ATP5F1A

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0045259 proton-transporting ATP synthase complex	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for CC. ATP5F1A is a core structural component of the proton-transporting ATP synthase complex (Complex V). This is well supported by cryo-EM structural data (PMID:37244256), immunocapture studies (PMID:12110673), and assembly studies (PMID:26297831). Reason: This is the defining complex membership for ATP5F1A. The alpha subunit is one of the major subunits of the F1 catalytic head. Cryo-EM structures show ATP5F1A as chains A/B/C in the alpha3-beta3 hexamer (PMID:37244256). IBA annotation is appropriate and well conserved across the ATPase alpha/beta chains family. Supporting Evidence: PMID:37244256 Biological energy currency ATP is produced by F1Fo-ATP synthase. However, the molecular mechanism for human ATP synthase action remains unknown. Here, we present snapshot images for three main rotational states and one substate of human ATP synthase using cryoelectron microscopy. PMID:12110673 The immunoprecipitated F(1)F(0) contained a full complement of subunits that were identified with specific antibodies against five of the subunits (alpha, beta, OSCP, d, and IF(1)) file:human/ATP5F1A/ATP5F1A-deep-research-falcon.md ATP5F1A encodes the alpha subunit of the mitochondrial F1 sector of F1FO-ATP synthase (Complex V) in Homo sapiens
GO:0015986 proton motive force-driven ATP synthesis	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for BP. Proton motive force-driven ATP synthesis is the core biological process in which ATP5F1A participates as part of Complex V. While the alpha subunit does not directly catalyze ATP synthesis (that occurs at the beta subunit), it is essential for the process through its structural and regulatory roles. Reason: Correct. ATP5F1A is an essential component of the Complex V machinery that carries out proton motive force-driven ATP synthesis. The alpha subunit provides non-catalytic nucleotide-binding sites that are required for the binding-change mechanism. Well supported by structural evidence (PMID:37244256) and assembly studies (PMID:26297831). Supporting Evidence: PMID:37244256 Biological energy currency ATP is produced by F1Fo-ATP synthase PMID:26297831 Mitochondrial ATP synthase is a motor enzyme in which a central shaft rotates in the stator casings fixed with the peripheral stator stalk.
GO:0046933 proton-transporting ATP synthase activity, rotational mechanism	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for MF with contributes_to qualifier. The alpha subunit contributes to the proton-transporting ATP synthase activity of the holoenzyme complex via the rotational mechanism. The contributes_to qualifier is essential here because ATP5F1A provides non-catalytic nucleotide-binding sites -- the catalytic sites reside on the beta subunit (ATP5F1B). Reason: The contributes_to qualifier is correct and important for the alpha subunit. Unlike the beta subunit which houses the catalytic nucleotide-binding sites, the alpha subunit provides structural support and non-catalytic nucleotide binding required for the rotational mechanism but does not itself catalyze ATP synthesis. UniProt states for P25705: "Subunit alpha does not bear the catalytic high-affinity ATP-binding sites." The rotational mechanism requires the full assembled complex. Supporting Evidence: PMID:37244256 The accommodation of the symmetry mismatch between F1 and Fo motors is resolved by the torsional flexing of the entire complex, especially the gamma subunit, and the rotational substep of the c subunit.
GO:0005524 ATP binding	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for MF. ATP binding is well established for the alpha subunit, which has non-catalytic nucleotide-binding sites. Cryo-EM structures (PMID:37244256) show ATP bound at multiple positions on the alpha subunit, and UniProt documents binding residues at positions 215, 217-220, 473, 475 as confirmed by PDB structures 8H9V and 8KI3. Reason: Correct. The alpha subunit binds ATP at its non-catalytic sites. While these are regulatory rather than catalytic binding sites, ATP binding itself is accurately annotated. The term GO:0005524 does not distinguish catalytic from non-catalytic binding, so this is appropriate. Supporting Evidence: PMID:37244256 Biological energy currency ATP is produced by F1Fo-ATP synthase. However, the molecular mechanism for human ATP synthase action remains unknown. Here, we present snapshot images for three main rotational states and one substate of human ATP synthase
GO:0043531 ADP binding	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for MF. ADP binding is a well-established function of the alpha subunit at its non-catalytic nucleotide-binding sites. The alpha subunit binds ADP and ATP at these regulatory sites as part of the binding-change mechanism. Reason: Correct. The alpha subunit has non-catalytic nucleotide-binding sites that bind both ADP and ATP. Well supported phylogenetically and structurally. Supporting Evidence: PMID:37244256 These structures reveal that the release of ADP occurs when the beta subunit of F1Fo-ATP synthase is in the open conformation, showing how ADP binding is coordinated during synthesis
GO:0000166 nucleotide binding	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation for MF based on UniProtKB keyword mapping. Nucleotide binding is correct but very general for ATP5F1A, which specifically binds ATP and ADP at non-catalytic sites. Reason: Correct but broad IEA annotation. The alpha subunit has well-characterized nucleotide (ADP/ATP) binding sites documented by cryo-EM (PMID:37244256). More specific terms like GO:0005524 (ATP binding) and GO:0043531 (ADP binding) are also present in the annotation set, so this broader term is acceptable as an IEA inference. Supporting Evidence: PMID:37244256 Biological energy currency ATP is produced by F1Fo-ATP synthase
GO:0005524 ATP binding	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for MF duplicating the IBA annotation for the same GO term. ATP binding is well established for the alpha subunit at its non-catalytic sites. Reason: Correct and consistent with the IBA annotation. Duplicate evidence codes for the same term are fine. UniProt documents ATP binding residues with structural evidence (PDB: 8H9V, 8KI3).
GO:0005739 mitochondrion	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for CC. Mitochondrial localization is well established for ATP5F1A, which has a mitochondrial transit peptide (residues 1-43, UniProt). Reason: Correct. ATP5F1A is a mitochondrial protein with a confirmed transit peptide. Localization to mitochondria is supported by multiple experimental methods and databases.
GO:0005743 mitochondrial inner membrane	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for CC. ATP5F1A is a peripheral membrane protein on the matrix side of the mitochondrial inner membrane, as part of the F1 head of the ATP synthase complex. Reason: Correct. UniProt states ATP5F1A localizes to "Mitochondrion inner membrane; Peripheral membrane protein; Matrix side" with evidence by similarity. The F1 head is attached to the inner membrane via the central and peripheral stalks.
