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.	REMOVE	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 has no plausible nuclear function. Its mature form is targeted to mitochondria via an N-terminal cleaved presequence, anchored to the inner mitochondrial membrane, and matures via HCCS-dependent heme c attachment in the IMS. Falcon: "CYC1 is a mitochondrial inner membrane protein." This annotation is an HT-proteomics artifact. 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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