ETFA

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005739 mitochondrion	IBA GO_REF:0000033	ACCEPT	Summary: ETFA is a mitochondrial protein; the organelle term is correct and is kept beside the matrix term. Reason: PAINT IBA (GO_REF:0000033) from the IBD on node PANTHER:PTN000097952. The organelle claim holds: the human protein carries a mitochondrial targeting route and is a matrix component of the ETF system (Reactome R-HSA-169260; UniProt SUBCELLULAR LOCATION Mitochondrion matrix), and mitochondrial location is the ancestral state of the eukaryotic ETF clade on which the node sits. Under the root-organelle policy the mitochondrion term is informative and is kept beside the sub-compartment rather than replaced: the matrix is already recorded by the GO:0005759 rows in this review. The earlier MODIFY-to-matrix verdict is withdrawn for that reason; the IBD node placement is not in dispute. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000097952 SUPPORTS TRANSFER IBD node and target ancestry support mitochondrial location; the organelle term is kept and the matrix is recorded separately. Supporting Evidence: PMID:8617498 Electron transfer flavoprotein (composed of alpha and beta subunits) is an obligatory electron acceptor for several dehydrogenases and is located in the mitochondrial matrix. Reactome:R-HSA-169260 Electron transfer flavoprotein (ETF) is a 63kDa heterodimer composed of alpha and beta subunits and binds one FAD and one AMP per dimer. ETF resides on the matrix face of the mitochondrial inner membrane. Reactome:R-HSA-169270 ETF-ubiquinone oxidoreductase (ETFDH), catalyses the re-oxidation of reduced ETF, with ubiquinone (CoQ) as the electron acceptor being reduced to ubiquinol (QH2)
GO:0009055 electron transfer activity	IBA GO_REF:0000033	ACCEPT	Summary: ETFA supplies the FAD-containing electron-transfer component of the human ETF heterodimer. Reason: The actual electron-transfer IBD at PTN000097951 is ancestral to human leaf PTN002534683, whose canonical alignment is exact. Its current IBD donor field lists human P13804, whereas the preserved GOA source also lists fly FBgn0010516; this is a version boundary, not circularity or evidence that the target is misplaced. Current fly Q7KN94/wal identity and its experimental source record were traced, but its original assay was not read here. Independent human evidence is direct: PMID:25416781 Methods and Figure 5 use untagged mature Δ19-ETFα with His6-ETFβ, receiving electrons from MCAD or GCDH and transferring them to DCIP. PMID:8962055 resolves the FAD-binding alpha domain in the human heterodimer. These establish the alpha subunit’s functional contribution, not autonomous isolated-alpha turnover or a test of the 284-residue product. The DCIP experiment does not itself measure ETFDH/ubiquinone reduction. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000097951 SUPPORTS TRANSFER Actual node/target ancestry and human sequence are verified; independent human heterodimer assays support the assertion. Current IBD versus captured GOA donor-list difference is preserved, and target self-evidence is legitimate. Supporting Evidence: PMID:10423253 Electron-transfer flavoprotein (ETF) serves as an intermediate electron carrier between primary flavoprotein dehydrogenases and terminal respiratory chains in mitochondria and prokaryotic cells. PMID:25416781 ETF acts as a mobile electron carrier that shuttles electrons between several FAD-containing dehydrogenases present in the mitochondrial matrix and the membrane-bound ETF:quinone oxidoreductase PMID:8962055 They function as electron shuttles between primary flavoprotein dehydrogenases involved in mitochondrial fatty acid and amino acid catabolism and the membrane-bound electron transfer flavoprotein ubiquinone oxidoreductase.
GO:0033539 fatty acid beta-oxidation using acyl-CoA dehydrogenase	IBA GO_REF:0000033	ACCEPT	Summary: ETFA contributes electron transfer to acyl-CoA-dehydrogenase-dependent fatty-acid beta-oxidation. Reason: The actual GO:0033539 IBD at PTN000097951 includes human P13804 evidence and is on the verified target ancestry; self-WITH is valid. The current term describes the beta-oxidation route initiated by acyl-CoA dehydrogenase. PMID:25416781 Methods and Figure 5 directly show recombinant human mature ETFα/β-dependent electron flow during MCAD oxidation of octanoyl-CoA, using DCIP as the terminal assay acceptor. R-HSA-169260 independently models the human ETF electron-accepting step in this pathway. ETFA performs electron-carrier work through its FAD-containing heterodimer, rather than merely being required by a perturbation phenotype; MCAD performs the acyl-CoA oxidation. The isolated assay is not complete beta-oxidation or respiratory-flux reconstitution and does not test the shorter natural ETFA product. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000097951 SUPPORTS TRANSFER Exact IBD/node placement and canonical alignment support transfer; actual human MCAD-to-ETF assay supplies target participation evidence. Supporting Evidence: PMID:9334218 Among these dehydrogenases are the four chain length-specific flavoprotein dehydrogenases of fatty acid beta-oxidation. PMID:25416781 Some of these dehydrogenases, e.g. medium chain acyl-CoA dehydrogenase (MCAD), are involved in β-oxidation of fatty acids Reactome:R-HSA-169260 Reducing equivalents from the beta-oxidation of fatty acyl CoAs are transferred to ETF, reducing the ETF-bound FAD to FADH2
GO:0050660 flavin adenine dinucleotide binding	IBA GO_REF:0000033	ACCEPT	Summary: The human ETFA alpha domain directly binds the ETF FAD cofactor. Reason: The actual FAD-binding IBD at PTN000097951 is on the P13804 target path and cites human descendant evidence; the 333-residue target alignment is exact and no target-path IBD NOT is present. PMID:8962055 Results, Description of Cofactor Binding Sites and Figure 4 caption resolve most FAD contacts in alpha domain II, including contacts to the isoalloxazine, pyrophosphate and adenosine portions, with additional beta-subunit contacts. AMP is instead buried in beta domain III. Thus FAD binding is target-specific within the heterodimer, not inferred simply from a generic flavoprotein name or reassigned from AMP. No separate binding measurement or functional equivalence is claimed for the 284-residue isoform. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000097951 SUPPORTS TRANSFER Verified IBD/target descent and exact sequence; actual human structural alpha–FAD contacts independently ground the inherited binding assertion. Human self-WITH is expected. Supporting Evidence: PMID:8962055 FAD lies in a cleft between the two subunits, with most of the FAD molecule residing in the C-terminal portion of the alpha subunit.
