CYC1

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0045275 respiratory chain complex III	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic propagation correctly assigns CYC1 to respiratory chain complex III. This is the defining cellular component for cytochrome c1 and a core annotation supported by multiple independent lines of evidence (genetics, structural biology, ComplexPortal). Reason: Cytochrome c1 is one of the three evolutionarily conserved catalytic subunits of the bc1 complex, alongside cytochrome b and the Rieske Fe-S protein. Both falcon and openai deep research, and the ComplexPortal IPI annotation (PMID:28844695), independently support this assignment. Supporting Evidence: file:human/CYC1/CYC1-deep-research-falcon.md Human CYC1 (UniProt P08574) encodes cytochrome c1, a nuclear-encoded core catalytic subunit of mitochondrial respiratory chain complex III (cytochrome bc1 / ubiquinol:cytochrome c oxidoreductase). PMID:39053894 MT‐CYB, the Rieske Fe‐S protein (UQCRFS1), and cytochrome c1 (CYC1) are the catalytic subunits.
GO:0006122 mitochondrial electron transport, ubiquinol to cytochrome c	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic propagation of the canonical Complex III biological process. CYC1 directly participates in this process by accepting electrons from the Rieske 2Fe-2S center and donating them to soluble cytochrome c. Core annotation. Reason: This is the precise BP term for the reaction CYC1 mediates as part of the bc1 complex. Falcon explicitly describes the Q-cycle path Rieske -> cytochrome c1 -> cytochrome c as the canonical electron transfer sequence in which CYC1 is the IMS-facing exit point. Supporting Evidence: file:human/CYC1/CYC1-deep-research-falcon.md One electron transfers from Qo to the Rieske 2Fe–2S center, then to cytochrome c1, then to cytochrome c.
GO:0005743 mitochondrial inner membrane	IEA GO_REF:0000120	ACCEPT	Summary: UniProt combined-IEA annotation correctly places CYC1 at the inner mitochondrial membrane. CYC1 is a single-pass IMM protein with a C-proximal transmembrane helix; the heme-bearing domain projects into the intermembrane space. Core localization. Reason: Confirmed by experimental IDA (PMID:28844695, ComplexPortal), Reactome TAS, and structural biology. Falcon notes the explicit topology with a single C-proximal transmembrane segment. Supporting Evidence: file:human/CYC1/CYC1-deep-research-falcon.md CYC1 is a mitochondrial inner membrane protein. Its heme-containing domain projects into the intermembrane space, where it meets cytochrome c; the protein is anchored by a single C-proximal transmembrane segment.
GO:0008121 quinol-cytochrome-c reductase activity	IEA GO_REF:0000120	ACCEPT	Summary: This complex-level molecular function (EC 7.1.1.8) is the activity of the bc1 holoenzyme. CYC1 does not catalyze quinol oxidation independently (the Qo/Qi sites are in cytochrome b and quinol oxidation requires the Rieske protein), but it is an obligate catalytic subunit and contributes to this activity. Retain as a core annotation in the contributes_to sense. Reason: Falcon notes CYC1's product is "not an independent metabolic enzyme in isolation; its primary function is as an electron-transfer subunit within complex III." The complex-level MF is appropriate as a contributes_to function, captured under core_functions. Supporting Evidence: file:human/CYC1/CYC1-deep-research-falcon.md CYC1's gene product (cytochrome c1) is not an independent metabolic enzyme in isolation; its primary function is as an electron-transfer subunit within complex III.
GO:0009055 electron transfer activity	IEA GO_REF:0000002	ACCEPT	Summary: Subunit-specific molecular function of cytochrome c1: heme c1 mediates rapid electron transfer (predicted up to ~8.3 x 10^6 s^-1) from the Rieske 2Fe-2S center to soluble cytochrome c. This is CYC1's independently-enabled molecular function and the primary MF term for the gene. Reason: InterPro mapping of the Cyt_c1 domain to electron transfer activity is biophysically and structurally accurate. Falcon documents the edge-to-edge geometry (~9.4 Å) and tunneling rates consistent with single-electron transfer. Supporting Evidence: file:human/CYC1/CYC1-deep-research-falcon.md cytochrome c–cytochrome c1 encounter geometry as ~17.4 Å Fe-to-Fe (≈9.4 Å edge-to-edge) and reports predicted electron-transfer rates up to ~8.3 × 10^6 s−1
GO:0016020 membrane	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: Generic "membrane" annotation is too unspecific given the well-supported mitochondrial inner membrane localization captured by other annotations (IDA, IEA, TAS). Overannotation - the more specific GO:0005743 should be used instead. Reason: Per project curation guidelines, when a more specific compartment term is supported, the generic "membrane" term should not be a primary annotation. Falcon and openai both consistently place CYC1 at the inner mitochondrial membrane.
