ATP5F1D encodes the delta (Ξ΄) subunit of the F1 catalytic head of mitochondrial ATP synthase (Complex V; F1Fo-ATP synthase). Together with the gamma (ATP5F1C) and epsilon (ATP5F1E) subunits it forms the central stalk that rotates within the alpha3/beta3 catalytic core, mechanically coupling proton flow through the membrane-embedded Fo sector to ATP synthesis in the F1 sector. It is a structural (non-catalytic) subunit: the nucleotide-binding catalytic sites reside on the alpha (ATP5F1A) and beta (ATP5F1B) subunits. The metazoan mitochondrial delta subunit is homologous to the bacterial epsilon subunit and belongs to the ATPase epsilon chain family. It localises to the mitochondrial inner membrane, with the F1 head projecting into the matrix, and its major biological role is proton motive force-driven mitochondrial ATP synthesis; along with the gamma subunit it is also required for biogenesis/assembly of the F1 sector. Biallelic loss-of-function variants cause mitochondrial complex V (ATP synthase) deficiency.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0045259 proton-transporting ATP synthase complex | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) annotation placing ATP5F1D as part of the proton-transporting ATP synthase complex. This is the correct, current complex term and is strongly supported by structural and biochemical evidence. Reason: ATP5F1D is a bona fide subunit of the mitochondrial F1Fo-ATP synthase (Complex V), confirmed by cryo-EM structure and by co-isolation of the intact complex. This is a core cellular-component annotation. Supporting Evidence: PMID:37244256 ATP is produced by F1Fo-ATP synthase file:human/ATP5F1D/ATP5F1D-uniprot.txt Component of the ATP synthase complex composed at least of |
| GO:0015986 proton motive force-driven ATP synthesis | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) annotation to proton motive force-driven ATP synthesis, the core biological process of ATP synthase and of this subunit. Reason: ATP5F1D couples proton translocation to ATP production as part of the ATP synthase central stalk. This is a core process annotation. Supporting Evidence: PMID:29478781 important role in coupling proton translocation and ATP production |
| GO:0046933 proton-transporting ATP synthase activity, rotational mechanism | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) annotation with the contributes_to qualifier to the rotational ATP synthase molecular activity. The contributes_to qualifier is appropriate: this is the activity of the whole complex, to which the structural delta subunit contributes but does not independently enable. Reason: Delta is part of the rotating central stalk that transmits torque to the catalytic alpha/beta subunits. The complex-level rotary activity is correctly captured with the contributes_to qualifier rather than enables, consistent with delta being a non-catalytic structural subunit. Supporting Evidence: PMID:29499186 The central stalk of mitochondrial ATP synthase consists of subunits |
| GO:0005739 mitochondrion | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation to the broad mitochondrion location. Correct but non-specific; the more informative curated location is the mitochondrial inner membrane. Reason: ATP5F1D is a mitochondrial protein; the broad IEA localization is not wrong. It is superseded in specificity by the inner-membrane annotation and is kept as a valid broad location. Supporting Evidence: file:human/ATP5F1D/ATP5F1D-uniprot.txt Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic (SubCell mapping) annotation to the mitochondrial inner membrane, the correct specific anatomical location for this F1 subunit. Reason: ATP synthase is embedded in the mitochondrial inner membrane, with the F1 head (including delta) projecting into the matrix. This is the preferred specific location. Supporting Evidence: file:human/ATP5F1D/ATP5F1D-uniprot.txt Mitochondrion inner membrane |
| GO:0015986 proton motive force-driven ATP synthesis | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO electronic annotation to proton motive force-driven ATP synthesis, consistent with the delta/epsilon ATP synthase domain signature. Reason: Correct process for an ATP synthase F1 subunit; duplicates the well-supported IBA annotation to the same term. Supporting Evidence: PMID:29478781 important role in coupling proton translocation and ATP production |
| GO:0045259 proton-transporting ATP synthase complex | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation to complex membership. Correct and duplicates the experimentally and phylogenetically supported complex annotation. Reason: ATP5F1D is a subunit of the ATP synthase complex; the IEA complex-membership call is accurate. Supporting Evidence: file:human/ATP5F1D/ATP5F1D-uniprot.txt Component of the ATP synthase complex composed at least of |