GO:0005739 mitochondrion	IEA GO_REF:0000117	ACCEPT	Summary: ETFA is a mitochondrial protein; the organelle term is correct and is kept beside the matrix term. Reason: Historical ARBA-based IEA row (GO_REF:0000117), retired from current GOA. The mitochondrial location is correct for ETFA and is supported by curated literature and Reactome independently of the rule. Under the root-organelle policy the mitochondrion term is kept rather than replaced by the matrix term, which this review records separately (GO:0005759 rows); the earlier MODIFY-to-matrix verdict is withdrawn. Supporting Evidence: Reactome:R-HSA-169260 Electron transfer flavoprotein (ETF) is a 63kDa heterodimer composed of alpha and beta subunits and binds one FAD and one AMP per dimer. ETF resides on the matrix face of the mitochondrial inner membrane. Reactome:R-HSA-169270 ETF-ubiquinone oxidoreductase (ETFDH), catalyses the re-oxidation of reduced ETF, with ubiquinone (CoQ) as the electron acceptor being reduced to ubiquinol (QH2)
GO:0005759 mitochondrial matrix	IEA GO_REF:0000044	ACCEPT	Summary: ETFA is a mitochondrial matrix protein. Reason: The actual UniProt subcellular-location source SL-0170 explicitly maps mitochondrion matrix to GO:0005759. The human P13804 record carries this location with PMID:3760196 provenance; that original experiment was not read in this database lane. Independently, both inspected human Reactome events reach ETFA physical entity 169262, whose own compartment is mitochondrial matrix. Thus the target-level matrix assertion is supported without inferring it from the HPA images or the event-level compartment alone. UniProt transit-peptide processing remains separate from alternative splicing, and the two natural products are not assumed to have equivalent localization. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0170 SUPPORTS TRANSFER Current official location definition and GO mapping are exact; the target UniProt record and human Reactome participant independently agree. Supporting Evidence: PMID:8617498 Electron transfer flavoprotein (composed of alpha and beta subunits) is an obligatory electron acceptor for several dehydrogenases and is located in the mitochondrial matrix. Reactome:R-HSA-169260 Electron transfer flavoprotein (ETF) is a 63kDa heterodimer composed of alpha and beta subunits and binds one FAD and one AMP per dimer. ETF resides on the matrix face of the mitochondrial inner membrane. Reactome:R-HSA-169270 ETF-ubiquinone oxidoreductase (ETFDH), catalyses the re-oxidation of reduced ETF, with ubiquinone (CoQ) as the electron acceptor being reduced to ubiquinol (QH2)
GO:0009055 electron transfer activity	IEA GO_REF:0000002	ACCEPT	Summary: The InterPro ETF-alpha family mapping is supported by human electron-transfer assays. Reason: Current IPR001308 is the electron transfer flavoprotein alpha subunit/FixB family and explicitly maps GO:0009055. The actual reviewed human P13804 match spans residues 14–332 of the 333-residue sequence. Family membership is corroborated by target experiments: PMID:25416781 Methods and Figure 5 assay recombinant mature Δ19-ETFα/His6-ETFβ electron transfer from MCAD or GCDH to artificial DCIP, while PMID:8962055 resolves the alpha FAD-binding domain within the heterodimer. This is ETF electron-carrier activity; it is not the separate ETFDH ubiquinone-reductase reaction, an isolated-alpha assay or functional validation of both natural products. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR001308 SUPPORTS TRANSFER Actual family-to-GO mapping and exact human match were inspected, with independent target biochemical and structural corroboration. Supporting Evidence: PMID:10423253 Electron-transfer flavoprotein (ETF) serves as an intermediate electron carrier between primary flavoprotein dehydrogenases and terminal respiratory chains in mitochondria and prokaryotic cells. PMID:25416781 ETF acts as a mobile electron carrier that shuttles electrons between several FAD-containing dehydrogenases present in the mitochondrial matrix and the membrane-bound ETF:quinone oxidoreductase PMID:8962055 They function as electron shuttles between primary flavoprotein dehydrogenases involved in mitochondrial fatty acid and amino acid catabolism and the membrane-bound electron transfer flavoprotein ubiquinone oxidoreductase.
GO:0050660 flavin adenine dinucleotide binding	IEA GO_REF:0000002	ACCEPT	Summary: The mapped ETF-alpha family’s FAD binding is directly supported in the human structure. Reason: Current IPR001308 explicitly maps GO:0050660 and matches reviewed human P13804 residues 14–332. The source family spans ETF-alpha/FixB proteins, so the human claim was checked independently rather than inferred from the family label alone. PMID:8962055 Description of ETF Polypeptide Fold and Cofactor Binding Sites resolves FAD predominantly in alpha domain II, with defined alpha contacts and some beta contacts; the AMP site is within beta domain III. This supports FAD binding by ETFA in the heterodimer and does not imply isolated-alpha activity, independent AMP binding or identical behavior of the shorter natural product. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR001308 SUPPORTS TRANSFER Exact current GO mapping and human sequence match were inspected; human structural cofactor contacts corroborate the prediction. Supporting Evidence: PMID:8962055 FAD lies in a cleft between the two subunits, with most of the FAD molecule residing in the C-terminal portion of the alpha subunit.