GO:0020037 heme binding	IEA GO_REF:0000002	ACCEPT	Summary: Heme binding is a core molecular function of CYC1. Cytochrome c1 contains a single covalently attached c-type heme (heme c1) ligated via the conserved CXXCH motif by holocytochrome c synthase (HCCS). Reason: Defining feature of the cytochrome c1 fold. Falcon: cytochrome c1 contains "a single c-type heme, heme c1, covalently attached and exposed for rapid electron transfer to cytochrome c." Supporting Evidence: file:human/CYC1/CYC1-deep-research-falcon.md Cytochrome c1 contains a single c-type heme, heme c1, covalently attached and exposed for rapid electron transfer to cytochrome c.
GO:0046872 metal ion binding	IEA GO_REF:0000043	MARK AS OVER ANNOTATED	Summary: Generic "metal ion binding" annotation is redundant with the more informative "heme binding" (GO:0020037), which already captures the Fe coordination by the c-type heme. Also derived via GO_REF:0000043 (UniProt keyword mapping) which has been deprecated for newer annotations. Reason: Heme binding subsumes the Fe coordination biology. Per project guidelines, avoid generic terms when a precise term exists. No evidence CYC1 binds metal ions outside the heme c1 cofactor.
GO:1902600 proton transmembrane transport	IEA GO_REF:0000108	MARK AS OVER ANNOTATED	Summary: Proton translocation by complex III is performed by the Q-cycle chemistry at the Qo and Qi sites of cytochrome b, not by CYC1 itself. This term was inferred logically from EC 7.1.1.8 (assigned to CYC1 via GO:0008121) but does not reflect a CYC1 subunit-specific activity. Overannotation at the subunit level. Reason: Falcon and openai both make clear that "cytochrome c1 itself does not directly bind quinone or pump protons" - CYC1's role is purely electron transfer. Inter-ontology logical inference from EC 7.1.1.8 propagates this whole-complex activity inappropriately to the cyt c1 subunit. Supporting Evidence: file:human/CYC1/CYC1-deep-research-falcon.md Although cytochrome c1 itself does not directly bind quinone or pump protons, it is an indispensable part of this proton-coupled electron transfer.
GO:0005515 protein binding	IPI PMID:17500595 Huntingtin interacting proteins are genetic modifiers of neu...	MARK AS OVER ANNOTATED	Summary: IntAct interaction with huntingtin (HTT, P42858) from a yeast-two-hybrid screen of Huntingtin interactors. Generic "protein binding" is uninformative and likely represents either an aggregation-related capture (HTT polyQ pulldown) or a high-throughput false positive rather than a physiological CYC1 binding partner. Reason: Per project curation guidelines, the generic "protein binding" (GO:0005515) term should be avoided in favor of more specific MF terms. CYC1's physiologically meaningful partners are its complex III co-subunits and cytochrome c, all of which are captured under respiratory chain complex III membership.
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MARK AS OVER ANNOTATED	Summary: IntAct interaction with KRT9 (P14927) from a large-scale human interactome map (BioPlex/Huttlin). Likely a high-throughput affinity capture artifact (keratin contamination is a well-known proteomic nuisance). Generic "protein binding" is uninformative for CYC1. Reason: Generic protein binding term, with the specific interactor being a common HT-AP-MS contaminant. CYC1's true binding partners (Rieske protein, cytochrome b, cytochrome c) are well captured by the respiratory chain complex III membership annotation.
