ATP5F1E

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005743 mitochondrial inner membrane	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) annotation placing epsilon at the mitochondrial inner membrane, where Complex V resides. This is the correct anatomical location for this structural subunit and is consistent with UniProt subcellular location and the cryo-EM structure. Reason: Complex V is embedded in the mitochondrial inner membrane; epsilon is an integral part of the F1 sector attached to the membrane-embedded Fo sector. Well supported by IBA and independent experimental/structural evidence. Supporting Evidence: PMID:37244256 present snapshot images for three main rotational states file:human/ATP5F1E/ATP5F1E-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion. Mitochondrion inner membrane.
GO:0042776 proton motive force-driven mitochondrial ATP synthesis	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) annotation to the core biological process of mitochondrial ATP synthesis driven by the proton-motive force. This is the central function of Complex V and of epsilon as one of its subunits. Reason: Epsilon is a subunit of the ATP synthase complex whose function is proton motive force-driven mitochondrial ATP synthesis. Directly supported experimentally by the disease phenotype (reduced ATP synthesis on epsilon mutation) and by the functionally active immunocaptured complex. Supporting Evidence: PMID:20566710 oligomycin-sensitive ATPase activity and mitochondrial ATP synthesis PMID:12110673 captured complex V displayed ATP hydrolysis activity that was
GO:0046933 proton-transporting ATP synthase activity, rotational mechanism	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) annotation to the rotational ATP synthase molecular function, using the contributes_to qualifier. This is the appropriate handling for epsilon: it is a non-catalytic central-stalk subunit that contributes to the complex-level rotary catalytic activity without itself enabling it. Reason: The catalytic sites reside on the alpha/beta subunits; epsilon is part of the rotating central stalk that transmits rotation to those sites. contributes_to is the correct qualifier for a subunit that participates in but does not independently possess the activity. Retained as a core (complex-level) function. Supporting Evidence: PMID:37244256 Biological energy currency ATP is produced by F1Fo-ATP synthase file:human/ATP5F1E/ATP5F1E-uniprot.txt central stalk (subunits gamma, delta, and epsilon) rotating inside the
GO:0005739 mitochondrion	IEA GO_REF:0000120	ACCEPT	Summary: Electronic annotation to the general mitochondrion compartment. Correct but less specific than the mitochondrial inner membrane localization. Reason: Correct high-level localization; consistent with the more specific GO:0005743 inner membrane annotations. Kept as a broader accepted term rather than modified, since IEA can legitimately be more general. Supporting Evidence: file:human/ATP5F1E/ATP5F1E-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion. Mitochondrion inner membrane.
GO:0005743 mitochondrial inner membrane	IEA GO_REF:0000120	ACCEPT	Summary: Electronic annotation (InterPro/UniProt SubCell) to the mitochondrial inner membrane, the correct anatomical location for Complex V. Reason: Consistent with UniProt subcellular location and with the IBA and experimental localization. This is the core anatomical location for the structural subunit. Supporting Evidence: file:human/ATP5F1E/ATP5F1E-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion. Mitochondrion inner membrane.