GO:0005515 protein binding	IPI PMID:24606901 Cochaperone binding to LYR motifs confers specificity of iro...	REMOVE	Summary: Bare protein-binding row; removed as uninformative under the protein-binding policy. Reason: Bare GO:0005515 protein binding is removed under the protein-binding policy because it conveys no functional information. Removal does not mean the reported interaction is false. The HSCB (HSC20) yeast two-hybrid screen hit was not individually validated for ETFA in the main text, and no informative MF (ETFA is not an Fe-S protein) follows from it. Supporting Evidence: PMID:24606901 We conducted a high-throughput yeast two-hybrid (Y2H) screen to search the human proteome for interacting partners of HSC20, aiming to identify Fe-S proteins and specific molecular recognition motifs that guide targeting of Fe-S clusters to appropriate recipients.
GO:0005515 protein binding	IPI PMID:26618866 ∆F508 CFTR interactome remodelling promotes rescue of cystic...	REMOVE	Summary: Bare protein-binding row; removed as uninformative under the protein-binding policy. Reason: Bare GO:0005515 protein binding is removed under the protein-binding policy because it conveys no functional information. Removal does not mean the reported interaction is false. ETFA appears in a CFTR co-purification interactome that the authors state contains direct and indirect interactors; no ETFA-specific function toward CFTR is shown. Supporting Evidence: PMID:26618866 These 638 proteins form the core CFTR interactome, and represent direct as well as indirect CFTR interactors (Supplementary Table S1–S3).
GO:0005515 protein binding	IPI PMID:27499296 Mitochondrial Protein Interaction Mapping Identifies Regulat...	MODIFY	Summary: The ETFB association is specifically formation of the ETF alpha/beta heterodimer. Reason: PMID:27499296 Figure 5 and the corresponding purification Methods study LYRM5 with ETF alpha/beta and recover a stable recombinant complex; current curated interaction records retain the ETFA–ETFB pair. Independently, the actual human ETF structure in PMID:8962055 Methods and Results resolves the extensive interface between unlike alpha and beta subunits. The current GO:0046982 definition directly describes binding a nonidentical protein to form a heterodimer, so it is more informative than generic binding. The structural and biochemical evidence concerns the assembled human ETF system; it does not demonstrate autonomous alpha-subunit activity or equivalence of the 284-residue alternative product. Proposed replacements: protein heterodimerization activity Supporting Evidence: PMID:27499296 We also establish LYRM5 as a “deflavinase” that directly regulates the electron transferring flavoprotein (ETF) PMID:8962055 Mammalian electron transfer flavoproteins (ETF) are heterodimers containing a single equivalent of flavin adenine dinucleotide (FAD).
GO:0005515 protein binding	IPI PMID:28380382 A Single Adaptable Cochaperone-Scaffold Complex Delivers Nas...	REMOVE	Summary: Bare protein-binding row; removed as uninformative under the protein-binding policy. Reason: Bare GO:0005515 protein binding is removed under the protein-binding policy because it conveys no functional information. Removal does not mean the reported interaction is false. The HSC20/HSCB co-immunoprecipitation proteomics concerns Fe-S cluster delivery to respiratory complexes; ETFA is a screen partner without an informative function. Supporting Evidence: PMID:28380382 Here we report that a transient subcomplex involved in CIII assembly, composed of LYRM7 bound to UQCRFS1, interacts with components of an Fe-S transfer complex, consisting of HSC20, its cognate chaperone HSPA9, and the holo-scaffold ISCU.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MODIFY	Summary: The BioPlex ETFB association corresponds to ETF heterodimerization. Reason: PMID:33961781 Methods establish human ORFeome affinity purification/mass spectrometry in 293T and HCT116 cells, and current IntAct target records identify the ETFA–ETFB pair. The full original screen table and exact clone sequence were not independently recovered. Nevertheless, the same partner-specific claim is resolved positively by the actual human ETF alpha/beta interface in PMID:8962055. Refine to protein heterodimerization activity rather than claiming that an AP-MS edge alone proves a direct interface. This does not assign all natural ETFA products the same interaction. Proposed replacements: protein heterodimerization activity Supporting Evidence: PMID:33961781 The first, BioPlex 3.0, results from affinity purification of 10,128 human proteins-half the proteome-in 293T cells and includes 118,162 interactions among 14,586 proteins. PMID:8962055 Mammalian electron transfer flavoproteins (ETF) are heterodimers containing a single equivalent of flavin adenine dinucleotide (FAD).
GO:0005515 protein binding	IPI PMID:35156780 CFTR interactome mapping using the mammalian membrane two-hy...	REMOVE	Summary: Bare protein-binding row; removed as uninformative under the protein-binding policy. Reason: Bare GO:0005515 protein binding is removed under the protein-binding policy because it conveys no functional information. Removal does not mean the reported interaction is false. ETFA was an initial MaMTH screen hit for CFTR whose own luciferase retests were unconfirmed in the paper's datasets; no informative function follows. Supporting Evidence: PMID:35156780 The MaMTH technology is a split ubiquitin‐based assay for measurement of the protein–protein interactions (PPIs) of full‐length integral membrane proteins directly in the context of living mammalian cells
GO:0005515 protein binding	IPI PMID:36012204 Differential CFTR-Interactome Proximity Labeling Procedures ...	REMOVE	Summary: Bare protein-binding row; removed as uninformative under the protein-binding policy. Reason: Bare GO:0005515 protein binding is removed under the protein-binding policy because it conveys no functional information. Removal does not mean the reported interaction is false. CFTR proximity labeling marks neighbouring proteins rather than binding partners, and ETFA was not enriched over controls in the reviewed tables. Supporting Evidence: PMID:36012204 These include, among others, BioID, TurboID and APEX2 proximity labeling enzymes [32,33,34,35], which are fused to the protein of interest.