GO:0005886 plasma membrane	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: IEA annotation for CC based on UniProt subcellular location mapping. ATP5F1A is present on the plasma membrane as part of the ecto-ATP synthase complex, documented experimentally by flow cytometry and immunofluorescence (PMID:10077593). Reason: Correct but represents a non-core localization. Plasma membrane localization relates to the ecto-ATP synthase function, which is secondary to the primary mitochondrial localization. Experimentally confirmed by Moser et al. who demonstrated cell surface presence by flow cytometry and immunofluorescence analysis (PMID:10077593). Supporting Evidence: PMID:10077593 The presence of this protein on the cell surface was confirmed by flow cytometry and immunofluorescence analysis.
GO:0006754 ATP biosynthetic process	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation for BP based on UniProt keyword mapping. ATP biosynthetic process is a core function of the ATP synthase complex to which ATP5F1A contributes as a structural and regulatory subunit. Reason: Correct. ATP5F1A is an essential component of Complex V which synthesizes ATP. While the catalytic activity resides in the beta subunit, the alpha subunit is required for the process. This is a broad but accurate term.
GO:0006811 monoatomic ion transport	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation for BP. This term refers to ion transport, which is related to the proton transport function of the ATP synthase complex but is extremely broad. Reason: While very general, this is not incorrect since the F1Fo-ATP synthase complex transports protons (H+) across the inner mitochondrial membrane. ATP5F1A contributes to this function as part of the complex. More specific annotations for proton transport are also present.
GO:0015986 proton motive force-driven ATP synthesis	IEA GO_REF:0000002	ACCEPT	Summary: IEA annotation for BP based on InterPro mapping. Duplicates the IBA annotation for the same term. Correct. Reason: Correct and consistent with the IBA annotation. Proton motive force-driven ATP synthesis is the core biological process of Complex V. Duplicate evidence from IEA is acceptable.
GO:0016469 proton-transporting two-sector ATPase complex	IEA GO_REF:0000117	ACCEPT	Summary: IEA annotation for CC based on ARBA machine learning model. This term describes the broader class of two-sector ATPase complexes (F-type, V-type, A-type). The mitochondrial ATP synthase is an F-type two-sector ATPase. Reason: Correct but general. The F1Fo ATP synthase is indeed a proton-transporting two-sector ATPase complex. More specific annotations for the proton-transporting ATP synthase complex (GO:0045259) are also present. As an IEA from ARBA, the broader term is acceptable.
GO:0032559 adenyl ribonucleotide binding	IEA GO_REF:0000002	ACCEPT	Summary: IEA annotation for MF based on InterPro mapping. Adenyl ribonucleotide binding includes both ATP and ADP binding, which is correct for the alpha subunit's non-catalytic nucleotide-binding sites. Reason: Correct but broad. The alpha subunit binds adenyl ribonucleotides (ATP and ADP) at its non-catalytic sites. More specific terms (GO:0005524 ATP binding, GO:0043531 ADP binding) are already annotated. As an IEA this broader term is acceptable.
GO:0045259 proton-transporting ATP synthase complex	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for CC, duplicating the IBA annotation for the same GO term. Correct. Reason: Correct and consistent with the IBA annotation. Duplicate evidence codes for the same term are fine.
GO:0046034 ATP metabolic process	IEA GO_REF:0000002	ACCEPT	Summary: IEA annotation for BP based on InterPro mapping. ATP metabolic process is very broad, encompassing both ATP synthesis and hydrolysis. Reason: Correct but very general. ATP5F1A is involved in ATP metabolism (primarily synthesis as part of Complex V, but the complex can also hydrolyze ATP). More specific annotations for ATP biosynthetic process and proton motive force-driven ATP synthesis are present.
GO:0046933 proton-transporting ATP synthase activity, rotational mechanism	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for MF, duplicating the IBA annotation for the same GO term. Note this IEA lacks the contributes_to qualifier that the IBA has, which is important for the alpha subunit since the catalytic activity resides in the beta subunit. Reason: Correct term but ideally should have the contributes_to qualifier as in the IBA annotation. For the alpha subunit, which provides non-catalytic nucleotide-binding sites, the contributes_to qualifier is particularly important. However, as an IEA the absence of the qualifier is a minor issue.
GO:1902495 transmembrane transporter complex	IEA GO_REF:0000117	ACCEPT	Summary: IEA annotation for CC based on ARBA. The ATP synthase complex is a transmembrane transporter complex that translocates protons across the membrane. Reason: Correct but very general. The F1Fo-ATP synthase is indeed a transmembrane transporter complex. More specific terms (GO:0045259, GO:0016469) are also annotated.
GO:1902600 proton transmembrane transport	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for BP. Proton transmembrane transport is a core process of the ATP synthase complex. Reason: Correct. The F1Fo-ATP synthase transports protons across the inner mitochondrial membrane as part of its catalytic cycle. ATP5F1A contributes to this as a structural subunit of the F1 head.
GO:0005515 protein binding	IPI PMID:11410595 Atp11p and Atp12p are assembly factors for the F(1)-ATPase i...	MARK AS OVER ANNOTATED	Summary: IPI protein binding from a study demonstrating that Atp11p and Atp12p (ATPAF1/ATPAF2) are assembly factors for F1-ATPase in human mitochondria (Wang et al. 2001). UniProt confirms the interaction with ATPAF2 (PubMed:11410595). This is a specific, functionally characterized interaction with an assembly chaperone. Reason: The interaction with ATPAF2 is specific and functionally meaningful -- ATPAF2 is a dedicated assembly factor for ATP5F1A. However, the generic "protein binding" term is uninformative. A more specific term capturing the chaperone/assembly factor interaction would be preferable, but such a term may not exist in GO. Supporting Evidence: PMID:11410595 Atp11p and Atp12p were first described as proteins required for assembly of the F(1) component of the mitochondrial ATP synthase in Saccharomyces cerevisiae
GO:0005515 protein binding	IPI PMID:15161933 Comprehensive proteomic analysis of interphase and mitotic 1...	MARK AS OVER ANNOTATED	Summary: IPI protein binding from a large-scale proteomic analysis of 14-3-3-binding proteins (Meek et al. 2004). ATP5F1A was identified as a 14-3-3-binding protein in HeLa cells. Reason: This is a high-throughput proteomic study identifying many 14-3-3-binding proteins. While the interaction may be real, the generic "protein binding" term is uninformative and the biological significance of 14-3-3 binding to ATP5F1A is not characterized. Supporting Evidence: PMID:15161933 Comprehensive proteomic analysis of interphase and mitotic 14-3-3-binding proteins.