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	MARK AS OVER ANNOTATED	Summary: IntAct interactions from a neurodegenerative-disease interactome screen (HTT/P42858, ATXN1/Q16342, ATXN3-3/Q8IWZ3-3). All partners are polyQ disease proteins; capture likely reflects co-aggregation or screen-specific bait rather than a physiological CYC1 binding function. Generic "protein binding" is uninformative. Reason: Same rationale as other IPI protein binding annotations: generic term, non-physiological partners. CYC1 has no established direct role in polyQ-aggregate biology.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: IntAct interaction with KRT9 (P14927) from BioPlex 3.0 cell-specific interactome maps. Same likely keratin contamination as PMID:28514442. Generic "protein binding" is uninformative. Reason: Generic protein binding term, partner likely an AP-MS contaminant. Per project guidelines, prefer more specific MF terms.
GO:0005739 mitochondrion	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Orthology-transferred annotation from mouse Cyc1. While true at a coarse level, the more specific mitochondrial inner membrane (GO:0005743) localization is well-supported and is the appropriate primary location. Reason: Mitochondrial inner membrane (GO:0005743) is the precise compartment; "mitochondrion" is too broad.
GO:0033762 response to glucagon	IEA GO_REF:0000107	REMOVE	Summary: Orthology-transferred annotation from rat Cyc1 (UniProtKB:D3ZFQ8) via Ensembl Compara. The original rat annotation likely derives from a glucagon-treated proteomics or expression study; this does not reflect a direct biological role of human CYC1 in glucagon signaling. Spurious annotation propagated by orthology. Reason: Neither falcon nor openai deep research describes any role for CYC1 in glucagon response. CYC1 is a constitutive OXPHOS structural/redox subunit; "response to glucagon" is at best a transcriptional/abundance correlate of OXPHOS in glucagon-stimulated tissues and not a function of cytochrome c1. No human experimental support exists.
GO:0045275 respiratory chain complex III	IEA GO_REF:0000107	ACCEPT	Summary: Orthology-transferred complex membership. Same conclusion as the IBA and IPI annotations - CYC1 is a core subunit of respiratory chain complex III. Reason: Independent corroboration of the core complex membership annotation. Supporting Evidence: file:human/CYC1/CYC1-deep-research-falcon.md cytochrome c1 is one of the three evolutionarily conserved catalytic subunits together with cytochrome b and the Rieske Fe-S protein.
GO:0005743 mitochondrial inner membrane	IDA PMID:28844695 Architecture of Human Mitochondrial Respiratory Megacomplex ...	ACCEPT	Summary: Direct experimental localization of CYC1 at the inner mitochondrial membrane via cryo-EM structure determination of the human respiratory megacomplex I2III2IV2 (Guo et al. 2017, ComplexPortal annotation). Highest-confidence evidence for this localization. Reason: Structural visualization in situ. Core localization annotation. Supporting Evidence: PMID:28844695 Architecture of Human Mitochondrial Respiratory Megacomplex I(2)III(2)IV(2).
GO:0006122 mitochondrial electron transport, ubiquinol to cytochrome c	NAS PMID:28844695 Architecture of Human Mitochondrial Respiratory Megacomplex ...	ACCEPT	Summary: ComplexPortal NAS annotation. The biological process is the canonical Complex III function and CYC1 is a direct participant. Core annotation. Reason: Consistent with IBA and with all primary biochemical and structural literature on cytochrome c1. Supporting Evidence: file:human/CYC1/CYC1-deep-research-falcon.md CYC1 acts specifically within the electron transport chain (ETC) as part of complex III, connecting the membrane quinone pool (CoQ/QH2) to the cytochrome c pool
GO:0045275 respiratory chain complex III	IPI PMID:28844695 Architecture of Human Mitochondrial Respiratory Megacomplex ...	ACCEPT	Summary: ComplexPortal IPI annotation from structural identification of CYC1 as a subunit of the megacomplex I2III2IV2. Core complex membership. Reason: Direct structural evidence places CYC1 in the dimeric Complex III within the respirasome. Supporting Evidence: PMID:28844695 Architecture of Human Mitochondrial Respiratory Megacomplex I(2)III(2)IV(2).