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	MODIFY	Summary: The original AP-MS ETFB–ETFA edge supports the independently established heterodimer. Reason: PMID:40205054 Methods describe human U2OS HA/FLAG affinity purification/mass spectrometry separately from imaging, fractionation and predicted structures. Its published NDEx AP-MS network has the exact ETFB-to-ETFA edge 629908, linking the stable human gene identifiers ENSG00000105379 and ENSG00000140374. This is the experimental network, not an AlphaFold prediction or membership in the broad mitochondrial assembly. The actual human structure in PMID:8962055 independently resolves the alpha/beta interface, justifying GO:0046982 protein heterodimerization activity. Exact AP-MS clone sequences were not verified, and no alternative-product equivalence is inferred. Proposed replacements: protein heterodimerization activity Supporting Evidence: PMID:40205054 A total of 2,174 proteins were successfully tagged and isolated from U2OS whole-proteome extracts using affinity purification, and interacting partners were identified by tandem MS (AP–MS) to yield a total of 36,842 interactions among 7,543 proteins PMID:8962055 Mammalian electron transfer flavoproteins (ETF) are heterodimers containing a single equivalent of flavin adenine dinucleotide (FAD).
GO:0005759 mitochondrial matrix	IDA PMID:3760196 Biosynthesis of electron transfer flavoprotein in a cell-fre...	ACCEPT	Summary: ETFA belongs to the mitochondrial matrix ETF system. Reason: The actual PMID:3760196 Methods, Results and Figures 1–6 show rat-liver mRNA translation followed by import into isolated rat mitochondria, and separate endogenous human fibroblast precursor-processing experiments using uncouplers and recovery. These establish the mitochondrial precursor/mature relationship, not direct human matrix subfractionation or the exact 19-residue cleavage site. The matrix assignment is independently explicit for human ETFA in Reactome entity 169262 and UniProt SL-0170. Accept the established compartment while keeping the measured rat/human experiments and curated matrix specificity distinct. Disease-associated short bands are not identified as the natural 284-residue splice product. Supporting Evidence: PMID:3760196 alpha-ETF was synthesized as a precursor (p alpha-ETF), 3,000 mol wt larger than its mature counterpart, and was translocated into the mitochondria and processed to the mature alpha-ETF. Reactome:R-HSA-169260 Electron transfer flavoprotein (ETF) is a 63kDa heterodimer composed of alpha and beta subunits and binds one FAD and one AMP per dimer. ETF resides on the matrix face of the mitochondrial inner membrane. Reactome:R-HSA-169270 ETF-ubiquinone oxidoreductase (ETFDH), catalyses the re-oxidation of reduced ETF, with ubiquinone (CoQ) as the electron acceptor being reduced to ubiquinol (QH2)
GO:0009055 electron transfer activity	IDA PMID:9334218 Expression and characterization of two pathogenic mutations ...	ACCEPT	Summary: Electron transfer is supported by independent actual human ETF experiments. Reason: The accessible PMID:9334218 abstract describes recombinant human ETFalpha T266M/G116R variants, flavin spectroscopy and dehydrogenase/ETF-QO electron-transfer assays; the operative original remained inaccessible. The molecular function is nevertheless established by the actual human ETF alpha/beta DCIP assays in PMID:25416781 and the FAD-bearing alpha structure in PMID:8962055. No uninspected kinetic detail or mutant assay is represented as independently verified. The directly measured activity belongs to the assembled human ETF alpha/beta heterodimer, whose FAD-binding alpha domain is resolved in PMID:8962055. It does not establish autonomous isolated-alpha turnover, activity of the 284-residue alternative product, or ETFDH’s separate ubiquinone-reductase chemistry. Supporting Evidence: PMID:9334218 In this disease, electron transfer from nine primary flavoprotein dehydrogenases to the main respiratory chain is impaired. PMID:25416781 ETF acts as a mobile electron carrier that shuttles electrons between several FAD-containing dehydrogenases present in the mitochondrial matrix and the membrane-bound ETF:quinone oxidoreductase PMID:8962055 They function as electron shuttles between primary flavoprotein dehydrogenases involved in mitochondrial fatty acid and amino acid catabolism and the membrane-bound electron transfer flavoprotein ubiquinone oxidoreductase.
GO:0005759 mitochondrial matrix	NAS PMID:8504797 cDNA cloning and mitochondrial import of the beta-subunit of...	ACCEPT	Summary: The matrix location is established independently of this historical ETFB-focused citation. Reason: The accessible PMID:8504797 abstract describes human ETFB cloning and import into mitochondria without a cleavable leader; its complete operative text was not recovered. Its focus does not prove that the original ETFA assertion was misattributed. Human ETFA matrix localization is independently explicit in Reactome entity 169262/P13804 and the UniProt SL-0170 mapping, with actual alpha-precursor import/processing experiments in PMID:3760196 as compatible evidence. Accept the location without representing the unavailable paper as an ETFA-specific import assay or extending the result to both natural products. Supporting Evidence: PMID:8504797 Incubation with intact mitochondria indicates that the cDNA-encoded beta-ETF polypeptide contains the information necessary to reach the mitochondrial matrix. PMID:3760196 alpha-ETF was synthesized as a precursor (p alpha-ETF), 3,000 mol wt larger than its mature counterpart, and was translocated into the mitochondria and processed to the mature alpha-ETF. Reactome:R-HSA-169260 Electron transfer flavoprotein (ETF) is a 63kDa heterodimer composed of alpha and beta subunits and binds one FAD and one AMP per dimer. ETF resides on the matrix face of the mitochondrial inner membrane. Reactome:R-HSA-169270 ETF-ubiquinone oxidoreductase (ETFDH), catalyses the re-oxidation of reduced ETF, with ubiquinone (CoQ) as the electron acceptor being reduced to ubiquinol (QH2)
GO:0009063 amino acid catabolic process	IDA PMID:25416781 Human METTL20 is a mitochondrial lysine methyltransferase th...	ACCEPT	Summary: ETFA performs electron-carrier work during amino-acid catabolism. Reason: PMID:25416781 Methods and Figure 5 assay the actual transfer of electrons from recombinant human glutaryl-CoA dehydrogenase supplied with glutaryl-CoA through mature ETFalpha/ETFbeta to DCIP. Thus ETF participates in the redox step used by glutaryl-CoA catabolism; this is direct biochemical work, not merely a knockout requirement. GCDH performs substrate dehydrogenation, while ETF supplies the electron-carrier step. The isolated reaction does not reconstruct the complete amino-acid degradation pathway and does not test the alternative 284-residue ETFA product. The broad amino-acid catabolic term is retained because ETF receives electrons from several amino-acid dehydrogenase systems, including GCDH and isovaleryl-CoA dehydrogenase, as described in the two originals. A single lysine- or glutaryl-CoA-specific descendant would narrow that biological scope; the directly reconstituted assay here is specifically the GCDH reaction. Supporting Evidence: PMID:25416781 others, including glutaryl-CoA dehydrogenase (GCDH) and isovaleryl-CoA dehydrogenase, are involved in the oxidation of amino acids PMID:8962055 They function as electron shuttles between primary flavoprotein dehydrogenases involved in mitochondrial fatty acid and amino acid catabolism and the membrane-bound electron transfer flavoprotein ubiquinone oxidoreductase.