GO:0005515 protein binding	IPI PMID:15324660 Proteomic, functional, and domain-based analysis of in vivo ...	MARK AS OVER ANNOTATED	Summary: IPI protein binding from another 14-3-3-binding protein study (Jin et al. 2004). Focused on cytoskeletal regulation and cellular organization. Reason: High-throughput 14-3-3 interaction proteomics study. Generic protein binding is uninformative. The biological relevance to ATP5F1A function is unclear. Supporting Evidence: PMID:15324660 Proteomic, functional, and domain-based analysis of in vivo 14-3-3 binding proteins involved in cytoskeletal regulation and cellular organization.
GO:0005515 protein binding	IPI PMID:19343720 Identification and characterization of proteins interacting ...	MARK AS OVER ANNOTATED	Summary: IPI protein binding from a study identifying proteins interacting with SIRT1 and SIRT3 (Law et al. 2009). UniProt confirms SIRT3 interaction with ATP5F1A. SIRT3 is a mitochondrial deacetylase that regulates the acetylation of OXPHOS components. Reason: While the SIRT3 interaction is biologically meaningful (SIRT3 deacetylates ATP5F1A as part of mitochondrial metabolic regulation), the generic "protein binding" term is uninformative. A more specific term would be preferable. Supporting Evidence: PMID:19343720 Identification and characterization of proteins interacting with SIRT1 and SIRT3
GO:0005515 protein binding	IPI PMID:19688755 LC-MS/MS as an alternative for SDS-PAGE in blue native analy...	MARK AS OVER ANNOTATED	Summary: IPI protein binding from an LC-MS/MS study analyzing protein complexes by blue native analysis (Wessels et al. 2009). This likely detected ATP5F1A as part of intact Complex V. Reason: Large-scale proteomic study. The detection of ATP5F1A in protein complexes is expected given that it is a subunit of Complex V. Generic protein binding is uninformative. Supporting Evidence: PMID:19688755 LC-MS/MS as an alternative for SDS-PAGE in blue native analysis of protein complexes.
GO:0005515 protein binding	IPI PMID:20618440 Proteomic and biochemical analysis of 14-3-3-binding protein...	MARK AS OVER ANNOTATED	Summary: IPI protein binding from proteomic analysis of 14-3-3-binding proteins during C2-ceramide-induced apoptosis (Pozuelo-Rubio 2010). Reason: Another 14-3-3 interaction proteomics study. Generic protein binding is uninformative. The biological relevance to ATP5F1A function is unclear. Supporting Evidence: PMID:20618440 Proteomic and biochemical analysis of 14-3-3-binding proteins during C2-ceramide-induced apoptosis.
GO:0005515 protein binding	IPI PMID:22309213 Identification of a molecular component of the mitochondrial...	MARK AS OVER ANNOTATED	Summary: IPI protein binding from a study identifying GCN5L1 (BLOC1S1) as a mitochondrial acetyltransferase component (Scott et al. 2012). UniProt confirms that ATP5F1A interacts with BLOC1S1 and that BLOC1S1 is required for acetylation of ATP5F1A. BLOC1S1 promotes acetylation of SIRT3 respiratory chain targets. Reason: The interaction with BLOC1S1/GCN5L1 is biologically meaningful for mitochondrial acetylation regulation, but the generic "protein binding" term is uninformative. The study showed that GCN5L1 interacts with and promotes acetylation of respiratory chain targets, including ATP5F1A. Supporting Evidence: PMID:22309213 GCN5L1 interacts with and promotes acetylation of SIRT3 respiratory chain targets and reverses global SIRT3 effects on mitochondrial protein acetylation, respiration and bioenergetics.
GO:0005515 protein binding	IPI PMID:27499296 Mitochondrial Protein Interaction Mapping Identifies Regulat...	MARK AS OVER ANNOTATED	Summary: IPI protein binding from mitochondrial protein interaction mapping study (Floyd et al. 2016). Focused mitochondrial interactome study identifying regulators of respiratory chain function. Reason: While this is a mitochondria-focused interaction study, the generic protein binding term is uninformative. The study mapped mitochondrial protein interactions but the specific functional significance for ATP5F1A is not captured by this annotation. Supporting Evidence: PMID:27499296 Mitochondrial Protein Interaction Mapping Identifies Regulators of Respiratory Chain Function.
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MARK AS OVER ANNOTATED	Summary: IPI protein binding from a large-scale human interactome mapping study (Huttlin et al. 2017). High-throughput study mapping the architecture of the human interactome. Reason: Large-scale interactome study. Generic protein binding is uninformative for a well-characterized enzyme subunit. Supporting Evidence: PMID:28514442 Architecture of the human interactome defines protein communities and disease networks.
GO:0005515 protein binding	IPI PMID:30021884 Histone Interaction Landscapes Visualized by Crosslinking Ma...	MARK AS OVER ANNOTATED	Summary: IPI protein binding from a histone interaction landscape study using crosslinking mass spectrometry in intact cell nuclei (Fasci et al. 2018). ATP5F1A detected as a histone-interacting protein. Reason: This study focused on histone interactions by crosslinking mass spectrometry. Detection of ATP5F1A likely reflects its abundance rather than a specific functional interaction with histones. Generic protein binding is uninformative. Supporting Evidence: PMID:30021884 Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei.
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	MARK AS OVER ANNOTATED	Summary: IPI protein binding from interactome mapping focused on neurodegenerative disease proteins (Haenig et al. 2020). UniProt documents an interaction with HTT (huntingtin). Reason: Disease-focused interactome study. Generic protein binding is uninformative. The interaction with neurodegenerative disease proteins is likely not a core function of ATP5F1A. Supporting Evidence: PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: IPI protein binding from dual proteome-scale network study showing cell-specific remodeling of the human interactome (Huttlin et al. 2021). Reason: Large-scale interactome study. Generic protein binding is uninformative. Supporting Evidence: PMID:33961781 Through affinity-purification mass spectrometry, we have created two proteome-scale, cell-line-specific interaction networks.