| GO:0046933 proton-transporting ATP synthase activity, rotational mechanism | IEA GO_REF:0000002 | MODIFY | Summary: InterPro2GO electronic annotation to the rotational ATP synthase activity with the enables qualifier. For a non-catalytic structural subunit, contributes_to is the more accurate qualifier (as used in the IBA/IDA versions of this term); enables slightly over-states delta's independent activity. Reason: Delta does not independently enable the rotary catalytic activity; the catalytic sites are on the alpha/beta subunits and delta is a structural central-stalk component. The essence (participation in the rotary ATP synthase MF) is sound but the qualifier/framing is better captured as a contribution to the complex activity, with the subunit's own MF being structural molecule activity. Proposed replacements: structural molecule activity Supporting Evidence: file:human/ATP5F1D/ATP5F1D-uniprot.txt In vivo, can only synthesize ATP although its ATP hydrolase |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MARK AS OVER ANNOTATED | Summary: IntAct IPI annotation from a large-scale interactome study (with/from ATP5F1E, the epsilon subunit). Bare protein binding is uninformative as a molecular function even though ATP5F1E is a genuine central-stalk complex partner. Reason: Per curation guidelines, bare protein binding (GO:0005515) is not an informative MF. The biologically meaningful relationship (interaction with the epsilon subunit within the ATP synthase central stalk) is already captured by the complex-membership and structural molecule activity annotations. Retained (not removed) per policy on experimental IPI annotations. Supporting Evidence: file:human/ATP5F1D/ATP5F1D-uniprot.txt central stalk (subunits gamma, delta, and epsilon) rotating inside the |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: IntAct IPI annotations from a binary interactome map (partners include ATP5F1E plus several non-mitochondrial nuclear/cytoplasmic proteins such as MDFI, SRSF11, TNS2, NOTCH2NLC, KRTAP10-8). Bare protein binding is uninformative. Reason: GO:0005515 protein binding conveys no specific molecular function. Most listed partners are high-throughput two-hybrid hits of unclear biological relevance to a mitochondrial inner-membrane subunit. The one relevant partner (ATP5F1E) is captured by complex membership. Retained per policy on experimental IPI annotations. Supporting Evidence: file:human/ATP5F1D/ATP5F1D-uniprot.txt central stalk (subunits gamma, delta, and epsilon) rotating inside the |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MARK AS OVER ANNOTATED | Summary: IntAct IPI annotation (with/from ATXN1) from a neurodegenerative-disease interactome study. Bare protein binding is uninformative and this partner is not an established ATP synthase interaction. Reason: GO:0005515 protein binding is non-informative as an MF, and interaction with ATXN1 has no established role in ATP5F1D function. Retained per policy on experimental IPI annotations rather than removed. Supporting Evidence: file:human/ATP5F1D/ATP5F1D-uniprot.txt central stalk (subunits gamma, delta, and epsilon) rotating inside the |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: IntAct IPI annotation (with/from ATP5F1E) from a proteome-scale interactome study. ATP5F1E is a genuine complex partner but bare protein binding remains uninformative. Reason: GO:0005515 protein binding does not describe a specific function. The relevant information (association with the epsilon subunit in the ATP synthase central stalk) is already captured by complex-membership and structural molecule activity annotations. Retained per policy on experimental IPI annotations. Supporting Evidence: file:human/ATP5F1D/ATP5F1D-uniprot.txt central stalk (subunits gamma, delta, and epsilon) rotating inside the |
| 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, the correct specific location. Reason: Consistent with all other location evidence; ATP synthase resides in the inner membrane. Supporting Evidence: file:human/ATP5F1D/ATP5F1D-uniprot.txt 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 core process of the complex. Reason: Correct core-process annotation, consistent with IBA/IEA/IDA evidence for the same process family. Supporting Evidence: PMID:29478781 important role in coupling proton translocation and ATP production |