GO:0022904 respiratory electron transport chain	IDA PMID:25416781 Human METTL20 is a mitochondrial lysine methyltransferase th...	ACCEPT	Summary: ETFA carries reducing equivalents into the ETF-linked respiratory electron-transfer route. Reason: The actual PMID:25416781 experiment establishes electron flow through human mature ETFalpha/ETFbeta from MCAD or GCDH to artificial DCIP, not direct oxygen consumption or an ETFDH/ubiquinone assay. Its physiological interpretation is supported by the current human Reactome route: ETF accepts reducing equivalents in R-HSA-169260 and passes them to ETFDH in R-HSA-169270; ETFDH, not ETFA, performs the modeled ubiquinone-reductase reaction. ETFA supplies the FAD-containing redox carrier that does work in this route, rather than being a passive consumed substrate. Accept participation at this bounded level without assigning all respiratory-chain chemistry or autonomous alpha catalysis. Supporting Evidence: PMID:25416781 In summary, ETF is involved in oxidation of several types of metabolites, and, in addition to complexes I and II, it is the third major provider of electrons to the ubiquinone pool of the mitochondrial respiratory chain. PMID:8962055 They function as electron shuttles between primary flavoprotein dehydrogenases involved in mitochondrial fatty acid and amino acid catabolism and the membrane-bound electron transfer flavoprotein ubiquinone oxidoreductase. Reactome:R-HSA-169260 Electron transfer flavoprotein (ETF) is a 63kDa heterodimer composed of alpha and beta subunits and binds one FAD and one AMP per dimer. ETF resides on the matrix face of the mitochondrial inner membrane. Reactome:R-HSA-169270 ETF-ubiquinone oxidoreductase (ETFDH), catalyses the re-oxidation of reduced ETF, with ubiquinone (CoQ) as the electron acceptor being reduced to ubiquinol (QH2)
GO:0033539 fatty acid beta-oxidation using acyl-CoA dehydrogenase	IDA PMID:25416781 Human METTL20 is a mitochondrial lysine methyltransferase th...	ACCEPT	Summary: ETFA provides the electron-carrier step used by acyl-CoA dehydrogenase-dependent beta-oxidation. Reason: PMID:25416781 Methods and Figure 5 directly assay human MCAD oxidation of octanoyl-CoA coupled to mature ETFalpha/ETFbeta and DCIP reduction. The experiment therefore establishes a biochemical electron-transfer role in the pathway, not just a downstream phenotype. MCAD catalyzes acyl-CoA oxidation and ETF receives/transfers reducing equivalents through its FAD-containing heterodimer. DCIP replaces the downstream physiological acceptor, so the assay is not a complete beta-oxidation cycle or respiratory-flux measurement. No activity is assigned specifically to the untested shorter ETFA product. Supporting Evidence: PMID:25416781 Some of these dehydrogenases, e.g. medium chain acyl-CoA dehydrogenase (MCAD), are involved in β-oxidation of fatty acids PMID:8962055 They function as electron shuttles between primary flavoprotein dehydrogenases involved in mitochondrial fatty acid and amino acid catabolism and the membrane-bound electron transfer flavoprotein ubiquinone oxidoreductase. Reactome:R-HSA-169260 Reducing equivalents from the beta-oxidation of fatty acyl CoAs are transferred to ETF, reducing the ETF-bound FAD to FADH2
GO:0045251 electron transfer flavoprotein complex	IPI PMID:8962055 Three-dimensional structure of human electron transfer flavo...	ACCEPT	Summary: ETFA forms the alpha subunit of the electron-transfer flavoprotein complex. Reason: PMID:8962055 reports the 2.1-Angstrom structure of recombinant human ETF produced from alpha/beta cDNAs in E. coli. The resolved domains form an extensive heterodimer interface, directly establishing complex membership. Residue labels such as alpha Gln21 are the paper’s numbering, not automatically current P13804 coordinates. The characterized reagent is the mature canonical alpha/beta system; the 284-residue alternative product was not structurally characterized. Supporting Evidence: PMID:8962055 Mammalian electron transfer flavoproteins (ETF) are heterodimers containing a single equivalent of flavin adenine dinucleotide (FAD).