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	MARK AS OVER ANNOTATED	Summary: IPI protein binding from multimodal cell maps study (2024). High-throughput study mapping structural and functional genomics. Reason: Large-scale high-throughput study. Generic protein binding is uninformative for ATP5F1A. Supporting Evidence: PMID:40205054 Multimodal cell maps as a foundation for structural and functional genomics.
GO:0002020 protease binding	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation for MF based on Ensembl Compara ortholog transfer. Protease binding may relate to the interaction with angiostatin, a proteolytic fragment of plasminogen, which binds the alpha subunit on the cell surface (PMID:10077593). Reason: This likely derives from the ecto-ATP synthase function where the alpha subunit binds angiostatin (a protease fragment of plasminogen) on the cell surface. While the interaction is experimentally documented (PMID:10077593), this is a secondary function associated with ecto-ATP synthase, not the core mitochondrial role. Supporting Evidence: PMID:10077593 Angiostatin binds ATP synthase on the surface of human endothelial cells
GO:0009986 cell surface	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation for CC based on Ensembl Compara. ATP5F1A is present on the cell surface as part of ecto-ATP synthase, demonstrated by flow cytometry and immunofluorescence (PMID:10077593). Reason: Correct but represents a non-core localization. Cell surface presence relates to the ecto-ATP synthase function. Primary localization is mitochondrial. Experimentally supported by Moser et al. (PMID:10077593). Supporting Evidence: PMID:10077593 The presence of this protein on the cell surface was confirmed by flow cytometry and immunofluorescence analysis.
GO:0014850 response to muscle activity	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation for BP from Ensembl Compara ortholog transfer. This is a pleiotropic response annotation likely transferred from a model organism where ATP5F1A expression changes with muscle activity. Reason: While mitochondrial ATP synthase subunit expression could reasonably be modulated by muscle activity (given the high energy demand of muscle), this is a downstream response rather than a core function of ATP5F1A. It reflects the metabolic adaptation of the OXPHOS system to energy demands.
GO:0016020 membrane	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation for CC from Ensembl Compara. Very broad term. ATP5F1A associates with multiple membranes (mitochondrial inner membrane, plasma membrane as ecto-ATP synthase). Reason: Correct but very broad. ATP5F1A is a peripheral membrane protein associated with the mitochondrial inner membrane and cell surface membrane. More specific terms are annotated elsewhere.
GO:0016887 ATP hydrolysis activity	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation for MF with contributes_to qualifier from Ensembl Compara. ATP hydrolysis is the reverse activity of ATP synthase, which can be activated in vitro. UniProt notes that in vivo the enzyme can only synthesize ATP, but its ATP hydrolase activity can be activated artificially in vitro. Reason: The contributes_to qualifier is appropriate. The Complex V can hydrolyze ATP (the reverse reaction) and this is regulated by IF1 (ATPIF1). The alpha subunit contributes to this activity as part of the complex. UniProt states: "In vivo, can only synthesize ATP although its ATP hydrolase activity can be activated artificially in vitro." The immunocapture study (PMID:12110673) directly measured ATP hydrolysis activity of the purified complex. Supporting Evidence: PMID:12110673 The captured complex V displayed ATP hydrolysis activity that was fully oligomycin and inhibitor protein IF(1)-sensitive.
GO:0043531 ADP binding	IEA GO_REF:0000107	ACCEPT	Summary: IEA annotation for MF from Ensembl Compara, duplicating the IBA annotation for the same GO term. Reason: Correct and consistent with the IBA annotation. Duplicate evidence codes are fine. The alpha subunit binds ADP at its non-catalytic nucleotide-binding sites.
GO:0045121 membrane raft	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation for CC from Ensembl Compara. Membrane raft localization may relate to the ecto-ATP synthase function on the cell surface. Reason: This likely relates to the ecto-ATP synthase localization in lipid raft/membrane raft domains on the cell surface, which has been documented for ATP synthase subunits (PMID:17643490 shows co-localization with MHC-I in punctate membrane domains). This is a secondary localization associated with the ecto function. Supporting Evidence: PMID:17643490 Confocal microscopy analysis of MHC-I and ecto-F1-ATPase beta chain expression on HepG2 cells shows a co-localization of both complexes in punctate membrane domains.
GO:0045471 response to ethanol	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation for BP from Ensembl Compara ortholog transfer. This is a broad response annotation likely reflecting that ATP synthase expression is modulated by ethanol exposure. Reason: Ethanol affects mitochondrial function and OXPHOS complex expression, so ATP5F1A expression changes in response to ethanol are plausible but represent a downstream effect rather than a core function. This is a pleiotropic response annotation.
GO:0071549 cellular response to dexamethasone stimulus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation for BP from Ensembl Compara. Dexamethasone can modulate mitochondrial function and gene expression, including OXPHOS components. Reason: Pleiotropic response annotation. Dexamethasone effects on ATP5F1A expression are a secondary consequence of glucocorticoid signaling on mitochondrial metabolism, not a core function.
GO:0071732 cellular response to nitric oxide	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation for BP from Ensembl Compara. Nitric oxide is known to inhibit mitochondrial respiration and can modify Complex V. Reason: Pleiotropic response annotation. NO affects mitochondrial OXPHOS function, and Complex V subunit expression or modification may change in response. This is a downstream effect, not a core function of ATP5F1A.
GO:0005739 mitochondrion	IDA GO_REF:0000052	ACCEPT	Summary: IDA annotation for CC based on curation of immunofluorescence data. Mitochondrial localization confirmed by immunofluorescence. Reason: Correct. Direct experimental evidence for mitochondrial localization via immunofluorescence. This is the primary localization for ATP5F1A.
