id: Q93050 gene_symbol: ATP6V0A1 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- ATP6V0A1 encodes the a1 isoform of the V0 membrane sector of the vacuolar H+-ATPase. It is a multi-pass membrane subunit that helps assemble the proton-translocation sector of V-ATPase complexes on endolysosomal, synaptic vesicle, secretory vesicle, melanosomal, and specialized plasma membranes. By contributing to ATP-driven proton transport, ATP6V0A1 supports acidification of lysosomes, endosomes, synaptic vesicles, and related organelles; pathogenic variants impair endolysosomal acidification and cause severe neurodevelopmental disease with synaptic and autophagy defects. alternative_products: - name: 1 (I) id: Q93050-2 - name: 2 (II) id: Q93050-1 sequence_note: VSP_012814 - name: '3' id: Q93050-3 sequence_note: VSP_043532, VSP_012814 existing_annotations: - term: id: GO:0016471 label: vacuolar proton-transporting V-type ATPase complex evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: part_of review: summary: >- Correct core complex annotation. ATP6V0A1 is a subunit of the V0 membrane sector of the vacuolar proton-transporting V-type ATPase complex. action: ACCEPT reason: >- The UniProt record and human V-ATPase structure place ATP6V0A1 in the V0 proton-translocation sector of the assembled V-ATPase complex. additional_reference_ids: - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt - PMID:33065002 supported_by: - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt supporting_text: proton transport subunit a, a ring of proteolipid subunits - reference_id: PMID:33065002 supporting_text: Here, we report cryo-EM structures of a human V-ATPase - term: id: GO:0046961 label: proton-transporting ATPase activity, rotational mechanism evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: contributes_to review: summary: >- Correct as a contributes_to annotation. ATP6V0A1 is not an isolated catalytic ATPase, but as the V0 a-subunit it contributes to the rotary proton-pumping activity of the complete V-ATPase. action: ACCEPT reason: >- Human V-ATPase is an ATP-driven proton pump; the a-subunit is part of the membrane proton-translocation domain that couples to V1 ATP hydrolysis. additional_reference_ids: - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt - PMID:33065002 - PMID:34909687 supported_by: - reference_id: PMID:33065002 supporting_text: ATP hydrolysis-driven proton pumps that acidify intracellular vesicles - reference_id: PMID:34909687 supporting_text: responsible for proton translocation - term: id: GO:0005886 label: plasma membrane evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: >- Supported but not core for ATP6V0A1. V-ATPases can be present at the plasma membrane in specialized contexts, but the main ATP6V0A1 function is organellar acidification. action: KEEP_AS_NON_CORE reason: >- Keep as a specialized-cell localization rather than a core location for the a1 isoform. additional_reference_ids: - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt - PMID:33065002 supported_by: - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt supporting_text: certain cell types, can be exported to the plasma membrane - term: id: GO:0007035 label: vacuolar acidification evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: >- Correct core biological process. ATP6V0A1 contributes to V-ATPase-mediated acidification of intracellular organelles. action: ACCEPT reason: >- Although lysosomal and endosomal terms are more precise in mammalian cells, vacuolar acidification captures the conserved V-ATPase role in organelle lumen acidification. additional_reference_ids: - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt - PMID:33065002 - PMID:33833240 supported_by: - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt supporting_text: acidification of various organelles, such as lysosomes, endosomes - reference_id: PMID:33833240 supporting_text: These data suggested that all ATP6V0A1 missense variants impaired lysosomal acidification in cell lines. - term: id: GO:0051117 label: ATPase binding evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: summary: >- Supported V0-V1 interface annotation, but non-core. ATP6V0A1 binds V1-sector ATPase subunits as part of V-ATPase assembly/regulation; this interaction is secondary to the proton-pump function. action: KEEP_AS_NON_CORE reason: >- The ATPase-binding term captures a real subunit-interface property but should not displace the complex-level proton transport function as the core molecular role. additional_reference_ids: - PMID:17360703 - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt supported_by: - reference_id: PMID:17360703 supporting_text: These interactions represent a novel link between the V(1) and V(0) domains in man - term: id: GO:0000220 label: vacuolar proton-transporting V-type ATPase, V0 domain evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: part_of review: summary: >- Correct V0-domain component annotation from