GO:0005739 mitochondrion	IDA GO_REF:0000052	ACCEPT	Summary: ETFA is a mitochondrial protein; the organelle term is correct and is kept beside the matrix term. Reason: Human Protein Atlas immunofluorescence (GO_REF:0000052) places ETFA in mitochondria. Whole-organelle co-staining cannot resolve the sub-compartment, so the direct observation is accepted at the organelle level, as the root-organelle policy requires. Matrix localization is recorded separately by the GO:0005759 rows; the earlier MODIFY-to-matrix verdict is withdrawn. Supporting Evidence: Reactome:R-HSA-169260 Electron transfer flavoprotein (ETF) is a 63kDa heterodimer composed of alpha and beta subunits and binds one FAD and one AMP per dimer. ETF resides on the matrix face of the mitochondrial inner membrane. Reactome:R-HSA-169270 ETF-ubiquinone oxidoreductase (ETFDH), catalyses the re-oxidation of reduced ETF, with ubiquinone (CoQ) as the electron acceptor being reduced to ubiquinol (QH2)
GO:0005515 protein binding	IPI PMID:35362222 S1P defects cause a new entity of cataract, alopecia, oral m...	MODIFY	Summary: ETFA co-purifies with MBTPS1/S1P together with ETFB; the informative part is the ETF heterodimer. Reason: The row's partners are ETFB and MBTPS1/S1P. The paper reports that S1P forms a trimeric complex with ETFA/ETFB in human cells and enhances ETF flavination and stability. Bare protein binding is uninformative (protein-binding policy); the informative, independently established part of the claim is the ETFA-ETFB heterodimer (PMID:8962055), so the row is modified to protein heterodimerization activity, consistent with the other ETFB-partner rows in this review. The MBTPS1 association is real but has no informative MF term on the ETF side; it is recorded in suggested_questions rather than as an annotation. Proposed replacements: protein heterodimerization activity Supporting Evidence: PMID:35362222 Furthermore, we found that S1P is a novel mitochondrial protein that forms a trimeric complex with ETFA/ETFB. S1P enhances ETFA/ETFB flavination and maintains its stability. PMID:8962055 Mammalian electron transfer flavoproteins (ETF) are heterodimers containing a single equivalent of flavin adenine dinucleotide (FAD).
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	ACCEPT	Summary: ETFA is a mitochondrial protein; the organelle term is correct and is kept beside the matrix term. Reason: MitoCoP high-confidence mitochondrial proteome (PMID:34800366) assigns ETFA to mitochondria from fractionation proteomics in several human cell lines. Organelle proteomics cannot resolve the sub-compartment, so the row is accepted at the organelle level per the root-organelle policy; matrix localization is recorded separately by the GO:0005759 rows. The earlier MODIFY-to-matrix verdict is withdrawn. Supporting Evidence: PMID:34800366 We defined a human mitochondrial high-confidence proteome (MitoCoP) of 1,134 protein-coding genes, including 91 proteins previously not localized to mitochondria experimentally. Reactome:R-HSA-169260 Electron transfer flavoprotein (ETF) is a 63kDa heterodimer composed of alpha and beta subunits and binds one FAD and one AMP per dimer. ETF resides on the matrix face of the mitochondrial inner membrane. Reactome:R-HSA-169270 ETF-ubiquinone oxidoreductase (ETFDH), catalyses the re-oxidation of reduced ETF, with ubiquinone (CoQ) as the electron acceptor being reduced to ubiquinol (QH2)
GO:0009055 electron transfer activity	IDA PMID:25416781 Human METTL20 is a mitochondrial lysine methyltransferase th...	ACCEPT	Summary: Human ETF alpha/beta directly mediates electron transfer from dehydrogenases. Reason: PMID:25416781 Methods specify human ORFs, untagged mature Δ19-ETFalpha and full-length His6-ETFbeta coexpressed in E. coli. The operative DCIP assay and Figure 5 use MCAD/octanoyl-CoA or GCDH/glutaryl-CoA and measure acceptor reduction at 600 nm; ETFbeta methylation and lysine-mutant controls alter ETF-mediated transfer. DCIP is an artificial terminal acceptor, so this experiment alone is not a reconstruction of ETFDH-to-ubiquinone electron transfer or whole respiratory flux. The directly measured activity belongs to the assembled human ETF alpha/beta heterodimer, whose FAD-binding alpha domain is resolved in PMID:8962055. It does not establish autonomous isolated-alpha turnover, activity of the 284-residue alternative product, or ETFDH’s separate ubiquinone-reductase chemistry. Supporting Evidence: PMID:25416781 ETF acts as a mobile electron carrier that shuttles electrons between several FAD-containing dehydrogenases present in the mitochondrial matrix and the membrane-bound ETF:quinone oxidoreductase PMID:8962055 They function as electron shuttles between primary flavoprotein dehydrogenases involved in mitochondrial fatty acid and amino acid catabolism and the membrane-bound electron transfer flavoprotein ubiquinone oxidoreductase.