GO:0005743 mitochondrial inner membrane	NAS PMID:26297831 Assembly of human mitochondrial ATP synthase through two sep...	ACCEPT	Summary: NAS annotation for CC citing the assembly study of human mitochondrial ATP synthase (Fujikawa et al. 2015). The study demonstrates that alpha subunits assemble into the F1-c-ring intermediate at the inner mitochondrial membrane. Reason: Correct. The alpha subunit is part of the F1 head which is attached to the inner mitochondrial membrane via the central stalk connected to the Fo sector. The assembly study shows that F1 (containing alpha subunits) assembles with the c-ring as an intermediate (PMID:26297831). Supporting Evidence: PMID:26297831 When expression of d-subunit, a stator stalk component, was knocked-down, human cells could not form ATP synthase holocomplex and instead accumulated two subcomplexes, one containing a central rotor shaft plus catalytic subunits (F1-c-ring)
GO:0015986 proton motive force-driven ATP synthesis	NAS PMID:26297831 Assembly of human mitochondrial ATP synthase through two sep...	ACCEPT	Summary: NAS annotation for BP citing the assembly study. The study addresses assembly of the ATP synthase rather than directly demonstrating the proton motive force-driven ATP synthesis activity, but the function is well established. Reason: While the cited study focuses on assembly, proton motive force-driven ATP synthesis is the core function of the complex that ATP5F1A assembles into. Well supported by other references. Supporting Evidence: PMID:26297831 Mitochondrial ATP synthase is a motor enzyme in which a central shaft rotates in the stator casings fixed with the peripheral stator stalk.
GO:0015986 proton motive force-driven ATP synthesis	IDA PMID:37244256 Structure of the human ATP synthase.	ACCEPT	Summary: IDA annotation for BP from the cryo-EM structure of human ATP synthase (Lai et al. 2023). The study resolved multiple rotational states demonstrating the proton motive force-driven ATP synthesis mechanism, with ATP5F1A visible as chains A/B/C. Reason: Correct. The structural study directly visualizes the rotary mechanism of ATP synthesis in the human enzyme, with the alpha subunit forming part of the catalytic hexameric head. Represents core function. Supporting Evidence: PMID:37244256 Biological energy currency ATP is produced by F1Fo-ATP synthase. However, the molecular mechanism for human ATP synthase action remains unknown. Here, we present snapshot images for three main rotational states and one substate of human ATP synthase
GO:0045259 proton-transporting ATP synthase complex	IDA PMID:37244256 Structure of the human ATP synthase.	ACCEPT	Summary: IDA annotation for CC from the cryo-EM structure of human ATP synthase. The study directly resolved ATP5F1A as part of the intact complex. Reason: Direct structural evidence. The cryo-EM structure (PDB: 8H9E and others) shows ATP5F1A as chains A/B/C in the intact human ATP synthase complex. Supporting Evidence: PMID:37244256 Structure of the human ATP synthase
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	ACCEPT	Summary: HTP annotation for CC from the quantitative high-confidence human mitochondrial proteome study (Morgenstern et al. 2021). ATP5F1A was identified with high confidence as part of the mitochondrial proteome. Reason: Correct. This high-quality mitochondrial proteomics study provides strong quantitative evidence for mitochondrial localization. ATP5F1A is one of the most abundant mitochondrial proteins. Supporting Evidence: PMID:34800366 We classified >8,000 proteins in mitochondrial preparations of human cells and defined a mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP).
GO:0005739 mitochondrion	IC PMID:12110673 A functionally active human F1F0 ATPase can be purified by i...	ACCEPT	Summary: IC annotation for CC citing the immunocapture study (Aggeler et al. 2002). ATP5F1A was identified as a subunit of immunocaptured F1Fo from heart tissue and fibroblasts. Reason: Correct. The immunocapture study isolated F1Fo from mitochondria, confirming the alpha subunit is a mitochondrial protein. The study identified ATP5F1A with specific antibodies. Supporting Evidence: PMID:12110673 The immunoprecipitated F(1)F(0) contained a full complement of subunits that were identified with specific antibodies against five of the subunits (alpha, beta, OSCP, d, and IF(1))
GO:0045259 proton-transporting ATP synthase complex	IDA PMID:12110673 A functionally active human F1F0 ATPase can be purified by i...	ACCEPT	Summary: IDA annotation for CC from the immunocapture study. ATP5F1A was directly identified as a component of the purified ATP synthase complex from heart tissue and fibroblasts. Reason: Direct experimental evidence. The alpha subunit was identified by specific antibodies in the immunocaptured F1Fo complex. Supporting Evidence: PMID:12110673 The immunoprecipitated F(1)F(0) contained a full complement of subunits that were identified with specific antibodies against five of the subunits (alpha, beta, OSCP, d, and IF(1))
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 for MF with contributes_to qualifier from the immunocapture study. The purified complex containing the alpha subunit displayed ATP hydrolysis activity (the reverse of ATP synthesis via the rotational mechanism), confirming the complex is functional. Reason: Correct. The contributes_to qualifier is appropriate since the alpha subunit contributes to but does not itself catalyze the activity. The study directly measured ATP hydrolysis activity of the immunocaptured complex. Supporting Evidence: PMID:12110673 The captured complex V displayed ATP hydrolysis activity that was fully oligomycin and inhibitor protein IF(1)-sensitive.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-164832	ACCEPT	Summary: TAS annotation for CC from Reactome pathway "ATPase synthesizes ATP". The F1 head where ATP5F1A resides faces the mitochondrial matrix. Reason: Correct. The F1 catalytic head, containing the alpha3-beta3 hexamer, faces the mitochondrial matrix. ATP5F1A is a matrix-exposed peripheral membrane protein.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-164834	ACCEPT	Summary: TAS annotation for CC from Reactome pathway "Enzyme-bound ATP is released". Duplicate CC annotation from a different Reactome reaction. Correct. Reason: Correct. Same localization from a different Reactome reaction in the ATP synthesis pathway. The alpha subunit is in the matrix-facing F1 head.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-164840	ACCEPT	Summary: TAS annotation for CC from Reactome pathway "ADP and Pi bind to ATPase". Duplicate CC annotation from a different Reactome reaction. Correct. Reason: Correct. Same localization from another Reactome reaction step. ADP and Pi binding occurs in the matrix-facing catalytic head.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-8949580	ACCEPT	Summary: TAS annotation for CC from Reactome pathway "F1Fo ATP synthase dimerizes". The dimerization occurs at the inner mitochondrial membrane, with the F1 head in the matrix. Reason: Correct. ATP synthase dimerization is relevant to cristae formation and the alpha subunit is located in the matrix.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-9838035	ACCEPT	Summary: TAS annotation for CC from Reactome pathway "CLPXP binds mitochondrial matrix proteins". ATP5F1A is a substrate of CLPXP protease in the mitochondrial matrix. Reason: Correct. ATP5F1A is a mitochondrial matrix-exposed protein that is recognized by CLPXP as a substrate for quality control/degradation.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-9838081	ACCEPT	Summary: TAS annotation for CC from Reactome pathway "LONP1 degrades mitochondrial matrix proteins". ATP5F1A is a substrate of LONP1 protease in the matrix. Reason: Correct. The matrix-facing F1 head exposes ATP5F1A to matrix proteases like LONP1 for quality control.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-9838093	ACCEPT	Summary: TAS annotation for CC from Reactome pathway "LONP1 binds mitochondrial matrix proteins". Same context as above. Reason: Correct. Duplicate CC annotation from the LONP1 binding step. ATP5F1A is in the mitochondrial matrix.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-9838289	ACCEPT	Summary: TAS annotation for CC from Reactome pathway "CLPXP degrades mitochondrial matrix proteins". Reason: Correct. Same localization from the CLPXP degradation reaction.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-9839105	ACCEPT	Summary: TAS annotation for CC from Reactome pathway "AFG3L2 degrades mitochondrial matrix proteins". Reason: Correct. ATP5F1A is exposed to matrix-side proteases for quality control.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-9839149	ACCEPT	Summary: TAS annotation for CC from Reactome pathway "AFG3L2 binds mitochondrial matrix proteins". Reason: Correct. Same mitochondrial matrix localization from the AFG3L2 binding step.