GO:0045333 cellular respiration	NAS PMID:28844695 Architecture of Human Mitochondrial Respiratory Megacomplex ...	KEEP AS NON CORE	Summary: Cellular respiration is a parent process of mitochondrial electron transport (GO:0006122) and oxidative phosphorylation. True but too general - the specific GO:0006122 already captures CYC1's role. Retain as a peripheral/non-core annotation. Reason: Technically correct but redundant with the more precise GO:0006122 and the complex III membership annotations.
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	MARK AS OVER ANNOTATED	Summary: High-throughput mitochondrial proteome profiling. Confirms mitochondrial localization but at a level less specific than the inner-membrane annotations. Overannotation at the parent compartment. Reason: Mitochondrial inner membrane (GO:0005743) is the appropriate compartment annotation; "mitochondrion" is too broad given strong evidence for IMM localization.
GO:0016020 membrane	HDA PMID:19946888 Defining the membrane proteome of NK cells.	MARK AS OVER ANNOTATED	Summary: High-throughput membrane proteome of NK cells. Generic membrane is too unspecific given strong evidence for inner mitochondrial membrane localization. Reason: GO:0005743 captures the precise compartment. HTP membrane proteome studies cannot distinguish IMM from other membranes.
GO:0005634 nucleus	HDA PMID:21630459 Proteomic characterization of the human sperm nucleus.	MARK AS OVER ANNOTATED	Summary: High-throughput sperm-nucleus proteome (Asia et al.). Detection of CYC1 in a sperm-nucleus fraction is almost certainly mitochondrial contamination (sperm contain a mitochondrial sheath that fractionates with nuclear preparations) rather than a genuine nuclear localization. No biological role for CYC1 in the nucleus is supported by any primary literature or by either deep research report. Reason: Cytochrome c1 was detected in a proteomic characterization of the human sperm nucleus. The detection is a real observation, but cytochrome c1 is a presequence-targeted subunit of respiratory complex III anchored in the mitochondrial inner membrane, with no described nuclear role, and sperm nuclear preparations carry over abundant mitochondrial proteins from the midpiece. With no independent support the nuclear term over-reads the proteomic hit; it has not been refuted, so it is not removed. Supporting Evidence: file:human/CYC1/CYC1-deep-research-falcon.md CYC1 is a mitochondrial inner membrane protein. Its heme-containing domain projects into the intermembrane space
GO:0005739 mitochondrion	HDA PMID:20833797 Phosphoproteome analysis of functional mitochondria isolated...	MARK AS OVER ANNOTATED	Summary: High-throughput mitochondrial phosphoproteome of human muscle. Confirms mitochondrial localization but at parent-compartment level. Reason: GO:0005743 (mitochondrial inner membrane) is the precise compartment.
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-164651	ACCEPT	Summary: Reactome TAS for the human "Electron transfer from ubiquinol to cytochrome c of complex III" reaction places CYC1 at the inner mitochondrial membrane. Core localization. Reason: Reactome's biochemical reaction model is consistent with all structural and biochemical evidence for cytochrome c1.
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-9906017	ACCEPT	Summary: Reactome TAS for the UQCRFS1 maturation pathway (peptidase cleavage of the UQCRFS1 N-terminal fragment) places CYC1 at the IMM as part of the maturing Complex III. Consistent core localization. Reason: Reactome pathway places CYC1 within Complex III at the IMM during complex assembly/maturation.
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-9906042	ACCEPT	Summary: Reactome TAS for the TTC19-mediated clearance of UQCRFS1 fragments from Complex III. Places CYC1 at the IMM as part of Complex III. Core localization. Reason: Same compartment as confirmed by structural, IDA, and other TAS evidence.
GO:0005739 mitochondrion	TAS PMID:2536365 Structural organization of the human mitochondrial cytochrom...	MARK AS OVER ANNOTATED	Summary: Traceable author statement from the original CYC1 gene cloning paper (Suzuki et al. 1989) describing CYC1 as a mitochondrial cytochrome c1 gene. While correct, "mitochondrion" is less specific than the well-supported inner mitochondrial membrane annotation. Reason: GO:0005743 (mitochondrial inner membrane) is the appropriate, more specific compartment; "mitochondrion" should not be the primary location annotation.

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Existing Annotations Review

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