ETFB

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0009055 electron transfer activity	IBA GO_REF:0000033	ACCEPT	Summary: ETFB contributes to electron transfer by the human ETF heterodimer. Reason: The actual electron-transfer IBD at PTN007689635 is ancestral to the exact human P38117 target sequence. The current IBD lists human P38117, whereas captured GOA additionally lists fly FBgn0039697; the latter maps to Q0KHZ6 with a current IDA source record. This version difference does not invalidate the node or make self-WITH circular. PMID:25416781 directly measures electron transfer using recombinant human untagged mature Δ19-ETFA plus full-length His6-ETFB: MCAD or GCDH transfers electrons through ETF to the artificial acceptor DCIP. Beta-site mutations and methylation modify this activity. PMID:8962055 resolves the beta contribution to the human heterodimer. The evidence is for assembled ETF, not isolated-beta turnover, direct ETFDH/ubiquinone reduction in that assay, or equivalent function of the 346-residue product. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN007689635 SUPPORTS TRANSFER Actual IBD placement and target descent are valid; human experimental grounding is explicit. The current IBD versus captured-GOA fly donor difference is retained as a version boundary. Supporting Evidence: 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. 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:0005739 mitochondrion	IBA GO_REF:0000033	ACCEPT	Summary: ETFB 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:PTN000480319. 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:PTN000480319 SUPPORTS TRANSFER IBD node and target ancestry support mitochondrial location; the organelle term is kept and the matrix is recorded separately. 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. 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) Reactome:R-HSA-8931858 ETF shuttles electrons between several FAD-containing dehydrogenases present in the mitochondrial matrix and the membrane-bound ETF:quinone oxidoreductase (Ramsay et al. 1987).
GO:0033539 fatty acid beta-oxidation using acyl-CoA dehydrogenase	IBA GO_REF:0000033	ACCEPT	Summary: ETFB participates in acyl-CoA-dehydrogenase-dependent fatty acid oxidation as an ETF electron-carrier subunit. Reason: The actual GO:0033539 IBD at PTN000480319 lies on the human target path and lists mouse MGI:106098 and human P38117. Mouse Q9DCW4 identity and its exact family alignment were verified; current mouse GOA has the experimental PMID:25023281 source, whose original was not re-read in this lane. Independent human PMID:25416781 Methods and Figure 5 show ETF-dependent electron transfer during MCAD oxidation of octanoyl-CoA, with beta-directed perturbations affecting transfer. ETFB therefore contributes to the dehydrogenase-linked pathway through the assembled electron carrier; MCAD performs acyl-CoA dehydrogenation. This is a functional step, not a process assignment based solely on disease or knockout necessity. The assay does not reconstitute the entire oxidation cycle or mitochondrial respiration. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000480319 SUPPORTS TRANSFER The actual beta-oxidation IBD is ancestral to the human target. Mouse identity and source record were traced, and direct human ETF evidence independently supports participation; self-WITH is valid. 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:7912128 Finally, transfection of wild-type beta-ETF cDNA into P411 fibroblasts suggests that wild-type beta-ETF cDNA complements the genetic defect and restores the beta-oxidation flux to normal levels. 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:0005739 mitochondrion	IEA GO_REF:0000117	ACCEPT	Summary: ETFB 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 ETFB 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. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00026962 SUPPORTS TRANSFER IBD node and target ancestry support mitochondrial location; the organelle term is kept and the matrix is recorded separately. 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. 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) Reactome:R-HSA-8931858 ETF shuttles electrons between several FAD-containing dehydrogenases present in the mitochondrial matrix and the membrane-bound ETF:quinone oxidoreductase (Ramsay et al. 1987).