GO:0015986 proton motive force-driven ATP synthesis	IEA GO_REF:0000002	ACCEPT	Summary: Electronic (InterPro2GO) annotation to proton motive force-driven ATP synthesis, the general (not mitochondria-specific) parent process. Correct for this ATP synthase subunit. Reason: Correct core process at a slightly more general level than GO:0042776; both are valid. Consistent with experimental evidence of ATP synthesis by the complex. Supporting Evidence: PMID:20566710 oligomycin-sensitive ATPase activity and mitochondrial ATP synthesis
GO:0045259 proton-transporting ATP synthase complex	IEA GO_REF:0000120	ACCEPT	Summary: Electronic annotation for membership in the proton-transporting ATP synthase complex (Complex V). This is the defining complex membership for epsilon. Reason: Epsilon is an established structural component of the F1Fo-ATP synthase complex, as shown by cryo-EM and biochemical subunit-composition studies. GO:0045259 is the current complex term the GOA carries and is the correct complex. Supporting Evidence: PMID:37244256 Biological energy currency ATP is produced by F1Fo-ATP synthase file:human/ATP5F1E/ATP5F1E-uniprot.txt central stalk (subunits gamma, delta, and epsilon) rotating inside the
GO:0046933 proton-transporting ATP synthase activity, rotational mechanism	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: Electronic (InterPro2GO) annotation asserting that epsilon ENABLES the rotational ATP synthase activity. This over-attributes the complex-level catalytic activity to a single non-catalytic structural subunit. Reason: Epsilon does not itself enable proton-transporting ATP synthase activity; the catalytic sites are on the alpha/beta subunits and epsilon is a central-stalk structural subunit. The parallel IBA and IDA annotations correctly use the contributes_to qualifier. The enables form is an over-annotation produced by domain-to-GO mapping (InterPro), which cannot capture the contributes_to distinction. Not removed because the underlying association with the activity is real at the complex level. Supporting Evidence: file:human/ATP5F1E/ATP5F1E-uniprot.txt central stalk (subunits gamma, delta, and epsilon) rotating inside the
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MARK AS OVER ANNOTATED	Summary: High-throughput affinity-capture interactome annotation (bare protein binding). The partner is ATP5F1D (delta subunit, UniProtKB:P30049), a genuine central-stalk neighbour, but the term itself conveys no specific molecular function. Reason: Per curation policy, bare protein binding (GO:0005515) is uninformative and is marked as over-annotated rather than removed. The interaction with ATP5F1D is consistent with epsilon and delta being adjacent central-stalk subunits, but this is already captured by the complex-membership annotations; no informative standalone MF is added. Supporting Evidence: file:human/ATP5F1E/ATP5F1E-uniprot.txt P56381; P30049: ATP5F1D; NbExp=5; IntAct=EBI-3904845, EBI-1049505;
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: Binary (Y2H) interactome annotation (bare protein binding). Reported partners include ATP5F1D (P30049) and AGTRAP (Q6RW13-2). Uninformative as a molecular function. Reason: Bare protein binding is not an informative molecular function and is marked as over-annotated per policy rather than removed. The ATP5F1D partner reflects central-stalk neighbourhood already captured by complex membership; the AGTRAP interaction is a high-throughput binary hit of unclear physiological relevance. Supporting Evidence: file:human/ATP5F1E/ATP5F1E-uniprot.txt P56381; Q6RW13-2: AGTRAP; NbExp=3; IntAct=EBI-3904845, EBI-11522760;
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: Proteome-scale interactome annotation (bare protein binding); partner ATP5F1D (P30049, delta subunit). Uninformative as a molecular function. Reason: Bare protein binding is retained but flagged as over-annotated per policy. The ATP5F1D interaction is consistent with epsilon-delta central-stalk contact already represented by complex membership, adding no specific MF information. Supporting Evidence: file:human/ATP5F1E/ATP5F1E-uniprot.txt P56381; P30049: ATP5F1D; NbExp=5; IntAct=EBI-3904845, EBI-1049505;
GO:0005743 mitochondrial inner membrane	NAS PMID:26297831 Assembly of human mitochondrial ATP synthase through two sep...	ACCEPT	Summary: ComplexPortal (NAS) annotation to the mitochondrial inner membrane. Consistent with all other localization evidence for Complex V. Reason: Correct anatomical location for the ATP synthase complex and its epsilon subunit; corroborated by IBA, IEA, and structural data. Supporting Evidence: file:human/ATP5F1E/ATP5F1E-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion. Mitochondrion inner membrane.