GO:0006754 ATP biosynthetic process	IMP PMID:21106936 Regenerative protein thymosin beta-4 is a novel regulator of...	ACCEPT	Summary: IMP annotation for BP from the thymosin beta-4 study (Freeman et al. 2011). The study showed that thymosin beta-4 increases cell surface ATP levels via ATP synthase, demonstrating ATP biosynthetic process. Although evidence comes from ecto-ATP synthase, the GO term (ATP biosynthetic process) describes a core function of ATP5F1A. Reason: The GO term GO:0006754 is correct for ATP5F1A. While the evidence comes from the ecto-ATP synthase context, ATP biosynthetic process is a core function of the gene. Consistent with IEA and NAS annotations to the same term. Supporting Evidence: PMID:21106936 we have identified an extracellular signaling pathway where Tβ4 increases cell surface ATP levels via ATP synthase
GO:0043536 positive regulation of blood vessel endothelial cell migration	IGI PMID:21106936 Regenerative protein thymosin beta-4 is a novel regulator of...	KEEP AS NON CORE	Summary: IGI annotation for BP from the thymosin beta-4 study. The study showed that thymosin beta-4 promotes HUVEC migration through ecto-ATP synthase, with ATP-responsive P2X4 receptor required for the migration effect. ATP5F1A participates as part of the ecto-ATP synthase complex. Reason: This is a downstream effect of ecto-ATP synthase function. While the interaction is experimentally demonstrated, positive regulation of endothelial cell migration is mediated through extracellular ATP/purinergic signaling and is a non-core function of ATP5F1A. Supporting Evidence: PMID:21106936 Silencing of the ATP-responsive purinergic receptor P2X4 with siRNA also blocked Tβ4-induced HUVEC migration in a transwell assay.
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 for BP from the immunocapture study (Aggeler et al. 2002). The purified complex containing ATP5F1A was functionally active with ATP hydrolysis (reverse of synthesis), demonstrating the complex's catalytic capability. Reason: Correct. This is the most specific BP annotation for ATP5F1A's core function. The immunocapture study isolated functional F1Fo from human heart tissue and fibroblasts, containing the alpha subunit, and demonstrated catalytic activity. While the alpha subunit is the non-catalytic subunit, it is essential for the process. Supporting Evidence: PMID:12110673 The captured complex V displayed ATP hydrolysis activity that was fully oligomycin and inhibitor protein IF(1)-sensitive.
GO:0045259 proton-transporting ATP synthase complex	IDA PMID:21106936 Regenerative protein thymosin beta-4 is a novel regulator of...	ACCEPT	Summary: IDA annotation for CC from the thymosin beta-4 study. The study identified F1-F0 ATP synthase as a target of thymosin beta-4 by pulldown and mass spectrometry, with ATP5F1A as part of the complex. Reason: Correct. The study directly identified F1-F0 ATP synthase components by mass spectrometry, confirming ATP5F1A as a complex member. Supporting Evidence: PMID:21106936 we identified F1-F0 ATP synthase, a known target of antiangiogenic angiostatin
GO:0046933 proton-transporting ATP synthase activity, rotational mechanism	IMP PMID:21106936 Regenerative protein thymosin beta-4 is a novel regulator of...	ACCEPT	Summary: IMP annotation for MF from the thymosin beta-4 study (Freeman et al. 2011). The study showed that oligomycin (an ATP synthase inhibitor) blocked the thymosin beta-4-induced increase in cell surface ATP levels, demonstrating ATP synthase activity. Although the evidence comes from ecto-ATP synthase on the cell surface, the GO term itself (proton- transporting ATP synthase activity, rotational mechanism) is a core function of ATP5F1A. Reason: The GO term GO:0046933 is correct for ATP5F1A regardless of whether evidence comes from mitochondrial or ecto-ATP synthase context. The term describes the molecular activity of the complex, which is a core function. The alpha subunit contributes to this activity via non-catalytic nucleotide binding sites. Consistent with IBA, IEA, IDA, and ISS annotations to the same term. Supporting Evidence: PMID:21106936 Blocking antibodies and antagonists (oligomycin, IC(50) ∼1.8 μM; piceatannol, IC(50) ∼1.05 μM; and angiostatin, IC(50) ∼2.9 μg/ml) of ATP synthase inhibited the Tβ4-induced increase in cell surface ATP levels, as measured by luciferase assay, and the Tβ4-induced increase in HUVEC migration, as measured by transwell migration assay
GO:0005515 protein binding	IPI PMID:21106936 Regenerative protein thymosin beta-4 is a novel regulator of...	MARK AS OVER ANNOTATED	Summary: IPI protein binding from the thymosin beta-4 study. The study identified the interaction between thymosin beta-4 and F1-F0 ATP synthase by pulldown experiments. However, the binding was specifically to the beta subunit (K_D 12 nM), not the alpha subunit. Reason: The study primarily demonstrates thymosin beta-4 binding to the beta subunit of ATP synthase (K_D 12 nM by SPR). The alpha subunit was co-isolated as part of the complex but was not shown to be the direct binding partner. Generic protein binding is uninformative. Supporting Evidence: PMID:21106936 By surface plasmon resonance, we determined for Tβ4 binding to the β subunit of ATP synthase a K(D) of 12 nM.