GO:0005759 mitochondrial matrix	IEA GO_REF:0000044	ACCEPT	Summary: The human ETF beta subunit acts in the mitochondrial matrix. Reason: Official UniProt SL-0170 explicitly maps mitochondrion matrix to GO:0005759, and the target P38117 record carries this location. Independently, human Reactome entity 169265 links to P38117 and assigns its own compartment to matrix in all three inspected source routes. The modeled chain is 2–255 after initiator-methionine removal, not ETFA-like cleavage of a 19-residue transit peptide. These records support the localization while leaving the 346-residue product and the unread original import assay separately bounded. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0170 SUPPORTS TRANSFER Exact current location-to-GO mapping; target UniProt and human Reactome participant agree on matrix. 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. 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) Reactome:R-HSA-8931858 ETF shuttles electrons between several FAD-containing dehydrogenases present in the mitochondrial matrix and the membrane-bound ETF:quinone oxidoreductase (Ramsay et al. 1987).
GO:0009055 electron transfer activity	IEA GO_REF:0000002	ACCEPT	Summary: The ETF beta-family mapping agrees with directly measured human heterodimer electron transfer. Reason: Current InterPro identifies IPR000049 at canonical residues 162–182 and IPR012255 at residues 4–255, with both entries explicitly mapping to GO:0009055. These are beta-specific conserved-site/family matches, not a generic flavin-fold inference. Human ETF structure and the recombinant alpha/beta DCIP-transfer assay independently establish the functional contribution. Most FAD contacts lie in alpha, while beta contributes the heterodimer architecture, cofactor environment and dehydrogenase-recognition region. This does not assign ETFDH ubiquinone-reductase activity or isolated-beta catalysis. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR000049 SUPPORTS TRANSFER Observed beta conserved-site match and explicit electron-transfer GO mapping. InterPro:IPR012255 SUPPORTS TRANSFER Observed beta-family match and explicit GO mapping, independently corroborated in human ETF. Supporting Evidence: 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. 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: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:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MODIFY	Summary: The BioPlex ETFA association has an independently established heterodimer interface. Reason: The actual BioPlex 3.0 network files contain ETFA–ETFB in 293T (line 43725, P13804/P38117, pInt 0.99999919048217) and HCT116 (line 24183, P38117-2/P13804, pInt 0.99999352548364). The Methods describe human tagged-ORF AP-MS and gene-level protein inference, so the HCT116 accession label does not independently verify the historical clone sequence or prove a 346-residue product-specific interaction. The human ETF structure in PMID:8962055 directly establishes the unlike-subunit interface. Refine the generic term to heterodimerization on that positive structural evidence, rather than treating every AP-MS association as binary. 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). file:human/ETFB/ETFB-uniprot.txt Heterodimer composed of an alpha and beta subunit
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	MODIFY	Summary: The U2OS AP-MS association is the established ETF alpha/beta heterodimer. Reason: PMID:40205054 Methods describe human U2OS tagged-bait AP-MS, distinct from the paper’s image and predicted-structure analyses. The deposited experimental AP-MS network 95bc75d5-d1d1-11ee-8a40-005056ae23aa contains ETFB node 569998 (ENSG00000105379; bait true), ETFA node 617814, and their exact edge 629908. This verifies the target association independently of a predicted complex. PMID:8962055 supplies direct human structural evidence that this particular pair forms a heterodimer, warranting GO:0046982. The original screen clone’s full sequence was not independently checked, and the current alternative product is not assigned equivalent behavior. 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). file:human/ETFB/ETFB-uniprot.txt Heterodimer composed of an alpha and beta subunit