GO:0005739 mitochondrion	HDA PMID:20833797 Phosphoproteome analysis of functional mitochondria isolated...	ACCEPT	Summary: ETFA is a mitochondrial protein; the organelle term is correct and is kept beside the matrix term. Reason: Phosphoproteomics of functional mitochondria isolated from human skeletal muscle (PMID:20833797) detected ETFA. Whole-organelle proteomics cannot resolve the sub-compartment, so the row is accepted at the organelle level per the root-organelle policy; matrix localization is recorded separately by the GO:0005759 rows. The earlier MODIFY-to-matrix verdict is withdrawn. Supporting Evidence: PMID:20833797 We performed a phosphoproteomics study of functional mitochondria isolated from human muscle biopsies with the aim to obtain a comprehensive overview of mitochondrial phosphoproteins. PMID:34800366 We defined a human mitochondrial high-confidence proteome (MitoCoP) of 1,134 protein-coding genes, including 91 proteins previously not localized to mitochondria experimentally. PMID:3760196 alpha-ETF was synthesized as a precursor (p alpha-ETF), 3,000 mol wt larger than its mature counterpart, and was translocated into the mitochondria and processed to the mature alpha-ETF. Reactome:R-HSA-169260 Electron transfer flavoprotein (ETF) is a 63kDa heterodimer composed of alpha and beta subunits and binds one FAD and one AMP per dimer. ETF resides on the matrix face of the mitochondrial inner membrane. Reactome:R-HSA-169270 ETF-ubiquinone oxidoreductase (ETFDH), catalyses the re-oxidation of reduced ETF, with ubiquinone (CoQ) as the electron acceptor being reduced to ubiquinol (QH2)
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-169260	ACCEPT	Summary: The beta-oxidation electron-transfer event contains human ETFA in the mitochondrial matrix. Reason: The actual chain is R-HSA-169260 → catalystActivity 169261 → ETF:FAD complex 169267 → component ETFA 169262 → referenceEntity 54490/P13804. ETFA itself, the ETF complex and the reaction are explicitly assigned mitochondrial matrix in the human model. The cofactor-containing heterodimer also includes ETFB 169265/P38117. The ETFA physical entity has startCoordinate 1 and endCoordinate -1, displayed as 1–?; these unresolved model coordinates are not a measured mature-chain boundary. The source supports matrix localization while the distinct human original assays support ETF electron transfer; it does not establish functions for every splice product. Supporting Evidence: Reactome:R-HSA-169260 Electron transfer flavoprotein (ETF) is a 63kDa heterodimer composed of alpha and beta subunits and binds one FAD and one AMP per dimer. ETF resides on the matrix face of the mitochondrial inner membrane. PMID:25416781 ETF acts as a mobile electron carrier that shuttles electrons between several FAD-containing dehydrogenases present in the mitochondrial matrix and the membrane-bound ETF:quinone oxidoreductase
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-169270	ACCEPT	Summary: Reduced and oxidized human ETF retain ETFA in the mitochondrial matrix during electron delivery to ETFDH. Reason: R-HSA-169270 has reduced ETF 169268 as input and oxidized ETF 169267 as output. Each complex contains ETFA 169262, explicitly localized to mitochondrial matrix and linked to human P13804. The catalytic activity 169271 instead points to ETFDH 448210/Q16134 at the mitochondrial inner membrane, with electron-transferring-flavoprotein dehydrogenase activity. Consequently the ETFA matrix assertion is valid even though the event also involves the inner membrane; ETFDH catalytic chemistry and membrane location are not transferred to ETFA. ETFA coordinates remain the model’s unresolved 1–?, and no isoform-specific experiment is inferred. Supporting Evidence: Reactome:R-HSA-169270 ETF-ubiquinone oxidoreductase (ETFDH), catalyses the re-oxidation of reduced ETF, with ubiquinone (CoQ) as the electron acceptor being reduced to ubiquinol (QH2)
GO:0009055 electron transfer activity	IDA PMID:10423253 The intraflavin hydrogen bond in human electron transfer fla...	ACCEPT	Summary: ETFA contributes electron transfer through the FAD-containing ETF heterodimer. Reason: The actual PMID:10423253 abstract reports human ETF reconstitution with 4′-deoxy-FAD and electron-transfer assays, but the original operative full text was inaccessible. Independent actual PMID:25416781 Methods and Figure 5 directly assay recombinant human untagged mature Δ19-ETFalpha with full-length His6-ETFbeta, receiving electrons from MCAD or GCDH and transferring them to DCIP. The directly measured activity belongs to the assembled human ETF alpha/beta heterodimer, whose FAD-binding alpha domain is resolved in PMID:8962055. It does not establish autonomous isolated-alpha turnover, activity of the 284-residue alternative product, or ETFDH’s separate ubiquinone-reductase chemistry. Supporting Evidence: PMID:10423253 Electron-transfer flavoprotein (ETF) serves as an intermediate electron carrier between primary flavoprotein dehydrogenases and terminal respiratory chains in mitochondria and prokaryotic cells. PMID:25416781 ETF acts as a mobile electron carrier that shuttles electrons between several FAD-containing dehydrogenases present in the mitochondrial matrix and the membrane-bound ETF:quinone oxidoreductase PMID:8962055 They function as electron shuttles between primary flavoprotein dehydrogenases involved in mitochondrial fatty acid and amino acid catabolism and the membrane-bound electron transfer flavoprotein ubiquinone oxidoreductase.
GO:0050660 flavin adenine dinucleotide binding	IDA PMID:10423253 The intraflavin hydrogen bond in human electron transfer fla...	ACCEPT	Summary: The alpha subunit directly binds FAD within human ETF. Reason: The actual PMID:10423253 abstract reports flavin removal/reconstitution of human ETF, but its full Methods/Results remained unavailable. Independent actual PMID:8962055 Results resolve FAD largely within the alpha C-terminal domain and identify alpha-side contacts including Thr266, Arg249 and His286 in the paper’s numbering; beta contributes contacts near the flavin as part of the assembled heterodimer. This positively establishes alpha FAD binding. AMP occupies the beta domain and is not transferred to ETFA, and the result does not establish binding by every alternative product. Supporting Evidence: PMID:10423253 The three-dimensional structures of human and Paracoccus denitrificans ETFs determined by X-ray crystallography indicate that the 4'-hydroxyl of the ribityl side chain of FAD is hydrogen bonded to N(1) of the flavin ring. PMID:8962055 FAD lies in a cleft between the two subunits, with most of the FAD molecule residing in the C-terminal portion of the alpha subunit.
GO:0050660 flavin adenine dinucleotide binding	IDA PMID:9334218 Expression and characterization of two pathogenic mutations ...	ACCEPT	Summary: Human ETFalpha has a directly resolved FAD-binding domain. Reason: The accessible PMID:9334218 abstract describes alpha-subunit variants and altered flavin behavior, but the operative original was not recovered. The actual human structure in PMID:8962055 independently resolves FAD in the alpha C-terminal domain, with specific alpha contacts and neighboring beta contributions. This establishes the same FAD-binding claim without treating the inaccessible variant paper as fully read. It does not imply alpha AMP binding, autonomous alpha electron-transfer activity, or functional equivalence of the shorter splice product. The inherited PMID:9334218 excerpt at this row concerns the upstream chain-length-specific acyl-CoA dehydrogenases, not ETFA–FAD contacts. It is preserved solely as historical citation context and does not support the FAD-binding claim; acceptance rests on the independently inspected human structure. Supporting Evidence: PMID:9334218 Among these dehydrogenases are the four chain length-specific flavoprotein dehydrogenases of fatty acid beta-oxidation. PMID:8962055 FAD lies in a cleft between the two subunits, with most of the FAD molecule residing in the C-terminal portion of the alpha subunit.