| GO:0045259 proton-transporting ATP synthase complex | NAS PMID:26297831 Assembly of human mitochondrial ATP synthase through two sep... | ACCEPT | Summary: ComplexPortal NAS annotation to complex membership (CPX-6151, mitochondrial proton-transporting ATP synthase complex). Reason: Correct and consistent with the curated ComplexPortal complex and structural evidence. Supporting Evidence: file:human/ATP5F1D/ATP5F1D-uniprot.txt Component of the ATP synthase complex composed at least of |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: HPA immunofluorescence IDA localizing ATP5F1D to mitochondria. Correct but broad. Reason: Experimental localization consistent with mitochondrial residence; the inner-membrane annotation is the more specific curated location. Supporting Evidence: file:human/ATP5F1D/ATP5F1D-uniprot.txt Mitochondrion inner membrane |
| GO:0045259 proton-transporting ATP synthase complex | NAS PMID:12539966 Role of copper in mitochondrial biogenesis via interaction w... | ACCEPT | Summary: NAS annotation to complex membership from a copper/mitochondrial-biogenesis review. The complex assignment is correct. Reason: ATP5F1D is a genuine subunit of the ATP synthase complex; the complex-membership call is accurate regardless of the review's copper focus. Supporting Evidence: file:human/ATP5F1D/ATP5F1D-uniprot.txt Component of the ATP synthase complex composed at least of |
| GO:0005198 structural molecule activity | IDA PMID:29499186 Role of the mitochondrial ATP synthase central stalk subunit... | ACCEPT | Summary: IDA annotation to structural molecule activity based on knockdown studies showing that delta (with gamma) is required for assembly and function of the ATP synthase central stalk / holocomplex. This is the correct subunit-level molecular function for a non-catalytic structural subunit. Reason: Delta is a structural constituent of the ATP synthase central stalk; it does not have an independent catalytic activity. Structural molecule activity is the appropriate MF, and it is the preferred core MF for this gene. Supporting Evidence: PMID:29499186 as driver of the c-oligomer attachment in the assembly file:human/ATP5F1D/ATP5F1D-uniprot.txt Belongs to the ATPase epsilon chain family |
| GO:0033615 mitochondrial proton-transporting ATP synthase complex assembly | IDA PMID:29499186 Role of the mitochondrial ATP synthase central stalk subunit... | ACCEPT | Summary: IDA annotation to ATP synthase complex assembly. shRNA knockdown of delta reduced the amount of assembled ATP synthase and impaired its function, demonstrating a role in biogenesis/assembly of the enzyme. Reason: Delta, together with gamma, is required for formation of the F1 assembly intermediate and for holocomplex assembly. This is a well-supported experimental process annotation. Supporting Evidence: PMID:29499186 displayed decreased ATP synthase PMID:29499186 as driver of the c-oligomer attachment in the assembly |
| GO:0045259 proton-transporting ATP synthase complex | IDA PMID:37244256 Structure of the human ATP synthase. | ACCEPT | Summary: IDA complex-membership annotation from the cryo-EM structure of the human ATP synthase, which resolves subunit delta within the assembled complex. Reason: Direct structural evidence for delta as a component of the assembled human ATP synthase complex. Strong core CC annotation. Supporting Evidence: PMID:37244256 ATP is produced by F1Fo-ATP synthase file:human/ATP5F1D/ATP5F1D-uniprot.txt Component of the ATP synthase complex composed at least of |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: High-throughput proteomics (HTP) annotation localizing ATP5F1D to mitochondria as part of a high-confidence human mitochondrial proteome. Reason: Consistent with the established mitochondrial localization; broad but correct. Supporting Evidence: file:human/ATP5F1D/ATP5F1D-uniprot.txt Mitochondrion inner membrane |
| GO:0005739 mitochondrion | IC PMID:12110673 A functionally active human F1F0 ATPase can be purified by i... | ACCEPT | Summary: IC (inferred by curator) annotation to mitochondrion, based on the immunocaptured human F1Fo ATPase complex (GO:0045259). Correct but broad. Reason: Curator inference of mitochondrial location from complex membership is sound; the inner-membrane term is the more specific curated location. Supporting Evidence: PMID:12110673 The captured complex V displayed ATP hydrolysis activity that was |
| GO:0045259 proton-transporting ATP synthase complex | IDA PMID:12110673 A functionally active human F1F0 ATPase can be purified by i... | ACCEPT | Summary: IDA complex-membership annotation from immunocapture of the functionally active human F1Fo ATPase, which contained a full complement of subunits. Reason: Delta co-isolates as part of the intact, functional ATP synthase complex. Solid experimental complex-membership annotation. Supporting Evidence: PMID:12110673 fully oligomycin and inhibitor protein IF(1)-sensitive |
