ETFB

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0009055 electron transfer activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (PAN-GO) inference that ETFB enables electron transfer activity. This is the core molecular function of the ETF heterodimer, in which the beta subunit is an integral partner. Well supported by structural, biochemical, and disease evidence. Reason: Electron transfer activity is the defining, experimentally established molecular function of the ETF complex (accepting electrons from matrix dehydrogenases and relaying them to ETFDH), and ETFB is an obligate structural/recognition component of the electron-transferring heterodimer. The IBA is consistent with the human IDA/TAS annotations below. Supporting Evidence: PMID:8962055 electron shuttles between primary flavoprotein dehydrogenases involved in 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	KEEP AS NON CORE	Summary: Phylogenetic inference that ETFB is active in the mitochondrion. Correct but less precise than the mitochondrial matrix localization directly demonstrated for the human protein. Reason: ETFB is a bona fide mitochondrial protein, but the specific and experimentally supported location is the mitochondrial matrix (GO:0005759, IDA below). Retain the broader mitochondrion term as non-core; the matrix term captures the precise location. Supporting Evidence: PMID:8504797 contains the information necessary to reach the mitochondrial matrix
GO:0033539 fatty acid beta-oxidation using acyl-CoA dehydrogenase	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic inference that ETFB is involved in fatty-acid beta-oxidation via acyl-CoA dehydrogenases. ETF is the obligatory electron acceptor for the matrix acyl-CoA dehydrogenases of fatty-acid beta-oxidation, so this is a core biological process for the gene. Reason: Fatty-acid beta-oxidation via acyl-CoA dehydrogenases depends on ETF accepting electrons from those dehydrogenases; loss of ETFB blocks this flux and causes MADD. Consistent with the human IDA annotation (PMID:25416781) and disease evidence (PMID:7912128). Supporting Evidence: PMID:25416781 e.g. medium chain acyl-CoA dehydrogenase (MCAD), are involved in β-oxidation of fatty acids PMID:7912128 cDNA complements the genetic defect and restores the beta-oxidation flux to
GO:0005739 mitochondrion	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: ARBA machine-learning electronic annotation to mitochondrion. Correct but superseded in precision by the mitochondrial-matrix annotations. Reason: Consistent with the experimentally supported mitochondrial-matrix localization; retain as a broader, non-core location term. Supporting Evidence: PMID:8504797 contains the information necessary to reach the mitochondrial matrix
GO:0005759 mitochondrial matrix	IEA GO_REF:0000044	ACCEPT	Summary: Electronic annotation mapping the UniProt subcellular-location term (Mitochondrion matrix) to GO:0005759. Matches the experimentally demonstrated matrix localization of ETFB. Reason: ETFB is imported into and resides in the mitochondrial matrix; this is the precise, core cellular location, directly supported by import assays (PMID:8504797) and UniProt. Supporting Evidence: PMID:8504797 contains the information necessary to reach the mitochondrial matrix
GO:0009055 electron transfer activity	IEA GO_REF:0000002	ACCEPT	Summary: InterPro2GO electronic annotation of electron transfer activity based on the ETF beta-subunit domain signatures (IPR000049, IPR012255). Consistent with the core molecular function. Reason: The InterPro-to-GO mapping correctly assigns the ETF electron transfer activity to ETFB via its family domains; redundant with, and supported by, the IDA/TAS/IBA annotations. Supporting Evidence: PMID:8962055 electron shuttles between primary flavoprotein dehydrogenases involved in