GO:0033539 fatty acid beta-oxidation using acyl-CoA dehydrogenase	IEA GO_REF:0000120	ACCEPT	Summary: The combined electronic inference is supported by the target-matching rule and direct human ETF function. Reason: Current ARBA00085069 condition set 3 (zero-based) requires FunFam 3.40.50.620:FF:000011 and Metazoa; both are present in the official human P38117 record. The rule explicitly assigns GO:0033539. Mouse Q9DCW4 and ENSMUSP00000004729 are the accompanying ortholog source; Q9DCW4 has a current experimental source record for this process as well as propagated rows. The ortholog chain is not treated as independent experimental replication. Human PMID:25416781 directly tests the MCAD→ETF electron-transfer step, while Reactome places the human beta-containing carrier in this pathway. The conclusion concerns ETFB participation in the heterodimer, not autonomous fatty-acid oxidation or functional equivalence of both products. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00085069 SUPPORTS TRANSFER Actual current disjunct 3 matches the target FunFam and Metazoa lineage; GO output is exact. UniProtKB:Q9DCW4 SUPPORTS TRANSFER Official mouse Etfb identity and current source records traced; independent human primary assay supplies target grounding. ensembl:ENSMUSP00000004729 SUPPORTS TRANSFER Official mouse UniProt cross-reference identifies this protein accession; no separate donor assay is inferred from the identifier. Supporting Evidence: 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:0005759 mitochondrial matrix	NAS PMID:8504797 cDNA cloning and mitochondrial import of the beta-subunit of...	ACCEPT	Summary: The matrix assertion is supported independently of the unavailable complete 1993 original. Reason: This NAS context cites the same human cDNA/import study as the IDA matrix assertion. Its verified abstract explicitly supports matrix import of a 255-residue ETFB product, but the complete import Methods and figure controls were not recovered. Independent current human Reactome participant 169265 places P38117 residues 2–255 in the matrix as part of ETF, while PMID:34800366 provides mitochondrial proteomic corroboration at broader resolution. These positive sources support retaining the location; they do not establish product equivalence or convert abstract access into a claim of full experimental inspection. 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. 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: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.
GO:0009063 amino acid catabolic process	IDA PMID:25416781 Human METTL20 is a mitochondrial lysine methyltransferase th...	ACCEPT	Summary: ETFB contributes the ETF carrier step used in amino-acid catabolism. Reason: PMID:25416781 Methods and Figure 5 reconstitute human ETF alpha/beta with glutaryl-CoA dehydrogenase and glutaryl-CoA, detecting electron transfer to DCIP. This demonstrates a carrier step coupled to GCDH rather than relying solely on metabolic necessity. The Introduction of the actual human ETF structure paper PMID:8962055 describes the shared mammalian carrier receiving electrons from isovaleryl-, glutaryl- and short/branched-chain dehydrogenases in amino-acid catabolism. That broader documented role supports retaining the class-level process rather than narrowing it to the one amino-acid donor tested in the 2014 assay. The 1996 passage is background synthesis, not a claim that its structure experiment assayed every donor. The assayed 2014 ETF contains mature Δ19-alpha and full-length His6-beta; beta is a carrier subunit, not the dehydrogenase or methyltransferase. Neither paper establishes equivalent 346-residue-product activity. Supporting Evidence: PMID:25416781 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: The ETF carrier provides an electron-entry route to the respiratory chain. Reason: PMID:25416781 directly assays human ETF alpha/beta accepting dehydrogenase-derived electrons with DCIP as the measured acceptor. The paper places this carrier upstream of ETF:ubiquinone oxidoreductase; the experiment itself does not reconstitute ETFDH, ubiquinone reduction, oxygen consumption or proton translocation. The actual human Reactome R-HSA-169270 chain distinguishes ETF beta participant 169265 in the ETF redox input/output complexes from the ETFDH/Q16134 catalyst. Thus the imported process term is appropriate for ETFB’s carrier contribution to the pathway, not as evidence that ETFB performs the downstream oxidoreductase or proton-pumping chemistry. 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. 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: ETFB participates in the electron-transfer step of acyl-CoA-dehydrogenase beta-oxidation. Reason: PMID:25416781 Methods and Figure 5 use octanoyl-CoA, MCAD, recombinant human ETF alpha/beta and DCIP to measure the coupled electron-transfer reaction; beta methylation and Lys200/Lys203 mutations alter carrier performance. The current GO:0033539 definition describes the beta-oxidation pathway initiated by acyl-CoA dehydrogenases. ETF contributes the electron-acceptor/carrier step rather than oxidizing the acyl-CoA substrate itself, so participation is supported by an actual reconstituted step and not only by disease necessity. The assay does not measure the entire respiratory chain and does not establish autonomous beta or alternative-product activity. Supporting Evidence: PMID:25416781 Accordingly, we found that METTL20-mediated methylation of ETFβ in vitro reduced its ability to receive electrons from the medium chain acyl-CoA dehydrogenase and the glutaryl-CoA dehydrogenase.