| 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: IDA annotation with the contributes_to qualifier to the rotational ATP synthase activity, based on the functionally active immunocaptured complex. The qualifier is appropriate for this structural subunit. Reason: The measured (oligomycin/IF1-sensitive) activity is that of the whole complex; delta contributes to it as a central-stalk component rather than enabling it independently. Correctly qualified as contributes_to. Supporting Evidence: PMID:12110673 The captured complex V displayed ATP hydrolysis activity that was |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-164832 | KEEP AS NON CORE | Summary: Reactome TAS annotation to the mitochondrial matrix (ATPase synthesizes ATP reaction). Defensible because the F1 head projects into the matrix, but the curated primary location is the inner membrane. Reason: The F1 sector including delta faces the matrix, so a matrix location is not wrong; however the enzyme is an integral inner-membrane complex, so this is kept as a non-core location secondary to the inner-membrane annotation. Supporting Evidence: PMID:29478781 the soluble F1 catalytic portion in the mitochondrial matrix |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-164834 | KEEP AS NON CORE | Summary: Reactome TAS annotation to the mitochondrial matrix (Enzyme-bound ATP is released reaction). Same rationale as the other Reactome matrix annotations. Reason: Defensible for the matrix-facing F1 head but secondary to the inner-membrane location. Supporting Evidence: PMID:29478781 the soluble F1 catalytic portion in the mitochondrial matrix |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-164840 | KEEP AS NON CORE | Summary: Reactome TAS annotation to the mitochondrial matrix (ADP and Pi bind to ATPase reaction). Same rationale as the other Reactome matrix annotations. Reason: Defensible for the matrix-facing F1 head but secondary to the inner-membrane location. Supporting Evidence: PMID:29478781 the soluble F1 catalytic portion in the mitochondrial matrix |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-8949580 | KEEP AS NON CORE | Summary: Reactome TAS annotation to the mitochondrial matrix (F1Fo ATP synthase dimerizes reaction). Same rationale as the other Reactome matrix annotations. Reason: Defensible for the matrix-facing F1 head but secondary to the inner-membrane location. Supporting Evidence: PMID:29478781 the soluble F1 catalytic portion in the mitochondrial matrix |
| GO:0005524 ATP binding | NAS PMID:12539966 Role of copper in mitochondrial biogenesis via interaction w... | MARK AS OVER ANNOTATED | Summary: NAS annotation (contributes_to) to ATP binding from a copper/mitochondrial-biogenesis review. The delta subunit does not itself bind nucleotides; the catalytic ATP/ADP sites are on the alpha and beta subunits. Reason: This is an over-annotation propagated from complex-level activity to a structural subunit. Structural, biochemical and evolutionary evidence show delta is a non-catalytic central-stalk subunit lacking nucleotide-binding sites; the supporting reference is a nutrition review, not a binding study. Kept (not removed) as it derives from an experimental NAS attribution of the complex. Supporting Evidence: file:human/ATP5F1D/ATP5F1D-uniprot.txt In vivo, can only synthesize ATP although its ATP hydrolase |
| GO:0043531 ADP binding | NAS PMID:12539966 Role of copper in mitochondrial biogenesis via interaction w... | MARK AS OVER ANNOTATED | Summary: NAS annotation (contributes_to) to ADP binding from the same copper-biogenesis review. As with ATP binding, the delta subunit does not bind nucleotides. Reason: Over-annotation of a complex-level property to a structural subunit; the nucleotide sites are on the alpha/beta subunits. Kept as it derives from an experimental NAS attribution. Supporting Evidence: file:human/ATP5F1D/ATP5F1D-uniprot.txt In vivo, can only synthesize ATP although its ATP hydrolase |
| 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: IDA annotation to the mitochondrial-specific proton motive force-driven ATP synthesis process, based on the functionally active immunocaptured human ATP synthase. This is the most specific and correct core-process term. Reason: Direct evidence that the intact complex (containing delta) carries out proton motive force-coupled ATP synthesis. This is the preferred core BP annotation. Supporting Evidence: PMID:12110673 The captured complex V displayed ATP hydrolysis activity that was |