GO:0015986 proton motive force-driven ATP synthesis	NAS PMID:26297831 Assembly of human mitochondrial ATP synthase through two sep...	ACCEPT	Summary: ComplexPortal (NAS) annotation to proton motive force-driven ATP synthesis, the process carried out by the complex of which epsilon is a subunit. Reason: Correct core process. The cited assembly study characterizes the human ATP synthase as a rotary motor enzyme that produces ATP, and epsilon is part of the rotor central shaft. Supporting Evidence: PMID:26297831 Mitochondrial ATP synthase is a motor enzyme in which a central shaft rotates
GO:0045259 proton-transporting ATP synthase complex	NAS PMID:26297831 Assembly of human mitochondrial ATP synthase through two sep...	ACCEPT	Summary: ComplexPortal (NAS) annotation for membership in the proton-transporting ATP synthase complex. The assembly study shows epsilon in the central rotor shaft intermediate of the human complex. Reason: Definitive complex membership for epsilon, supported by assembly-intermediate analysis and structural data. GO:0045259 is the current term carried by the GOA. Supporting Evidence: PMID:26297831 the central rotor shaft and the stator stalk are formed
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	ACCEPT	Summary: High-throughput mitochondrial proteome localization to mitochondrion. Correct but general; consistent with the more specific inner-membrane annotations. Reason: Epsilon is a bona fide mitochondrial protein detected in the high-confidence mitochondrial proteome. Broader than the inner-membrane term but not incorrect. Supporting Evidence: file:human/ATP5F1E/ATP5F1E-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion. Mitochondrion inner membrane.
GO:0005739 mitochondrion	IC PMID:12110673 A functionally active human F1F0 ATPase can be purified by i...	ACCEPT	Summary: Curator-inferred (IC) mitochondrion localization based on membership in the ATP synthase complex (GO:0045259). Correct, general localization. Reason: Reasonable inference from complex membership; consistent with all other localization evidence. Broader than the inner-membrane term but valid. Supporting Evidence: PMID:12110673 immunoprecipitated F(1)F(0) contained a full complement of
GO:0045259 proton-transporting ATP synthase complex	IDA PMID:12110673 A functionally active human F1F0 ATPase can be purified by i...	ACCEPT	Summary: Direct experimental (IDA) demonstration that epsilon is part of the ATP synthase complex: immunocaptured functionally active human F1Fo contained the full complement of subunits including epsilon. Reason: Strong experimental support for complex membership from immunocapture and mass spectrometry of the intact human enzyme. Core annotation. Supporting Evidence: PMID:12110673 immunoprecipitated F(1)F(0) contained a full complement of
GO:0046933 proton-transporting ATP synthase activity, rotational mechanism	IDA PMID:12110673 A functionally active human F1F0 ATPase can be purified by i...	ACCEPT	Summary: Direct experimental (IDA) annotation with the contributes_to qualifier: the immunocaptured complex containing epsilon shows oligomycin/IF1-sensitive ATPase (rotary) activity. Epsilon contributes to, but does not independently enable, this activity. Reason: Correct use of contributes_to for a non-catalytic structural subunit of the rotary enzyme. Retained as a core complex-level function. Note the in-vitro ATP hydrolysis reported here is the artificial reverse of the physiological ATP-synthesis reaction. Supporting Evidence: PMID:12110673 captured complex V displayed ATP hydrolysis activity that was PMID:12110673 fully oligomycin and inhibitor protein IF(1)-sensitive
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-164832	ACCEPT	Summary: Reactome (TAS) localization of epsilon to the mitochondrial matrix, reflecting that the F1 head (with the central stalk including epsilon) projects into the matrix. Reason: Compatible with the biology: the F1 sector and its central-stalk subunits face/protrude into the matrix while the complex is anchored in the inner membrane. Kept as a valid Reactome pathway-context location; the inner membrane (GO:0005743) remains the primary structural location. Supporting Evidence: file:human/ATP5F1E/ATP5F1E-uniprot.txt central stalk (subunits gamma, delta, and epsilon) rotating inside the
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-164834	ACCEPT	Summary: Reactome (TAS) matrix localization associated with the "Enzyme-bound ATP is released" step of ATP synthesis. Reflects the matrix-facing F1/central-stalk position of epsilon. Reason: Consistent with the matrix-facing orientation of the F1 sector. Valid within the Reactome pathway context; inner membrane is the primary structural location. Supporting Evidence: file:human/ATP5F1E/ATP5F1E-uniprot.txt central stalk (subunits gamma, delta, and epsilon) rotating inside the