GO:0005515 protein binding	IPI PMID:27499296 Mitochondrial Protein Interaction Mapping Identifies Regulat...	MARK AS OVER ANNOTATED	Summary: IntAct-curated physical interaction (IPI) of ETFB with ETFA (P13804) and ETFRF1/LYRM5 (Q6IPR1), from a mitochondrial interaction-mapping study. These are real, biologically meaningful interactions (ETFA is the partner subunit; ETFRF1 is the ETF deflavinase), but the GO term itself is the uninformative generic "protein binding". Reason: The underlying interactions are genuine and important, but bare protein binding (GO:0005515) conveys no specific molecular function. Per curation policy the experimental IPI is retained rather than removed; the informative content (partner-subunit assembly, ETFRF1-mediated deflavination) is captured in core_functions and the ETF-complex annotation. Supporting Evidence: PMID:27499296 LYRM5 interacts with and deflavinates
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: IntAct-curated interactions of ETFB with ETFA (P13804) and ETFRF1 (Q6IPR1) from the proteome-scale BioPlex AP-MS interactome. Uninformative generic protein-binding term. Reason: High-throughput AP-MS interactome data; the ETFA and ETFRF1 interactions are consistent with the known ETF complex biology, but the generic protein binding term adds no specific functional information. Retained as an experimental IPI per policy. Supporting Evidence: PMID:33961781 BioPlex 3.0, results from affinity purification
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	MARK AS OVER ANNOTATED	Summary: IntAct-curated interaction of ETFB with ETFA (P13804) from a multimodal (AP-MS + immunofluorescence) cell-map study. Generic protein-binding term. Reason: The ETFA interaction reflects the constitutive ETF heterodimer, but the bare protein binding term is uninformative. Retained as an experimental IPI per policy; specific content is captured by the ETF-complex annotation. Supporting Evidence: PMID:40205054 interacting partners were identified by tandem MS (AP–MS)
GO:0033539 fatty acid beta-oxidation using acyl-CoA dehydrogenase	IEA GO_REF:0000120	ACCEPT	Summary: Combined multi-method electronic annotation (with mouse ortholog Q9DCW4) to fatty-acid beta-oxidation using acyl-CoA dehydrogenase. Consistent with the curated IDA/IBA annotations of the same term. Reason: Redundant electronic support for a core biological process that is independently established experimentally (PMID:25416781) and by disease complementation (PMID:7912128). Supporting Evidence: PMID:25416781 e.g. medium chain acyl-CoA dehydrogenase (MCAD), are involved in β-oxidation of fatty acids
GO:0005759 mitochondrial matrix	NAS PMID:8504797 cDNA cloning and mitochondrial import of the beta-subunit of...	ACCEPT	Summary: ComplexPortal (CPX-2731) non-traceable-author-statement assignment of the matrix location, citing the ETFB cloning/import study. Correct core location. Reason: The cited study demonstrated that beta-ETF is imported into the mitochondrial matrix; the matrix is the established core location of the ETF complex. Supporting Evidence: PMID:8504797 contains the information necessary to reach the mitochondrial matrix
GO:0009063 amino acid catabolic process	IDA PMID:25416781 Human METTL20 is a mitochondrial lysine methyltransferase th...	ACCEPT	Summary: ComplexPortal IDA assigning ETFB to amino-acid catabolism, reflecting that several ETF-partner dehydrogenases (e.g. glutaryl-CoA and isovaleryl-CoA dehydrogenases) act in amino-acid oxidation. ETF is their obligatory electron acceptor. Reason: ETF accepts electrons from dehydrogenases involved in amino-acid catabolism (glutaryl-CoA, isovaleryl-CoA dehydrogenases), and ETFB methylation reduces electron uptake from GCDH; loss of ETFB disrupts amino-acid catabolic flux (part of the MADD phenotype). A core biological process, though broader than the fatty-acid term. Supporting Evidence: PMID:25416781 glutaryl-CoA dehydrogenase (GCDH) and isovaleryl-CoA dehydrogenase, are involved in the oxidation of amino acids