InterPro. ATP6V0A1 is the a-subunit of the V0 membrane sector. action: ACCEPT reason: >- The V0-domain annotation is central to ATP6V0A1 identity and is supported by UniProt and human V-ATPase structural work. additional_reference_ids: - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt - PMID:33065002 supported_by: - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt supporting_text: proton transport subunit a, a ring of proteolipid subunits - term: id: GO:0030665 label: clathrin-coated vesicle membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: >- Plausible non-core localization. UniProt maps ATP6V0A1 to clathrin-coated vesicle membrane by similarity, consistent with V-ATPase function in vesicular compartments. action: KEEP_AS_NON_CORE reason: >- This is a specific vesicle-membrane localization, but the core localization/function is broader endolysosomal and synaptic vesicle acidification. additional_reference_ids: - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt supported_by: - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt supporting_text: secretory vesicle, synaptic vesicle - term: id: GO:0030672 label: synaptic vesicle membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: >- Correct neuronal vesicle localization. ATP6V0A1 is annotated to synaptic vesicle membrane, and mutant mouse evidence supports a role in synaptic vesicle proton-dependent neurotransmitter loading. action: ACCEPT reason: >- The a1 isoform is brain enriched and supports proton-gradient-dependent synaptic vesicle function. additional_reference_ids: - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt - PMID:33833240 supported_by: - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt supporting_text: secretory vesicle, synaptic vesicle - reference_id: PMID:33833240 supporting_text: the neurotransmitter content of synaptic vesicles was indeed lowered in Atp6v0a1A512P/A512P mice, presumably due to the reduced proton pump activity. - term: id: GO:0033179 label: proton-transporting V-type ATPase, V0 domain evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: part_of review: summary: >- Correct V0-domain component annotation. This is the generic V0-domain term and is already consistent with the PN projection. action: ACCEPT reason: >- ATP6V0A1 is the a-subunit of the V0 proton-translocation sector of V-ATPase. additional_reference_ids: - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt - PMID:33065002 supported_by: - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt supporting_text: proton transport subunit a, a ring of proteolipid subunits - term: id: GO:0042470 label: melanosome evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: >- Supported but non-core localization. ATP6V0A1 was identified in melanosome fractions, but melanosomes are a specialized lysosome-related organelle context rather than the core role of the gene. action: KEEP_AS_NON_CORE reason: >- Retain melanosome localization as a specialized organelle location supported by proteomics and UniProt, not as the main ATP6V0A1 function. additional_reference_ids: - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt - PMID:12643545 - PMID:17081065 supported_by: - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt supporting_text: melanosome fractions from stage I to stage IV - reference_id: PMID:12643545 supporting_text: identify protein components of early melanosomes - term: id: GO:0046961 label: proton-transporting ATPase activity, rotational mechanism evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: >- Correct V-ATPase activity term. ATP6V0A1 contributes to the rotary proton-pumping activity of the complete V-ATPase; the term is appropriate when interpreted in the complex-subunit context already captured by the IBA contributes_to row. action: MODIFY reason: >- The GO term itself is correct for the V-ATPase complex activity, but the IEA qualifier should be changed from enables to contributes_to because ATP6V0A1 is a V0-sector subunit rather than an isolated catalytic ATPase. proposed_replacement_terms: - id: GO:0046961 label: proton-transporting ATPase activity, rotational mechanism additional_reference_ids: - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt - PMID:33065002 supported_by: - reference_id: PMID:33065002 supporting_text: ATP hydrolysis-driven proton pumps that acidify intracellular vesicles - term: id: GO:1902600 label: proton transmembrane transport evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: involved_in review: summary: >- Correct core process. The V0 a-subunit participates directly in proton transmembrane transport across organelle membranes. action: ACCEPT reason: >- ATP6V0A1 is part of the membrane proton-translocation domain, and pathogenic variants perturb proton translocation/acidification. additional_reference_ids: - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt - PMID:34909687 supported_by: - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt supporting_text: proton transport subunit a, a ring of proteolipid subunits - reference_id: PMID:34909687 supporting_text: responsible for proton translocation - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:7896830 qualifier: enables review: summary: >- Remove. The cited publication defines binding of papillomavirus E5 to the 16 kDa V-ATPase proteolipid subunit, not ATP6V0A1/a1. action: REMOVE reason: >- This appears to be a mismatched or over-propagated protein-binding annotation. ATP6V0A1 has other valid interaction evidence, but PMID:7896830 does not support ATP6V0A1 protein binding. additional_reference_ids: - PMID:7896830 supported_by: - reference_id: PMID:7896830 supporting_text: The 16K subunit of the vacuolar H(+)-ATPase binds specifically - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: >- Too broad. ATP6V0A1 has cytoplasmic domains but is a multi-pass membrane V-ATPase subunit; cytoplasm alone loses the informative membrane/complex localization. action: MARK_AS_OVER_ANNOTATED reason: >- Prefer membrane-sector and organelle membrane annotations over a broad cytoplasm location. additional_reference_ids: - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt supported_by: - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt supporting_text: Required for assembly and activity of the vacuolar ATPase - term: id: GO:0048471 label: perinuclear region of cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: >- Plausible but non-core transferred localization. Perinuclear cytoplasm is compatible with endolysosomal/Golgi-region organelles but is less informative than the specific membrane compartments. action: KEEP_AS_NON_CORE reason: >- Keep as broad cellular context from orthology transfer, while relying on lysosomal/endosomal/synaptic vesicle membrane terms for core localization. additional_reference_ids: - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt supported_by: - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt supporting_text: acidification of various organelles, such as lysosomes, endosomes - term: id: GO:0097401 label: synaptic vesicle lumen acidification evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: >- Correct neuronal process. ATP6V0A1 supports synaptic vesicle proton gradients needed for neurotransmitter loading. action: ACCEPT reason: >- Mouse variant data show lowered synaptic vesicle neurotransmitter content, consistent with reduced V-ATPase proton-pump activity. additional_reference_ids: - PMID:33833240 - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt supported_by: - reference_id: PMID:33833240 supporting_text: the neurotransmitter content of synaptic vesicles was indeed lowered in Atp6v0a1A512P/A512P mice, presumably due to the reduced proton pump activity. - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt supporting_text: secretory vesicle, synaptic vesicle - term: id: GO:0007042 label: lysosomal lumen acidification evidence_type: NAS original_reference_id: PMID:33065002 qualifier: involved_in review: summary: >- Correct core lysosomal process. Human ATP6V0A1 variants impair lysosomal acidification, and the V-ATPase complex maintains lysosomal pH. action: ACCEPT reason: >- This is one of the strongest ATP6V0A1 process annotations and is directly aligned with the PN lysosomal acidification row. additional_reference_ids: - PMID:33065002 - PMID:33833240 - PMID:34909687 supported_by: - reference_id: PMID:33065002 supporting_text: pH homeostasis of endosomes and lysosomes - reference_id: PMID:33833240 supporting_text: These data suggested that all ATP6V0A1 missense variants impaired lysosomal acidification in cell lines. - reference_id: PMID:34909687 supporting_text: direct impairment of endolysosome acidification and failure of lysosomal functions. - term: id: GO:0016020 label: membrane evidence_type: IDA original_reference_id: PMID:33065002 qualifier: located_in review: summary: >- Correct but too broad. ATP6V0A1 is a membrane protein, but generic membrane does not capture its V0-sector/endolysosomal and vesicular membrane identity. action: MARK_AS_OVER_ANNOTATED reason: >- Use specific V-ATPase complex and organelle membrane annotations where possible. additional_reference_ids: - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt - PMID:33065002 supported_by: - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt supporting_text: Required for assembly and activity of the vacuolar ATPase - term: id: GO:0033176 label: proton-transporting V-type ATPase complex evidence_type: NAS original_reference_id: PMID:33065002 qualifier: part_of review: summary: >- Correct complex annotation. ATP6V0A1 is part of the proton-transporting V-type ATPase complex described structurally in human cells. action: ACCEPT reason: >- The complete human V-ATPase structure and UniProt subunit summary support complex membership. additional_reference_ids: - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt - PMID:33065002 supported_by: - reference_id: PMID:33065002 supporting_text: Here, we report cryo-EM structures of a human V-ATPase - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt supporting_text: proton transport subunit a, a ring of proteolipid subunits - term: id: GO:0048388 label: endosomal lumen acidification evidence_type: NAS original_reference_id: PMID:32001091 qualifier: involved_in review: summary: >- Correct process annotation. V-ATPase acidifies endosomes, and ATP6V0A1 contributes to the proton-translocation sector. action: ACCEPT reason: >- Endosomal acidification is a core organelle-acidification output of V-ATPase. additional_reference_ids: - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt - PMID:33065002 - Reactome:R-HSA-74723 supported_by: - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt supporting_text: acidification of various organelles, such as lysosomes, endosomes - reference_id: PMID:33065002 supporting_text: pH homeostasis of endosomes and lysosomes - reference_id: Reactome:R-HSA-74723 supporting_text: The effect of the proton pump is to allow entry of [H+] ions into the lumen of the endosome. - term: id: GO:1902600 label: proton transmembrane transport evidence_type: NAS original_reference_id: PMID:33065002 qualifier: involved_in review: summary: >- Correct core process. ATP6V0A1 contributes to ATP-driven proton transport across cellular membranes. action: ACCEPT reason: >- This process is supported by V-ATPase structure/function literature and ATP6V0A1 disease variants that impair acidification. additional_reference_ids: - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt - PMID:33065002 - PMID:34909687 supported_by: - reference_id: PMID:33065002 supporting_text: ATP hydrolysis-driven proton pumps that acidify intracellular vesicles - reference_id: PMID:34909687 supporting_text: responsible for proton translocation - term: id: GO:0042470 label: melanosome evidence_type: EXP original_reference_id: PMID:12643545 qualifier: located_in review: summary: >- Supported but non-core localization from melanosome proteomics. action: KEEP_AS_NON_CORE reason: >- Melanosome localization is experimentally supported, but it is a specialized lysosome-related organelle location rather than the main ATP6V0A1 role. additional_reference_ids: - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt - PMID:12643545 supported_by: - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt supporting_text: melanosome fractions from stage I to stage IV - reference_id: PMID:12643545 supporting_text: identify protein components of early melanosomes - term: id: GO:0042470 label: melanosome evidence_type: EXP original_reference_id: PMID:17081065 qualifier: located_in review: summary: >- Supported but non-core localization from melanosome proteomics across developmental stages. action: KEEP_AS_NON_CORE reason: >- Retain as specialized lysosome-related organelle localization; do not treat as the core function. additional_reference_ids: - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt - PMID:17081065 supported_by: - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt supporting_text: melanosome fractions from stage I to stage IV - reference_id: PMID:17081065 supporting_text: melanosome proteomes at various developmental stages - term: id: GO:0000220 label: vacuolar proton-transporting V-type ATPase, V0 domain evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: part_of review: summary: >- Correct orthology-supported V0-domain annotation. action: ACCEPT reason: >- The V0-domain role is conserved across V-ATPase a-subunit family members and supported by the human UniProt record. additional_reference_ids: - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt - file:interpro/panther/PTHR11629/PTHR11629-metadata.yaml supported_by: - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt supporting_text: proton transport subunit a, a ring of proteolipid subunits - reference_id: file:interpro/panther/PTHR11629/PTHR11629-metadata.yaml supporting_text: VACUOLAR PROTON ATPASES - term: id: GO:0005765 label: lysosomal membrane evidence_type: TAS original_reference_id: PMID:22982048 qualifier: located_in review: summary: >- Correct lysosomal membrane localization. Although the original TAS citation is indirect, ATP6V0A1 localization and functional evidence strongly support lysosomal V-ATPase membership. action: ACCEPT reason: >- ATP6V0A1 localizes with lysosomal V-ATPase in cell assays and disease variants impair lysosomal acidification. additional_reference_ids: - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt - PMID:33833240 supported_by: - reference_id: PMID:33833240 supporting_text: These data suggested that all ATP6V0A1 missense variants impaired lysosomal acidification in cell lines. - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt supporting_text: acidification of various organelles, such as lysosomes, endosomes - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-6798743 qualifier: located_in review: summary: >- Supported specialized-cell localization. Reactome places V-ATPase-containing secretory vesicle membranes at the plasma membrane during degranulation. action: KEEP_AS_NON_CORE reason: >- This is a contextual trafficking/localization annotation and not the primary ATP6V0A1 function. additional_reference_ids: - Reactome:R-HSA-6798743 - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt supported_by: - reference_id: Reactome:R-HSA-6798743 supporting_text: Secretory vesicles provide a reservoir of membrane-associated receptors - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt supporting_text: certain cell types, can be exported to the plasma membrane - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-6800426 qualifier: located_in review: summary: >- Supported specialized neutrophil granule/plasma membrane context, but non-core. action: KEEP_AS_NON_CORE reason: >- Retain as a Reactome-derived specialized localization while keeping organelle acidification as the core role. additional_reference_ids: - Reactome:R-HSA-6800426 - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt supported_by: - reference_id: Reactome:R-HSA-6800426 supporting_text: Ficoli-1 rich granules are a relatively new fourth neutrophil granule population - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt supporting_text: certain cell types, can be exported to the plasma membrane - term: id: GO:0030667 label: secretory granule membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-6798743 qualifier: located_in review: summary: >- Supported secretory granule membrane context for V-ATPase-containing vesicles, but non-core. action: KEEP_AS_NON_CORE reason: >- Secretory granules are one organelle class acidified by V-ATPase; this is narrower cellular context rather than a separate core function. additional_reference_ids: - Reactome:R-HSA-6798743 - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt supported_by: - reference_id: Reactome:R-HSA-6798743 supporting_text: Secretory vesicles provide a reservoir of membrane-associated receptors - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt supporting_text: acidification of various organelles, such as lysosomes, endosomes - term: id: GO:0101003 label: ficolin-1-rich granule membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-6800426 qualifier: located_in review: summary: >- Supported ficolin-1-rich granule membrane context in neutrophil degranulation, but non-core. action: KEEP_AS_NON_CORE reason: >- This specific granule class is a specialized immune-cell localization; ATP6V0A1 core function remains V-ATPase proton transport. additional_reference_ids: - Reactome:R-HSA-6800426 - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt supported_by: - reference_id: Reactome:R-HSA-6800426 supporting_text: Ficoli-1 rich granules are a relatively new fourth neutrophil granule population - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt supporting_text: acidification of various organelles, such as lysosomes, endosomes - term: id: GO:0007035 label: vacuolar acidification evidence_type: TAS original_reference_id: PMID:22982048 qualifier: involved_in review: summary: >- Correct organelle acidification process. The original lipofuscin paper is indirect for ATP6V0A1, but independent ATP6V0A1 and V-ATPase evidence strongly supports vacuolar/endolysosomal acidification. action: ACCEPT reason: >- Retain the process because it is supported by direct ATP6V0A1 mutant acidification assays and general V-ATPase structure/function evidence. additional_reference_ids: - PMID:33833240 - PMID:33065002 - PMID:22982048 supported_by: - reference_id: PMID:33833240 supporting_text: These data suggested that all ATP6V0A1 missense variants impaired lysosomal acidification in cell lines. - reference_id: PMID:33065002 supporting_text: ATP hydrolysis-driven proton pumps that acidify intracellular vesicles - term: id: GO:0016241 label: regulation of macroautophagy evidence_type: IMP original_reference_id: PMID:22982048 qualifier: involved_in review: summary: >- Keep as non-core. V-ATPase dysfunction causes autophagy defects, but this reflects lysosomal/endolysosomal acidification and autophagic flux rather than ATP6V0A1 acting as a dedicated macroautophagy regulator. action: KEEP_AS_NON_CORE reason: >- Aoto and Bott show autophagy defects when ATP6V0A1/V-ATPase function is impaired; the direct core function is proton pumping and organelle acidification. additional_reference_ids: - PMID:33833240 - PMID:34909687 - PMID:22982048 - PMID:28024296 supported_by: - reference_id: PMID:33833240 supporting_text: Lysosomal dysfunction resulting in cell death, impaired autophagy, and reduced mTORC1 signaling and synaptic connectivity - reference_id: PMID:22982048 supporting_text: macroautophagy is responsible for the uptake of lipofuscin into the lysosomes. - reference_id: PMID:28024296 supporting_text: localized to the late endosome/lysosome and interacts with the lysosomal v-ATPase to negatively