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-164840	ACCEPT	Summary: Reactome (TAS) matrix localization associated with the "ADP and Pi bind to ATPase" step. Reflects the matrix-facing catalytic/central-stalk region of the complex. Reason: Compatible with epsilon's position in the matrix-facing F1 central stalk. Valid Reactome pathway-context location; inner membrane remains the primary structural location. Supporting Evidence: file:human/ATP5F1E/ATP5F1E-uniprot.txt central stalk (subunits gamma, delta, and epsilon) rotating inside the
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-8949580	ACCEPT	Summary: Reactome (TAS) matrix localization associated with the "F1Fo ATP synthase dimerizes" step. Reflects the matrix-facing F1/central-stalk position of epsilon. Reason: Consistent with the matrix-facing orientation of the F1 sector containing epsilon. Valid within the Reactome pathway context; inner membrane is the primary structural location. Supporting Evidence: file:human/ATP5F1E/ATP5F1E-uniprot.txt central stalk (subunits gamma, delta, and epsilon) rotating inside the
GO:0042776 proton motive force-driven mitochondrial ATP synthesis	IDA PMID:12110673 A functionally active human F1F0 ATPase can be purified by i...	ACCEPT	Summary: Direct experimental (IDA) annotation to mitochondrial ATP synthesis, based on the functionally active immunocaptured human F1Fo complex containing epsilon. Reason: Core biological process, experimentally supported. The purified complex containing epsilon is functionally active (oligomycin/IF1-sensitive), demonstrating its role in ATP synthesis. Supporting Evidence: PMID:12110673 captured complex V displayed ATP hydrolysis activity that was
GO:0045259 proton-transporting ATP synthase complex	IMP PMID:20566710 Mitochondrial ATP synthase deficiency due to a mutation in t...	ACCEPT	Summary: Mutant-phenotype (IMP) evidence for complex membership: a homozygous ATP5E p.Tyr12Cys mutation reduces the assembled ATP synthase complex and its activity, and the mutant epsilon is present in the residual complex, establishing epsilon as a required structural subunit. Reason: The disease mutation directly links epsilon to the integrity and function of the ATP synthase complex; patient fibroblasts show reduced ATP synthase content and activity. Core complex-membership annotation, and additionally demonstrates a role in F1 assembly. Supporting Evidence: PMID:20566710 p.Tyr12Cys mutation in the epsilon subunit encoded by the nuclear gene ATP5E PMID:20566710 essential role of the epsilon subunit in the biosynthesis and assembly of the F1
GO:0045259 proton-transporting ATP synthase complex	TAS PMID:10727396 Cloning, characterization and mapping of the human ATP5E gen...	ACCEPT	Summary: Author-statement (TAS) annotation for membership in the ATP synthase complex, from the paper that cloned and characterized the human ATP5E gene encoding the epsilon subunit. Reason: Correct complex membership. The cloning paper identifies ATP5E as encoding the epsilon subunit of human ATP synthase; complex membership is corroborated by structural and biochemical studies. Supporting Evidence: PMID:10727396 A cDNA encoding the epsilon subunit of human ATP synthase, ATP5E, was isolated
GO:0005198 structural molecule activity	IDA PMID:20566710 Mitochondrial ATP synthase deficiency due to a mutation in t...	NEW	Summary: Proposed molecular-function annotation capturing that epsilon acts as a non-catalytic structural constituent of the ATP synthase central stalk. Its molecular role is to maintain the structural integrity of the complex rather than to catalyze a reaction. Reason: Epsilon has no independent catalytic activity; the informative subunit-level molecular function is structural molecule activity (contributing to the integrity of Complex V). Loss of epsilon destabilizes/reduces the assembled complex, consistent with a structural role. This is added because the existing MF annotations either use contributes_to (for the complex-level rotary activity) or are the uninformative protein binding term. Supporting Evidence: PMID:20566710 essential role of the epsilon subunit in the biosynthesis and assembly of the F1 file:human/ATP5F1E/ATP5F1E-uniprot.txt central stalk (subunits gamma, delta, and epsilon) rotating inside the

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