GO:0022904 respiratory electron transport chain	IDA PMID:25416781 Human METTL20 is a mitochondrial lysine methyltransferase th...	ACCEPT	Summary: ComplexPortal IDA linking ETFB to the respiratory electron transport chain. ETF relays electrons from matrix dehydrogenases into the ubiquinone pool via ETFDH, acting as a third major electron entry point after complexes I and II. Reason: ETF feeds electrons into the respiratory-chain ubiquinone pool through ETFDH; the cited study explicitly frames ETF as the third major provider of electrons to the ubiquinone pool of the respiratory chain. Core process. Supporting Evidence: PMID:25416781 it is the third major provider of electrons to the ubiquinone pool of the mitochondrial respiratory chain
GO:0033539 fatty acid beta-oxidation using acyl-CoA dehydrogenase	IDA PMID:25416781 Human METTL20 is a mitochondrial lysine methyltransferase th...	ACCEPT	Summary: ComplexPortal IDA for fatty-acid beta-oxidation using acyl-CoA dehydrogenase. The cited study shows ETFB receives electrons from medium-chain acyl-CoA dehydrogenase (MCAD), a core beta-oxidation enzyme. Reason: Directly supported experimental annotation for a core beta-oxidation process. ETF is the electron acceptor for the acyl-CoA dehydrogenases of fatty-acid beta-oxidation, and ETFB methylation modulates electron uptake from MCAD. Supporting Evidence: PMID:25416781 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: ComplexPortal part_of annotation to the electron transfer flavoprotein complex, based on the human ETF crystal structure showing the alpha/beta heterodimer. This is the specific, core complex for ETFB. Reason: The 2.1-A crystal structure defines ETF as a heterodimer in which the beta subunit contributes the third structural domain and the AMP site; ETFB is an obligate part of the ETF complex (ComplexPortal CPX-2731). Precise and correct. Supporting Evidence: PMID:8962055 third domain is made up entirely by the beta subunit
GO:0005739 mitochondrion	IDA GO_REF:0000052	KEEP AS NON CORE	Summary: HPA immunofluorescence-based IDA placing ETFB in the mitochondrion. Consistent with the established mitochondrial-matrix localization. Reason: Correct mitochondrial localization at organelle resolution; the more precise matrix term is the core location. Retain as non-core. Supporting Evidence: PMID:8504797 contains the information necessary to reach the mitochondrial matrix
GO:0005515 protein binding	IPI PMID:35362222 S1P defects cause a new entity of cataract, alopecia, oral m...	MARK AS OVER ANNOTATED	Summary: UniProt/IntAct IPI recording interaction of ETFB with ETFA (P13804) and MBTPS1/S1P (Q14703). MBTPS1 forms a trimeric complex with ETFA/ETFB that promotes FAD incorporation and stabilizes the heterodimer. Real interactions, but the GO term is generic protein binding. Reason: The MBTPS1 and ETFA interactions are genuine and functionally meaningful (MBTPS1 stabilizes and flavinates the ETF heterodimer), but the bare protein binding term is uninformative. Retained as an experimental IPI per policy; the regulatory content is noted in the notes and core functions rather than as protein binding. Supporting Evidence: PMID:35362222 protein that forms a trimeric complex with ETFA/ETFB. S1P enhances ETFA/ETFB
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	KEEP AS NON CORE	Summary: High-throughput assignment of ETFB to the mitochondrion from a high-confidence quantitative mitochondrial-proteome study. Consistent with the established localization. Reason: Corroborates mitochondrial localization at organelle resolution; the matrix term is the precise core location. Retain as non-core. Supporting Evidence: PMID:8504797 contains the information necessary to reach the mitochondrial matrix
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-8931858	ACCEPT	Summary: Reactome traceable-author-statement (ETFBKMT/METTL20 methylation reaction) placing ETFB in the mitochondrial matrix. Correct core location. Reason: Consistent with the experimentally established matrix localization; the Reactome reaction annotation correctly reflects the matrix compartment where ETFB is methylated and functions. Supporting Evidence: PMID:8504797 contains the information necessary to reach the mitochondrial matrix