GO:0016020 membrane	IDA PMID:21106936 Regenerative protein thymosin beta-4 is a novel regulator of...	ACCEPT	Summary: IDA annotation for CC from the thymosin beta-4 study. This likely refers to the cell surface membrane where ecto-ATP synthase is found. Reason: Correct. ATP5F1A is associated with membranes -- both the mitochondrial inner membrane and the plasma membrane (as ecto-ATP synthase). Very broad but acceptable. Supporting Evidence: PMID:21106936 we identified F1-F0 ATP synthase, a known target of antiangiogenic angiostatin
GO:0043532 angiostatin binding	IPI PMID:21106936 Regenerative protein thymosin beta-4 is a novel regulator of...	KEEP AS NON CORE	Summary: IPI annotation for MF from the thymosin beta-4 study. However, this annotation appears incorrectly attributed to this reference. The original angiostatin binding to ATP5F1A was demonstrated in PMID:10077593 (Moser et al. 1999), where angiostatin was shown to bind the alpha/beta subunits of ATP synthase on the cell surface. Reason: Angiostatin binding to ATP5F1A is well documented (PMID:10077593) and confirmed by multiple studies. However, it is a non-core function related to ecto-ATP synthase. The referenced study (PMID:21106936) does mention angiostatin as an ATP synthase antagonist but the primary evidence for angiostatin binding to the alpha subunit comes from PMID:10077593. Supporting Evidence: PMID:10077593 Angiostatin also bound to the recombinant alpha-subunit of human ATP synthase, and this binding was not inhibited by a 2,500-fold molar excess of plasminogen. PMID:21106936 we identified F1-F0 ATP synthase, a known target of antiangiogenic angiostatin
GO:0005515 protein binding	IPI PMID:11741979 Interaction of the C-terminal domain of p43 and the alpha su...	MARK AS OVER ANNOTATED	Summary: IPI protein binding from the p43/EMAP II study (Chang et al. 2002). The study demonstrated that EMAP II (C-terminal domain of p43) binds the alpha subunit of ATP synthase on the cell surface and inhibits endothelial cell proliferation. Reason: The interaction with EMAP II is specific and functionally characterized (EMAP II binds cell-surface alpha-ATP synthase and inhibits endothelial cell growth). However, the generic "protein binding" term is uninformative. This is also a non-core ecto-ATP synthase function. Supporting Evidence: PMID:11741979 The isolated protein was determined to be the alpha subunit of ATP synthase. The interaction of EMAP II and alpha-ATP synthase was confirmed by enzyme-linked immunosorbent assay and in vitro pull down assays
GO:0070062 extracellular exosome	HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres...	KEEP AS NON CORE	Summary: HDA annotation for CC from in-depth proteomic analysis of exosomes isolated from expressed prostatic secretions in urine. ATP5F1A was identified in exosomal fractions. Reason: Detection of ATP5F1A in extracellular exosomes is consistent with its abundance and the known presence of mitochondrial proteins in exosomes. This is a non-core localization. Supporting Evidence: PMID:23533145 In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine.
GO:0016020 membrane	HDA PMID:19946888 Defining the membrane proteome of NK cells.	ACCEPT	Summary: HDA annotation for CC from a study defining the membrane proteome of NK cells. ATP5F1A was identified in the membrane fraction. Reason: Correct. ATP5F1A is a membrane-associated protein (mitochondrial inner membrane and potentially cell surface). Detection in the membrane proteome is expected. Supporting Evidence: PMID:19946888 Defining the membrane proteome of NK cells.
GO:0003723 RNA binding	HDA PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-bi...	MARK AS OVER ANNOTATED	Summary: HDA annotation for MF from the mammalian mRNA-binding protein atlas study (Castello et al. 2012). ATP5F1A was detected as an mRNA-binding protein in this large-scale UV crosslinking study. Reason: This is from a large-scale UV crosslinking study that identified thousands of mRNA-binding proteins. Many abundant proteins are detected in such screens due to non-specific crosslinking. RNA binding is not a characterized function of ATP5F1A and is likely an artifact of the protein's high abundance. Supporting Evidence: PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.
GO:0005739 mitochondrion	HDA PMID:20833797 Phosphoproteome analysis of functional mitochondria isolated...	ACCEPT	Summary: HDA annotation for CC from a phosphoproteome analysis of functional mitochondria isolated from resting human muscle (Zhao et al. 2011). ATP5F1A was identified as a phosphorylated mitochondrial protein. Reason: Correct. ATP5F1A was identified in functional mitochondria from human muscle, consistent with its well-established mitochondrial localization and known phosphorylation sites (UniProt documents multiple phosphoserine sites). Supporting Evidence: PMID:20833797 We performed a phosphoproteomics study of functional mitochondria isolated from human muscle biopsies
GO:0070062 extracellular exosome	HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos...	KEEP AS NON CORE	Summary: HDA annotation for CC from large-scale proteomics and phosphoproteomics of urinary exosomes. ATP5F1A was identified in exosomal fractions. Reason: Detection in urinary exosomes is consistent with the abundance of ATP5F1A and the known presence of mitochondrial proteins in exosomal fractions. Non-core localization. Supporting Evidence: PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exosomes.
GO:0005515 protein binding	IPI PMID:19285951 High affinity interaction between histidine-rich glycoprotei...	MARK AS OVER ANNOTATED	Summary: IPI protein binding from a study demonstrating that histidine-rich glycoprotein (HRG) interacts with the alpha subunit of ATP synthase on the surface of T-cells (Ohta et al. 2009). The interaction was specific (K_D 66 nM) and mediates HRG/Con A-induced morphological changes. Reason: The HRG-ATP5F1A interaction is specific and well-characterized (K_D 66 nM). However, generic "protein binding" is uninformative. This is an ecto-ATP synthase interaction. UniProt confirms: "Interacts with HRG; the interaction occurs on the surface of T-cells." Supporting Evidence: PMID:19285951 HRG specifically interacted with mitochondrial ATP synthase with a dissociation constant of 66 nM.