GO:0045251 electron transfer flavoprotein complex	IPI PMID:8962055 Three-dimensional structure of human electron transfer flavo...	ACCEPT	Summary: Human ETFB is a structural and functional subunit of the ETF complex. Reason: PMID:8962055 Methods and Results report the 2.1 Å structure of recombinant human ETF alpha/beta, with continuous beta density from Leu4 to Ile255 and an extensive unlike-subunit interface. The FAD cleft spans the subunits, while AMP is buried entirely in beta domain III and is proposed to have a structural role. This directly establishes beta membership in GO:0045251. The AMP proposal is not an independently established catalytic function, and neither the crystallized 255-residue beta framework nor the assembled complex demonstrates equivalent activity of the 346-residue alternative product. Supporting Evidence: PMID:8962055 The structure of human ETF solved to 2.1-A resolution reveals that the ETF molecule is comprised of three distinct domains: two domains are contributed by the alpha subunit and the third domain is made up entirely by the beta subunit.
GO:0005739 mitochondrion	IDA GO_REF:0000052	ACCEPT	Summary: ETFB 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 ETFB 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: PMID:8504797 Incubation with intact mitochondria indicates that the cDNA-encoded beta-ETF polypeptide contains the information necessary to reach 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) Reactome:R-HSA-8931858 ETF shuttles electrons between several FAD-containing dehydrogenases present in the mitochondrial matrix and the membrane-bound ETF:quinone oxidoreductase (Ramsay et al. 1987).
GO:0005515 protein binding	IPI PMID:35362222 S1P defects cause a new entity of cataract, alopecia, oral m...	MODIFY	Summary: ETFB co-purifies with MBTPS1/S1P together with ETFA; the informative part is the ETF heterodimer. Reason: The row's partners are ETFA 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 ETFA-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: ETFB 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 ETFB 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:8504797 Incubation with intact mitochondria indicates that the cDNA-encoded beta-ETF polypeptide contains the information necessary to reach the mitochondrial matrix. 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 Reactome:R-HSA-8931858	ACCEPT	Summary: The ETFB methylation substrate and product are explicitly placed in the human mitochondrial matrix. Reason: R-HSA-8931858 consumes ETFB entity 169265 and produces Me3K200,Me3K203-ETFB entity 8931874. Both link to human P38117 and retain matrix location and coordinates 2–255. Its catalystActivity 8931855 instead points to ETFBKMT entity 8876686. PMID:25416781 Methods and Figures 3–5 independently distinguish beta-subunit methylation from METTL20/ETFBKMT catalytic activity. This source supports location of the substrate; it does not make ETFB a methyltransferase. 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. Reactome:R-HSA-8931858 ETF shuttles electrons between several FAD-containing dehydrogenases present in the mitochondrial matrix and the membrane-bound ETF:quinone oxidoreductase (Ramsay et al. 1987). 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	IDA PMID:8504797 cDNA cloning and mitochondrial import of the beta-subunit of...	ACCEPT	Summary: The established human ETFB matrix location is retained with the original-access limit explicit. Reason: PMID:8504797’s verified abstract explicitly reports a human 255-residue cDNA product reaching the mitochondrial matrix in an intact-organelle import experiment, without a cleavable leader and with valinomycin-sensitive import. Publisher access recovered only partial indexed construct/translation Methods, not the operative import section, controls or organelle-species details. The positive localization is independently corroborated by the current human Reactome ETFB entity 169265 (P38117, residues 2–255, matrix) in R-HSA-169260/169270, and by target-specific mitochondrial proteomics in PMID:34800366. Retain this well-supported compartment without claiming a full original assay read or extrapolating to the 346-residue natural product. Initiator-methionine removal at residue 1 is distinct from the cleavable ETFA targeting presequence. 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. 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) 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.