regulate mTORC1 activation - term: id: GO:0070062 label: extracellular exosome evidence_type: HDA original_reference_id: PMID:23533145 qualifier: located_in review: summary: >- High-throughput exosome localization, not a core ATP6V0A1 compartment. action: MARK_AS_OVER_ANNOTATED reason: >- Exosome proteomics can reflect vesicular trafficking or membrane protein carryover; it does not define the main site of ATP6V0A1 function. additional_reference_ids: - PMID:23533145 supported_by: - reference_id: PMID:23533145 supporting_text: exosome preparations were characterized by a shotgun proteomics procedure. - term: id: GO:0070062 label: extracellular exosome evidence_type: HDA original_reference_id: PMID:19056867 qualifier: located_in review: summary: >- High-throughput urinary exosome localization, not a core ATP6V0A1 compartment. action: MARK_AS_OVER_ANNOTATED reason: >- Retain the evidence as a high-throughput detection but do not treat extracellular exosome as a primary functional localization. additional_reference_ids: - PMID:19056867 supported_by: - reference_id: PMID:19056867 supporting_text: Here, we used LC-MS/MS to profile the proteome of human urinary exosomes. - term: id: GO:0030670 label: phagocytic vesicle membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-1222516 qualifier: located_in review: summary: >- Supported specialized phagocytic vesicle membrane context. V-ATPase acidifies phagosomes, but this is a cell-context-specific location. action: KEEP_AS_NON_CORE reason: >- Reactome supports V-ATPase-driven phagosomal acidification; the annotation should remain secondary to the general endolysosomal/synaptic vesicle acidification function. additional_reference_ids: - Reactome:R-HSA-1222516 - PMID:33065002 supported_by: - reference_id: Reactome:R-HSA-1222516 supporting_text: ATP hydrolysis drives a 120 degree rotation of the rotor which leads to movement of three protons into the phagosome - reference_id: PMID:33065002 supporting_text: ATP hydrolysis-driven proton pumps that acidify intracellular vesicles - term: id: GO:0010008 label: endosome membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-5252133 qualifier: located_in review: summary: >- Correct endosome membrane localization in a V-ATPase assembly/accessory-subunit pathway context. action: ACCEPT reason: >- ATP6V0A1 contributes to V-ATPase complexes on endosomal membranes where proton pumping acidifies the endosomal lumen. additional_reference_ids: - Reactome:R-HSA-5252133 - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt - PMID:33065002 supported_by: - reference_id: PMID:33065002 supporting_text: pH homeostasis of endosomes and lysosomes - term: id: GO:0010008 label: endosome membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-74723 qualifier: located_in review: summary: >- Correct endosome membrane localization for endosome acidification. action: ACCEPT reason: >- Endosome membrane is a core V-ATPase location and directly matches endosomal acidification evidence. additional_reference_ids: - Reactome:R-HSA-74723 - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt - PMID:33065002 supported_by: - reference_id: Reactome:R-HSA-74723 supporting_text: The effect of the proton pump is to allow entry of [H+] ions into the lumen of the endosome. - reference_id: PMID:33065002 supporting_text: pH homeostasis of endosomes and lysosomes - term: id: GO:0010008 label: endosome membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-917841 qualifier: located_in review: summary: >- Correct endosome membrane localization in transferrin receptor endosome acidification. action: ACCEPT reason: >- This is a specific Reactome endosomal acidification context for the same core V-ATPase function. additional_reference_ids: - Reactome:R-HSA-917841 - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt - PMID:33065002 supported_by: - reference_id: Reactome:R-HSA-917841 supporting_text: Acidification of Tf:TfR1 containing endosome - reference_id: PMID:33065002 supporting_text: pH homeostasis of endosomes and lysosomes - term: id: GO:0005886 label: plasma membrane evidence_type: IDA original_reference_id: PMID:17360703 qualifier: located_in review: summary: >- Supported but non-core plasma membrane localization. The cited interaction work supports V0-V1 linkage, while UniProt treats plasma membrane export as cell-type-specific. action: KEEP_AS_NON_CORE reason: >- Use as specialized localization context only; organelle membrane acidification remains the primary role. additional_reference_ids: - PMID:17360703 - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt supported_by: - reference_id: PMID:17360703 supporting_text: These interactions represent a novel link between the V(1) and V(0) domains in man - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt supporting_text: certain cell types, can be exported to the plasma membrane - term: id: GO:0051117 label: ATPase binding evidence_type: IPI original_reference_id: PMID:17360703 