GO:0005759 mitochondrial matrix	IDA PMID:8504797 cDNA cloning and mitochondrial import of the beta-subunit of...	ACCEPT	Summary: UniProt IDA for mitochondrial matrix, from the beta-ETF cloning study demonstrating energy-dependent import of the polypeptide into the matrix. Directly supports the core location. Reason: The cited import experiments show that the cDNA-encoded beta-ETF reaches the mitochondrial matrix; this is the primary experimental evidence for the core location. Supporting Evidence: PMID:8504797 contains the information necessary to reach the mitochondrial matrix
GO:0009055 electron transfer activity	IDA PMID:25416781 Human METTL20 is a mitochondrial lysine methyltransferase th...	ACCEPT	Summary: UniProt IDA for electron transfer activity, from the METTL20/ETFB study that measured ETF-mediated electron transfer from acyl-CoA dehydrogenases to an artificial acceptor and showed methylation of ETFB reduces this activity. Core molecular function. Reason: Direct assay evidence that ETFB participates in electron transfer (accepting electrons from MCAD and GCDH), and that modification of the ETFB recognition loop modulates the rate. This is the defining molecular function. Supporting Evidence: PMID:25416781 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: Reactome TAS (electron transfer from fatty-acid beta-oxidation to ETF) placing ETFB in the matrix compartment. Correct core location. Reason: Consistent with experimentally established matrix localization; Reactome correctly situates the ETF electron-uptake reaction in the mitochondrial matrix. Supporting Evidence: PMID:8504797 contains the information necessary to reach the mitochondrial matrix
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-169270	ACCEPT	Summary: Reactome TAS (ETFDH re-oxidizes reduced ETF, reducing CoQ) placing ETFB in the matrix. Correct core location. Reason: Consistent with the established matrix localization of ETF; correctly reflects the compartment of the ETF/ETFDH electron-relay reaction. Supporting Evidence: PMID:8504797 contains the information necessary to reach the mitochondrial matrix
GO:0009055 electron transfer activity	TAS PMID:7912128 Mutations and polymorphisms of the gene encoding the beta-su...	ACCEPT	Summary: TAS for electron transfer activity, citing the ETFB glutaric-acidemia-II mutation study. The GA2B mutation R164Q reduces ETF electron transfer activity, supporting the core molecular function. Reason: Disease-mutation evidence corroborates that ETFB is required for ETF electron transfer activity; complementation with wild-type beta-ETF cDNA restores beta-oxidation flux. Consistent with the IDA/IBA annotations. Supporting Evidence: PMID:7912128 cDNA complements the genetic defect and restores the beta-oxidation flux to
GO:0005759 mitochondrial matrix	TAS PMID:8617498 Assignment of Etfdh, Etfb, and Etfa to chromosomes 3, 7, and...	ACCEPT	Summary: TAS for mitochondrial matrix, citing the mouse Etf/Etfdh chromosomal mapping paper, which states ETF is located in the mitochondrial matrix and is an obligatory electron acceptor for several dehydrogenases. Correct core location. Reason: The cited review-style statement correctly places ETF in the mitochondrial matrix, consistent with human experimental import data. Supporting Evidence: PMID:8617498 obligatory electron acceptor for several dehydrogenases

Gene Description

Existing Annotations Review

Core Functions

Beta subunit of the electron-transfer flavoprotein (ETF) heterodimer; together with ETFA it accepts electrons from matrix FAD-dependent dehydrogenases and relays them to ETF-ubiquinone oxidoreductase, functioning as a mobile electron carrier.

As part of ETF, accepts electrons from acyl-CoA dehydrogenases of mitochondrial fatty-acid beta-oxidation (e.g. medium-chain acyl-CoA dehydrogenase), coupling beta-oxidation to the respiratory chain; the ETFB recognition loop docks these dehydrogenases.

References

📚 Additional Documentation

Notes

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