GO:0009055 electron transfer activity	IDA PMID:25416781 Human METTL20 is a mitochondrial lysine methyltransferase th...	ACCEPT	Summary: ETFB contributes to electron transfer by the assembled ETF heterodimer. Reason: PMID:25416781 Experimental Procedures specify human untagged mature Δ19-ETFalpha coexpressed with full-length N-terminal His6-ETFbeta in bacteria. The electron-transfer assay follows MCAD- or GCDH-dependent reduction of DCIP using octanoyl-CoA or glutaryl-CoA; Results/Figure 5 compare beta Lys200/Lys203 methylation and mutants. This directly measures the assembled carrier’s activity and connects beta modification to its performance. Isolated beta is not shown to carry out the same reaction: the paper reports its instability and uses alpha/beta for these measurements. Retain electron transfer as ETFB’s contribution to the complex, with no methyltransferase role, autonomous beta turnover, or equivalent 346-residue activity inferred. Supporting Evidence: PMID:25416781 Accordingly, we found that METTL20-mediated methylation of ETFβ in vitro reduced its ability to receive electrons from the medium chain acyl-CoA dehydrogenase and the glutaryl-CoA dehydrogenase.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-169260	ACCEPT	Summary: Human ETFB is a matrix component of the ETF electron-transfer complex. Reason: The explicit human source chain is R-HSA-169260 → catalystActivity 169261 → ETF:FAD complex 169267 → ETFB component 169265 → referenceEntity 54492/P38117. ETFB itself has compartment GO:0005759 and coordinates 2–255. PMID:25416781 independently assays a human alpha/beta heterodimer receiving electrons from MCAD, rather than an autonomous beta enzyme. The event and participant support matrix location without assigning all functions to the untested longer splice product. 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. 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 ETF both contain human ETFB in the matrix. Reason: R-HSA-169270 has reduced ETF complex 169268 as input and ETF:FAD 169267 as output; each contains matrix ETFB 169265/P38117. The distinct catalystActivity 169271 points to inner-membrane ETFDH entity 448210/Q16134. Thus the beta-subunit matrix assertion is supported by its own participant, while ETFDH-mediated ubiquinone reduction and membrane localization are not attributed to ETFB. The model represents the canonical 2–255 chain. 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. 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	TAS PMID:7912128 Mutations and polymorphisms of the gene encoding the beta-su...	ACCEPT	Summary: The electron-transfer function is independently established despite incomplete access to the clinical original. Reason: PMID:7912128’s verified abstract reports human ETFB variants and restoration of beta-oxidation flux after wild-type beta-cDNA complementation, but the complete Methods/Results were not recovered. That necessity/rescue endpoint alone is not a direct electron-transfer assay. Independently, PMID:25416781 measures MCAD/GCDH-to-DCIP electron transfer with recombinant human alpha/beta and beta-site perturbations, and PMID:8962055 resolves the carrier heterodimer. These positive originals support the shared electron-transfer function as a beta-subunit contribution, without claiming independent beta catalysis or attributing ETFDH-mediated ubiquinone reduction to ETFB. Supporting Evidence: PMID:7912128 Finally, transfection of wild-type beta-ETF cDNA into P411 fibroblasts suggests that wild-type beta-ETF cDNA complements the genetic defect and restores the beta-oxidation flux to normal levels. 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	TAS PMID:8617498 Assignment of Etfdh, Etfb, and Etfa to chromosomes 3, 7, and...	ACCEPT	Summary: The matrix location is retained using independent human evidence. Reason: PMID:8617498’s verified abstract concerns mouse Etfa/Etfb/Etfdh chromosomal assignment and states the ETF matrix context; its operative original was not accessible. This is not grounds to reverse the human TAS assertion or claim wrong-gene attribution. Independently, the human ETFB cDNA/import abstract in PMID:8504797 and current Reactome participant 169265 (human P38117, residues 2–255, GO:0005759) support matrix localization. The target MitoCoP entry supplies broader mitochondrial corroboration. Acceptance concerns the supported human location, not a claim that the inaccessible mapping paper measured human matrix import or that both natural products were tested. 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:8504797 Incubation with intact mitochondria indicates that the cDNA-encoded beta-ETF polypeptide contains the information necessary to reach 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. 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.