qualifier: enables supporting_entities: - UniProtKB:O75348 review: summary: >- Supported V0-V1 interaction with ATP6V1G1/G1, but non-core molecular function. action: KEEP_AS_NON_CORE reason: >- The G-subunit/a-subunit interaction links V1 and V0 domains and is relevant to assembly/regulation, but proton transport is the core function. additional_reference_ids: - PMID:17360703 supported_by: - reference_id: PMID:17360703 supporting_text: These interactions represent a novel link between the V(1) and V(0) domains in man - term: id: GO:0051117 label: ATPase binding evidence_type: IPI original_reference_id: PMID:17360703 qualifier: enables supporting_entities: - UniProtKB:Q96LB4 review: summary: >- Supported V0-V1 interaction with ATP6V1G3/G3, but non-core molecular function. action: KEEP_AS_NON_CORE reason: >- The G-subunit/a-subunit interaction links V1 and V0 domains and is relevant to assembly/regulation, but proton transport is the core function. additional_reference_ids: - PMID:17360703 supported_by: - reference_id: PMID:17360703 supporting_text: similar G1/a1, G3/a1, and G1/a4 interactions were also demonstrated - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:12649290 qualifier: enables review: summary: >- The PFK-1 interaction with the a1 subunit is supported, but generic protein binding is an uninformative over-annotation for ATP6V0A1. action: MARK_AS_OVER_ANNOTATED reason: >- Keep the interaction as context for possible metabolic regulation, but do not treat generic protein binding as a core molecular function. additional_reference_ids: - PMID:12649290 supported_by: - reference_id: PMID:12649290 supporting_text: An in vitro bead-bound PFK-1 pull-down assay showed that this interaction was also true for the ubiquitously expressed a1 subunit. - term: id: GO:0046610 label: lysosomal proton-transporting V-type ATPase, V0 domain evidence_type: IC original_reference_id: file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_candidate_additions.tsv qualifier: part_of review: summary: >- NEW annotation from conservative PN projection review. ATP6V0A1 already has generic V0-domain and lysosomal membrane/acidification annotations; GO:0046610 adds the lysosomal V0-domain specificity supported by the PN row and independent ATP6V0A1/V-ATPase evidence. action: NEW reason: >- The PN candidate is not accepted merely by propagation. It is retained because ATP6V0A1 is a V0-sector a-subunit, V-ATPase operates on lysosomal/endolysosomal membranes, and ATP6V0A1 variants directly impair lysosomal/endolysosomal acidification. additional_reference_ids: - file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_candidate_additions.tsv - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt - PMID:33833240 - PMID:34909687 supported_by: - reference_id: file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_candidate_additions.tsv supporting_text: "ATP6V0A1\t\tGO:0046610\tlysosomal proton-transporting V-type ATPase, V0 domain" - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt supporting_text: proton transport subunit a, a ring of proteolipid subunits - reference_id: PMID:33833240 supporting_text: These data suggested that all ATP6V0A1 missense variants impaired lysosomal acidification in cell lines. - reference_id: PMID:34909687 supporting_text: direct impairment of endolysosome acidification and failure of lysosomal functions. references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - id: GO_REF:0000024 title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity findings: [] - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt findings: [] - id: GO_REF:0000107 title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara findings: [] - id: PMID:12643545 title: 'Proteomic analysis of early melanosomes: identification of novel melanosomal proteins.' findings: [] - id: PMID:12649290 title: The a-subunit of the V-type H+-ATPase interacts with phosphofructokinase-1 in humans. findings: [] - id: PMID:17081065 title: Proteomic and bioinformatic characterization of the biogenesis and function of melanosomes. findings: [] - id: PMID:17360703 title: V1 and V0 domains of the human H+-ATPase are linked by an interaction between the G and a subunits. findings: [] - id: PMID:19056867 title: Large-scale proteomics and phosphoproteomics of urinary exosomes. findings: [] - id: PMID:22982048 title: Lipofuscin is formed independently of macroautophagy and lysosomal activity in stress-induced prematurely senescent human fibroblasts. findings: [] - id: PMID:23533145 title: In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine. findings: [] - id: PMID:32001091 title: Structure and Roles of V-type ATPases. findings: [] - id: PMID:33065002 title: Structures of a Complete Human V-ATPase Reveal Mechanisms of Its Assembly. findings: - statement: Human V-ATPase structures support ATP6V0A1/V0 complex membership and ATP-driven proton-pump function. - id: PMID:7896830 title: Vacuolar H(+)-ATPase mutants transform cells