| GO:0009060 aerobic respiration | IMP PMID:29478781 Biallelic Mutations in ATP5F1D, which Encodes a Subunit of A... | KEEP AS NON CORE | Summary: IMP annotation to aerobic respiration based on the disease study: biallelic ATP5F1D variants impaired ATP synthase assembly and reduced complex V activity, and Drosophila ATPsynΞ΄ knockdown caused lethality rescued by wild-type human ATP5F1D. Patient iPSC-cardiomyocytes showed impaired maximal respiration. Reason: ATP synthase is the terminal step of oxidative phosphorylation, so loss of ATP5F1D impairs aerobic ATP production; the annotation is supported. It is kept as non-core because the more precise core process is proton motive force-driven mitochondrial ATP synthesis, and aerobic respiration is a broader downstream/parent process. Supporting Evidence: PMID:29478781 individuals exhibited impaired assembly of F1FO ATP synthase and subsequent PMID:29478781 impaired maximal respiration in response to palmitate supplementation |
| GO:0033615 mitochondrial proton-transporting ATP synthase complex assembly | IMP PMID:29478781 Biallelic Mutations in ATP5F1D, which Encodes a Subunit of A... | ACCEPT | Summary: IMP annotation to ATP synthase complex assembly from the disease study, where patient fibroblasts with ATP5F1D variants showed impaired assembly of F1Fo ATP synthase and reduced complex V, without change in ATP5F1D steady-state level (a defect in assembly rather than protein stability). Reason: Loss-of-function ATP5F1D variants directly impair assembly of the ATP synthase complex, demonstrating a role in complex biogenesis. Well-supported experimental process annotation, consistent with the IDA assembly annotation from PMID:29499186. Supporting Evidence: PMID:29478781 individuals exhibited impaired assembly of F1FO ATP synthase and subsequent |
| GO:0005743 mitochondrial inner membrane | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation to the mitochondrial inner membrane by orthology (mouse Q9D3D9). Correct specific location. Reason: Consistent with all other localization evidence; the ATP synthase is an integral inner membrane complex. Supporting Evidence: file:human/ATP5F1D/ATP5F1D-uniprot.txt Mitochondrion inner membrane |
| GO:0042776 proton motive force-driven mitochondrial ATP synthesis | NAS PMID:12539966 Role of copper in mitochondrial biogenesis via interaction w... | ACCEPT | Summary: NAS annotation to proton motive force-driven mitochondrial ATP synthesis from the copper-biogenesis review. The process assignment is correct and matches the IDA-supported core process. Reason: Correct core-process term for the subunit; duplicates the IDA annotation to GO:0042776. Supporting Evidence: PMID:12539966 either indirectly or directly, alters ATP synthase function |
| GO:0046688 response to copper ion | NAS PMID:12539966 Role of copper in mitochondrial biogenesis via interaction w... | MARK AS OVER ANNOTATED | Summary: NAS annotation to response to copper ion from a copper-deficiency review, which reports that the delta-subunit protein decreases under copper deficiency. This is a downstream effect on the protein, not a molecular/physiological function of ATP5F1D in copper response. Reason: The cited review describes altered ATP synthase subunit levels as a secondary consequence of dietary copper deficiency, not a role for ATP5F1D in sensing or responding to copper. This is an over-annotation. Kept (not removed) as it derives from an experimental NAS attribution. Supporting Evidence: PMID:12539966 Decreases in the delta subunit |
| GO:0005739 mitochondrion | NAS PMID:12887009 ATP synthases: insights into their motor functions from sequ... | ACCEPT | Summary: NAS annotation to mitochondrion from a review on ATP synthase motor function. Correct but broad. Reason: Consistent with established mitochondrial localization; superseded in specificity by the inner-membrane annotation. Supporting Evidence: file:human/ATP5F1D/ATP5F1D-uniprot.txt Mitochondrion inner membrane |
| GO:0045259 proton-transporting ATP synthase complex | NAS PMID:1531933 Molecular cloning of an import precursor of the delta-subuni... | ACCEPT | Summary: NAS complex-membership annotation from the original cloning paper of the human ATP synthase delta-subunit import precursor. Correct. Reason: Establishes ATP5F1D as the delta subunit of the human mitochondrial ATP synthase complex; consistent with all downstream structural evidence. Supporting Evidence: file:human/ATP5F1D/ATP5F1D-uniprot.txt Component of the ATP synthase complex composed at least of |
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