GO:0005515 protein binding	IPI PMID:27499296 Mitochondrial Protein Interaction Mapping Identifies Regulat...	MODIFY	Summary: The ETFA interaction is specifically assembly of the ETF alpha/beta heterodimer. Reason: PMID:27499296 Figure 5D/E and the corresponding purification Methods recover recombinant ETF alpha/beta with LYRM5; the current IntAct record retains the exact ETFA–ETFB pair. Independently, PMID:8962055 Methods and Results resolve the extensive interface of recombinant human alpha and beta subunits, including beta density from Leu4 through Ile255. This is the binding of unlike proteins to form a heterodimer, matching current GO:0046982. The original LYRM5 purification Methods do not independently resolve every ETF construct boundary, and no equivalent interaction or activity of the 346-residue alternative product is inferred from the 255-residue structural model. Proposed replacements: protein heterodimerization activity Supporting Evidence: PMID:27499296 We likewise discovered that LYRM5 interacts with and deflavinates the electron-transferring flavoprotein that shuttles electrons to coenzyme Q (CoQ). PMID:8962055 Mammalian electron transfer flavoproteins (ETF) are heterodimers containing a single equivalent of flavin adenine dinucleotide (FAD). file:human/ETFB/ETFB-uniprot.txt Heterodimer composed of an alpha and beta subunit
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	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 in this row is LYRM5/ETFRF1 (BioPlex AP-MS); the regulatory deflavinase activity belongs to LYRM5 (PMID:27499296), and no informative MF replacement exists for ETFB. 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: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: Human ETFB is a constituent of the ETF heterodimer. Reason: The current ARBA00092488 endpoint returned 404, so its condition sets were not recovered and are not invented. The complex assertion is independently established: PMID:8962055 purified and crystallized recombinant human ETF, resolving beta density from L4 through I255 in the paper’s numbering together with the alpha subunit, FAD and AMP. PMID:25416781 coexpresses and copurifies human alpha/beta ETF, and human Reactome complexes 169267/169268 explicitly contain ETFB169265/P38117. This supports GO:0045251 despite the unavailable proximate rule. It does not equate ETF with ETFDH or establish assembly of the 346-residue product. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00092488 SOURCE STALE OR MISSING Current endpoint is404; specific conditions are unavailable. The biological complex assertion is independently supported by human structure, biochemical assembly and explicit Reactome membership. Supporting Evidence: PMID:8962055 Mammalian electron transfer flavoproteins (ETF) are heterodimers containing a single equivalent of flavin adenine dinucleotide (FAD). PMID:25416781 Electron transfer flavoprotein (ETF) is a FAD-containing, mitochondrial protein composed of two subunits: α and β (ETFα and ETFβ, respectively) 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.
GO:0016208 AMP binding	IDA PMID:15159392 Extensive domain motion and electron transfer in the human e...	NEW	Summary: ETFB binds the single AMP of the ETF heterodimer, seen in human ETF crystal structures. Reason: No GOA row records the AMP cofactor, although it is a structurally resolved, subunit-specific property of ETFB: UniProt curates AMP-binding residues from the human ETF and ETF-MCAD crystal structures (PubMed:15159392, PubMed:15975918, PubMed:8962055) and states that ETFB binds an AMP molecule with a probably structural role. Reactome likewise describes one FAD and one AMP per heterodimer. The FAD is bound mostly by ETFA, so AMP binding is the ligand-binding function that distinguishes the beta subunit, and it is already the molecular_function of this review's first core function. IDA is used because the binding residues come from experimental structures. Supporting Evidence: file:human/ETFB/ETFB-uniprot.txt ETFB binds an AMP molecule that probably has a purely structural role 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.

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