and define a binding site for the papillomavirus E5 oncoprotein. findings: [] - id: Reactome:R-HSA-1222516 title: Intraphagosomal pH is lowered to 5 by V-ATPase findings: [] - id: Reactome:R-HSA-5252133 title: ATP6AP1 binds V-ATPase findings: [] - id: Reactome:R-HSA-6798743 title: Exocytosis of secretory granule membrane proteins findings: [] - id: Reactome:R-HSA-6800426 title: Exocytosis of ficolin-rich granule membrane proteins findings: [] - id: Reactome:R-HSA-74723 title: Endosome acidification findings: [] - id: Reactome:R-HSA-917841 title: Acidification of Tf:TfR1 containing endosome findings: [] - id: PMID:33833240 title: ATP6V0A1 encoding the a1-subunit of the V0 domain of vacuolar H(+)-ATPases is essential for brain development in humans and mice. findings: - statement: ATP6V0A1 disease variants impair lysosomal acidification and synaptic vesicle neurotransmitter loading in cell and mouse models. - id: PMID:34909687 title: Variants in ATP6V0A1 cause progressive myoclonus epilepsy and developmental and epileptic encephalopathy. findings: - statement: ATP6V0A1 variants impair endolysosomal acidification and lysosomal function. - id: PMID:28024296 title: mTORC1 and muscle regeneration are regulated by the LINC00961-encoded SPAR polypeptide. findings: - statement: SPAR localizes to late endosome/lysosome, interacts with lysosomal V-ATPase, and negatively regulates amino-acid-stimulated mTORC1 activation. - id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt title: UniProt record for ATP6V0A1 (Q93050) findings: [] - id: file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_candidate_additions.tsv title: Proteostasis PN projected candidate additions for ATP6V0A1 findings: - statement: PN projection flags GO:0046610 as more specific than existing ATP6V0A1 GOA annotations. - id: file:interpro/panther/PTHR11629/PTHR11629-metadata.yaml title: PANTHER family PTHR11629 metadata for vacuolar proton ATPases findings: [] core_functions: - description: >- ATP6V0A1 is the a1 subunit of the V0 membrane sector of V-ATPase and contributes to rotary ATP-driven proton transport by the assembled complex. contributes_to_molecular_function: id: GO:0046961 label: proton-transporting ATPase activity, rotational mechanism directly_involved_in: - id: GO:1902600 label: proton transmembrane transport in_complex: id: GO:0033179 label: proton-transporting V-type ATPase, V0 domain supported_by: - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt supporting_text: proton transport subunit a, a ring of proteolipid subunits - reference_id: PMID:33065002 supporting_text: ATP hydrolysis-driven proton pumps that acidify intracellular vesicles - reference_id: PMID:34909687 supporting_text: responsible for proton translocation - description: >- As part of V-ATPase complexes on endolysosomal and synaptic vesicle membranes, ATP6V0A1 supports acidification of lysosomes, endosomes, and synaptic vesicles, with downstream effects on protein degradation, autophagic flux, mTORC1/Notch signaling contexts, and neurotransmitter loading. contributes_to_molecular_function: id: GO:0046961 label: proton-transporting ATPase activity, rotational mechanism directly_involved_in: - id: GO:0007042 label: lysosomal lumen acidification - id: GO:0048388 label: endosomal lumen acidification - id: GO:0097401 label: synaptic vesicle lumen acidification - id: GO:0007035 label: vacuolar acidification locations: - id: GO:0005765 label: lysosomal membrane - id: GO:0010008 label: endosome membrane - id: GO:0030672 label: synaptic vesicle membrane in_complex: id: GO:0033176 label: proton-transporting V-type ATPase complex supported_by: - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt supporting_text: acidification of various organelles, such as lysosomes, endosomes - reference_id: PMID:33065002 supporting_text: pH homeostasis of endosomes and lysosomes - reference_id: PMID:33833240 supporting_text: These data suggested that all ATP6V0A1 missense variants impaired lysosomal acidification in cell lines. - reference_id: PMID:33833240 supporting_text: the neurotransmitter content of synaptic vesicles was indeed lowered in Atp6v0a1A512P/A512P mice, presumably due to the reduced proton pump activity. proposed_new_terms: [] suggested_questions: - question: For human ATP6V0A1, which cell types have direct evidence for a1-containing V-ATPase at the plasma membrane rather than endolysosomal or secretory vesicle membranes? - question: Do the annotated UniProt isoforms differ in compartment targeting or V0 assembly efficiency in neurons or other tissues? suggested_experiments: - hypothesis: ATP6V0A1 isoforms differ in endolysosomal versus synaptic vesicle targeting in neuronal cells. description: Express tagged ATP6V0A1 isoforms at near-endogenous levels in neurons and quantify colocalization with lysosomal, endosomal, and synaptic vesicle markers together with compartment pH reporters. experiment_type: isoform-resolved localization and organelle pH assay