GO:0005743 mitochondrial inner membrane	IDA PMID:19016746 Identification of mitochondrial F(1)F(0)-ATP synthase intera...	ACCEPT	Summary: IDA annotation for CC from a study identifying galectin-3 interaction with mitochondrial F1F0-ATP synthase in colon cancer cells (Kim et al. 2008). The study showed that galectin-3 and ATP synthase co-localized in the inner membrane vesicles of mitochondria. Reason: Correct. The study demonstrated by subcellular fractionation that ATP synthase is in the inner mitochondrial membrane, co-localized with galectin-3. Supporting Evidence: PMID:19016746 Galectin-3 and ATP synthase were co-isolated in the inner membrane vesicles of mitochondria.
GO:0005524 ATP binding	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation for MF based on manual transfer from ortholog by curator judgment. ATP binding is well established for the alpha subunit at its non-catalytic nucleotide-binding sites. Reason: Correct. The alpha subunit binds ATP at non-catalytic regulatory sites. Well supported by structural evidence (PMID:37244256) and UniProt binding site annotations.
GO:0005739 mitochondrion	NAS PMID:1830491 Nucleotide sequence of a cDNA for the alpha subunit of human...	ACCEPT	Summary: NAS annotation for CC citing the original cDNA cloning paper for the alpha subunit (Kataoka & Biswas 1991). The paper describes cloning the cDNA for the alpha subunit of human mitochondrial ATP synthase. Reason: Correct. The original cloning paper established the identity of this gene as encoding the alpha subunit of mitochondrial ATP synthase. Supporting Evidence: PMID:1830491 A full length cDNA clone of the alpha subunit of mitochondrial ATP synthase (EC 3.6.1.34) has been isolated from a cDNA library prepared from LX-1 human tumor cells
GO:0006629 lipid metabolic process	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS annotation for BP based on ortholog transfer. Lipid metabolic process may relate to the ecto-ATP synthase role in HDL/apolipoprotein metabolism, where cell surface ATP synthase is involved in HDL endocytosis. Reason: This likely refers to the ecto-ATP synthase function in HDL metabolism. Cell-surface ATP synthase has been implicated in apolipoprotein A-I-stimulated HDL endocytosis in hepatocytes. While this is a legitimate function, it is secondary to the core mitochondrial role.
GO:0006754 ATP biosynthetic process	NAS PMID:1830491 Nucleotide sequence of a cDNA for the alpha subunit of human...	ACCEPT	Summary: NAS annotation for BP citing the original cDNA cloning paper. The paper describes ATP5F1A as a subunit of mitochondrial ATP synthase, implying its role in ATP biosynthesis. Reason: Correct. The original paper identified this gene as encoding a subunit of ATP synthase (EC 3.6.1.34), which is responsible for ATP biosynthesis. Supporting Evidence: PMID:1830491 A full length cDNA clone of the alpha subunit of mitochondrial ATP synthase (EC 3.6.1.34) has been isolated
GO:0046933 proton-transporting ATP synthase activity, rotational mechanism	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation for MF based on ortholog transfer. The proton-transporting ATP synthase activity is well established for this complex. Note this annotation lacks the contributes_to qualifier that is appropriate for the alpha subunit. Reason: Correct term. Ideally should have the contributes_to qualifier for the alpha subunit since catalytic activity resides in the beta subunit, but as an ISS the annotation is acceptable.
GO:0042288 MHC class I protein binding	IDA PMID:17643490 Ecto-F1-ATPase and MHC-class I close association on cell mem...	KEEP AS NON CORE	Summary: IDA annotation for MF from the study showing close association between ecto-F1-ATPase and MHC class I on cell membranes (Vantourout et al. 2008). The study demonstrated that biotinylated F1-ATPase cell surface components co-immunoprecipitate with MHC-I molecules and co-localize in punctate membrane domains. Reason: This is a specific and experimentally supported annotation related to the ecto-ATP synthase function. MHC class I association is relevant to immune recognition (gamma/delta T cell activation) and represents a specialized function on the cell surface. Non-core relative to the primary mitochondrial function. Supporting Evidence: PMID:17643490 biotinylated F1-ATPase cell surface components co-immunoprecipitate with MHC-I molecules confirming the association of both complexes on Raji cells. Confocal microscopy analysis of MHC-I and ecto-F1-ATPase beta chain expression on HepG2 cells shows a co-localization of both complexes in punctate membrane domains.
GO:0001937 negative regulation of endothelial cell proliferation	IMP PMID:10077593 Angiostatin binds ATP synthase on the surface of human endot...	KEEP AS NON CORE	Summary: IMP annotation for BP from the angiostatin binding study (Moser et al. 1999). The study showed that angiostatin binding to ATP synthase alpha/beta subunits on the cell surface mediates its antiproliferative effect, which was inhibited by anti-alpha-subunit antibody. Reason: This is a well-documented ecto-ATP synthase function. Angiostatin binding to cell surface ATP5F1A mediates inhibition of endothelial cell proliferation. However, this is a non-core function related to the ecto-ATP synthase role, not the primary mitochondrial function. Supporting Evidence: PMID:10077593 Angiostatin's antiproliferative effect on endothelial cells was inhibited by as much as 90% in the presence of anti-alpha-subunit ATP synthase antibody.
GO:0005886 plasma membrane	IDA PMID:10077593 Angiostatin binds ATP synthase on the surface of human endot...	KEEP AS NON CORE	Summary: IDA annotation for CC from the angiostatin study. Direct experimental evidence for plasma membrane localization by flow cytometry and immunofluorescence. Reason: Correct. The study provided direct evidence for cell surface/plasma membrane localization using flow cytometry and immunofluorescence. This is the ecto-ATP synthase localization, secondary to mitochondrial localization. Supporting Evidence: PMID:10077593 The presence of this protein on the cell surface was confirmed by flow cytometry and immunofluorescence analysis.
GO:0005515 protein binding	IPI PMID:10077593 Angiostatin binds ATP synthase on the surface of human endot...	MARK AS OVER ANNOTATED	Summary: IPI protein binding from the angiostatin study. The study demonstrated specific binding of angiostatin to the alpha/beta subunits of ATP synthase on the cell surface, and confirmed binding to recombinant alpha subunit. Reason: The interaction with angiostatin is specific and well-characterized. However, generic "protein binding" is uninformative. The more specific GO:0043532 (angiostatin binding) is already annotated for this gene, making this generic annotation redundant. Supporting Evidence: PMID:10077593 Angiostatin also bound to the recombinant alpha-subunit of human ATP synthase, and this binding was not inhibited by a 2,500-fold molar excess of plasminogen.

Gene Description

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