF-1.cytochrome c complex. 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...	ACCEPT	Summary: ISS annotation for apoptotic signaling pathway, inferred from mouse ortholog (UniProtKB:P00004). Roberg et al. 2002 (PMID:12107093) showed that cathepsin D injection causes apoptosis with cytochrome c redistribution and caspase activation. The ISS from mouse is appropriate since the apoptotic function of cytochrome c is conserved across mammals. However, this is a broader term than GO:0097193 (intrinsic apoptotic signaling pathway) which is already annotated. Both are acceptable. Reason: Correct but broader than GO:0097193. The apoptotic signaling function of cytochrome c is conserved in mouse, making the ISS transfer appropriate. Supporting Evidence: PMID:12107093 microinjection of cathepsin D into the cytosol of human fibroblasts caused apoptosis, which was detected as 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	ACCEPT	Summary: TAS annotation from Reactome pathway R-HSA-163214 (Electron transfer from reduced cytochrome c to molecular oxygen). Cytochrome c is associated with the inner mitochondrial membrane in the intermembrane space, where it interacts with Complex III and Complex IV embedded in the inner membrane. However, cytochrome c is a soluble protein of the IMS, not an integral or peripheral inner membrane protein. GO:0005758 (mitochondrial intermembrane space) is more accurate than GO:0005743. That said, UniProt notes cytochrome c is "Loosely associated with the inner membrane" via electrostatic and cardiolipin interactions, so this annotation is not entirely wrong. Reason: While GO:0005758 (mitochondrial intermembrane space) is the more precise localization, cytochrome c is indeed loosely associated with the inner membrane surface via cardiolipin binding. Reactome correctly places it in the context of inner membrane electron transport. Supporting Evidence: file:human/CYCS/CYCS-deep-research-falcon.md cytochrome c is localized to the mitochondrial intermembrane space (IMS), associated with the inner mitochondrial membrane via electrostatic and hydrophobic interactions, including binding to cardiolipin-rich cristae surfaces
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-164651	ACCEPT	Summary: TAS from Reactome R-HSA-164651 (Electron transfer from ubiquinol to cytochrome c of complex III). Same reasoning as above -- cytochrome c is loosely associated with the inner membrane during electron transfer. Reason: Consistent with the Reactome annotation for Complex III reaction context. Cytochrome c is associated with the inner membrane surface during its electron carrier function.
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-3341294	ACCEPT	Summary: TAS from Reactome R-HSA-3341294 (Superoxide reduces cytochrome c). This reaction occurs in the IMS at the inner membrane surface. Same reasoning as above. Reason: Consistent with inner membrane association during superoxide scavenging by cytochrome c in the IMS.
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-9866217	ACCEPT	Summary: TAS from Reactome R-HSA-9866217 (HCCS inserts heme into cytochrome c). HCCS is the holocytochrome c synthase that catalyzes heme attachment to apocytochrome c at the inner membrane. The heme insertion occurs at or near the inner membrane in the IMS. Reason: Appropriate localization for the heme attachment reaction catalyzed by HCCS at the inner membrane.
GO:0097194 execution phase of apoptosis	TAS PMID:9267021 Apaf-1, a human protein homologous to C. elegans CED-4, part...	MODIFY	Summary: TAS annotation for the execution phase of apoptosis, citing Zou et al. 1997 (PMID:9267021). This landmark paper identified Apaf-1 and showed that cytochrome c binding to Apaf-1 leads to caspase-3 activation, which is the execution phase of apoptosis. However, cytochrome c's direct role is in the initiation/signaling phase (binding Apaf-1, activating caspase-9) rather than the execution phase per se (which involves effector caspases cleaving cellular substrates). CYCS acts upstream of execution. GO:0097193 (intrinsic apoptotic signaling pathway) is the more appropriate process term. Reason: Cytochrome c participates in the initiation of apoptosis by binding Apaf-1 and activating caspase-9. The execution phase (caspase-3/7-mediated substrate cleavage) occurs downstream of cytochrome c's direct action. GO:0097193 (intrinsic apoptotic signaling pathway) more accurately describes CYCS's role. The existing annotation for GO:0097193 already captures this. 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, leading to apoptosis
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: TAS from Reactome R-HSA-1592231 (Expression of CYCS). Cytochrome c is synthesized in the cytosol before import into mitochondria. Correct in the context of protein synthesis, though the functional localization is the IMS. Reason: Correct. Cytochrome c is synthesized in the cytosol as apocytochrome c before mitochondrial import.
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 A cell-free system based on cytosols of normally growing cells is established that reproduces aspects of the apoptotic program in vitro...protein sequence revealed that this protein is cytochrome c
GO:0045333 cellular respiration	TAS PMID:10383829 A soluble version of the receptor-like protein tyrosine phos...	ACCEPT	Summary: TAS annotation for cellular respiration from Drosopoulos et al. 1999 (PMID:10383829). However, this publication is about RPTPkappa (receptor-like protein tyrosine phosphatase kappa) stimulating neurite outgrowth. It has no apparent connection to cytochrome c or cellular respiration. This reference appears to be incorrectly linked to this annotation. Nevertheless, the biological process annotation itself is correct -- cytochrome c is essential for cellular respiration as the electron carrier between Complex III and IV. Reason: The GO term cellular respiration is correct for CYCS, as it is an essential component of the mitochondrial electron transport chain. The reference PMID:10383829 appears to be incorrectly linked (it is about RPTPkappa signaling, not cytochrome c), but the annotation itself is valid and supported by extensive other evidence. Supporting Evidence: PMID:9515723 The reduced cytochrome c is oxidized by cytochrome oxidase
GO:0043293 apoptosome	IPI PMID:10206961 An APAF-1.cytochrome c multimeric complex is a functional ap...	NEW	Summary: Cytochrome c is a structural component of the apoptosome, a multisubunit complex composed of Apaf-1, cytochrome c, and procaspase-9. Zou et al. 1999 (PMID:10206961) demonstrated that cytochrome c binds Apaf-1 to form a multimeric complex that recruits and activates procaspase-9. This CC annotation is present in the UniProt GO section (IPI:ComplexPortal) but was not in the GOA TSV used to generate this review. It should be added as it captures a core component annotation for the apoptotic function. Reason: Cytochrome c is a bona fide component of the apoptosome. The apoptosome annotation (GO:0043293) is listed in UniProt for this protein and accurately captures its structural role in apoptotic signaling. This is an important CC annotation complementing the BP annotation GO:0097193. Supporting Evidence: PMID:10206961 APAF-1 oligomerization, forming a large multimeric APAF-1.cytochrome c complex. Such a complex can be isolated using gel filtration chromatography and is by itself sufficient to recruit and activate procaspase-9. The stoichiometric ratio of procaspase-9 to APAF-1 is approximately 1 to 1 in the complex

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Bioreason Rl Predictions

Bioreason Rl Review

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