GO:0005739 mitochondrion	TAS PMID:3170610 Molecular cloning and nucleotide sequence of cDNAs encoding ...	ACCEPT	Summary: ETFA is a mitochondrial protein; the organelle term is correct and is kept beside the matrix term. Reason: The cited cloning paper (PMID:3170610) reports mitochondrial processing of the translated alpha-ETF precursor, consistent with mitochondrial import (also shown in PMID:3760196). The mitochondrion term is correct and, per the root-organelle policy, is kept beside the matrix term recorded by the GO:0005759 rows rather than replaced; the earlier MODIFY-to-matrix verdict is withdrawn. Supporting Evidence: PMID:3170610 The identity of the p alpha-ETF clones was confirmed by hybrid selected translation, by transcription/translation of a cDNA, and by mitochondrial processing of the protein produced by these translations. PMID:3760196 alpha-ETF was synthesized as a precursor (p alpha-ETF), 3,000 mol wt larger than its mature counterpart, and was translocated into the mitochondria and processed to the mature alpha-ETF. PMID:34800366 We defined a human mitochondrial high-confidence proteome (MitoCoP) of 1,134 protein-coding genes, including 91 proteins previously not localized to mitochondria experimentally. Reactome:R-HSA-169260 Electron transfer flavoprotein (ETF) is a 63kDa heterodimer composed of alpha and beta subunits and binds one FAD and one AMP per dimer. ETF resides on the matrix face of the mitochondrial inner membrane. Reactome:R-HSA-169270 ETF-ubiquinone oxidoreductase (ETFDH), catalyses the re-oxidation of reduced ETF, with ubiquinone (CoQ) as the electron acceptor being reduced to ubiquinol (QH2)
GO:0005759 mitochondrial matrix	TAS PMID:8617498 Assignment of Etfdh, Etfb, and Etfa to chromosomes 3, 7, and...	ACCEPT	Summary: ETFA is the alpha component of the matrix-localized ETF heterodimer. Reason: The accessible PMID:8617498 abstract explicitly places the ETF alpha/beta system in the mitochondrial matrix, while its experimental focus is mouse chromosomal mapping. Its operative full text remained unavailable and is not represented as a human subcellular assay. Independent human participant-level Reactome records and the UniProt SL-0170 mapping substantiate the location; PMID:3760196 supplies actual precursor/import and human processing evidence with separate species scopes. This supports the existing matrix claim without assigning ETFDH’s inner-membrane location to ETFA. Supporting Evidence: PMID:8617498 Electron transfer flavoprotein (composed of alpha and beta subunits) is an obligatory electron acceptor for several dehydrogenases and is located in the mitochondrial matrix. PMID:3760196 alpha-ETF was synthesized as a precursor (p alpha-ETF), 3,000 mol wt larger than its mature counterpart, and was translocated into the mitochondria and processed to the mature alpha-ETF. Reactome:R-HSA-169260 Electron transfer flavoprotein (ETF) is a 63kDa heterodimer composed of alpha and beta subunits and binds one FAD and one AMP per dimer. ETF resides on the matrix face of the mitochondrial inner membrane. Reactome:R-HSA-169270 ETF-ubiquinone oxidoreductase (ETFDH), catalyses the re-oxidation of reduced ETF, with ubiquinone (CoQ) as the electron acceptor being reduced to ubiquinol (QH2)
GO:0005515 protein binding	IPI PMID:27499296 Mitochondrial Protein Interaction Mapping Identifies Regulat...	REMOVE	Summary: Bare protein-binding row; removed as uninformative under the protein-binding policy. Reason: Bare GO:0005515 protein binding is removed under the protein-binding policy because it conveys no functional information. Removal does not mean the reported interaction is false. The partner here is LYRM5/ETFRF1, which binds the ETF complex and removes its FAD (deflavination); that activity belongs to LYRM5, and no GO MF term captures ETF being the target of a regulator, so no informative replacement exists. Supporting Evidence: PMID:27499296 We likewise discovered that LYRM5 interacts with and deflavinates the electron-transferring flavoprotein that shuttles electrons to coenzyme Q (CoQ).
GO:0045251 electron transfer flavoprotein complex	IEA GO_REF:0000117	ACCEPT	Summary: ETFA is the alpha subunit of the electron transfer flavoprotein complex. Reason: The current ARBA00092488 endpoint returned HTTP404, so its conditions and target-matching disjunct were not inspected. Independent human evidence establishes complex membership: PMID:8962055 resolves the recombinant ETF alpha/beta heterodimer, and Reactome complexes 169267/169268 explicitly contain P13804 and P38117. The original structure’s residue labels are paper numbering; current P13804 has Q20/S21 and the later functional assay explicitly uses a Δ19 alpha construct. Acceptance rests on the structural and curated complex evidence, not a claimed rule replay, isolated-alpha activity or equivalence of the alternative product. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00092488 SOURCE STALE OR MISSING Current official endpoint returns 404; no rule conditions were inspected. Acceptance rests on independent human structural and curated complex evidence, not a claimed rule replay. Supporting Evidence: PMID:8962055 Mammalian electron transfer flavoproteins (ETF) are heterodimers containing a single equivalent of flavin adenine dinucleotide (FAD). Reactome:R-HSA-169260 Electron transfer flavoprotein (ETF) is a 63kDa heterodimer composed of alpha and beta subunits and binds one FAD and one AMP per dimer. ETF resides on the matrix face of the mitochondrial inner membrane. Reactome:R-HSA-169270 ETF-ubiquinone oxidoreductase (ETFDH), catalyses the re-oxidation of reduced ETF, with ubiquinone (CoQ) as the electron acceptor being reduced to ubiquinol (QH2)

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