ATP6V0A4 encodes the a4 isoform of the membrane-integral a subunit of the V-type proton ATPase V0 sector. The protein is a multi-pass V-ATPase component that helps couple ATP hydrolysis in the V1 sector to proton translocation through V0. It is especially important in renal acid-base physiology, where a4-containing pumps are targeted to apical membranes of intercalated cells and other nephron segments to support urinary acidification, and it is also expressed in the inner ear where loss of function can contribute to sensorineural hearing loss. Like other V-ATPase a subunits, ATP6V0A4 participates in acidification of membrane-bounded compartments and specialized extracellular-facing membranes, with its best-supported human roles centered on kidney proton secretion and V-ATPase assembly/coupling.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0016471 vacuolar proton-transporting V-type ATPase complex | IBA GO_REF:0000033 | ACCEPT | Summary: vacuolar proton-transporting V-type ATPase complex is the correct complex context for ATP6V0A4 as an a4 V0-sector subunit of V-ATPase. Reason: ATP6V0A4 is a membrane-integral component of the V0 sector of the V-ATPase holoenzyme; the complex-level annotation is a core representation of its function. Supporting Evidence: file:human/ATP6V0A4/ATP6V0A4-uniprot.txt Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase) PMID:32001091 V-ATPases are membrane-embedded protein complexes that function as ATP hydrolysis-driven proton pumps PMID:33065002 V-ATPases are ATP-driven proton pumps |
| GO:0046961 proton-transporting ATPase activity, rotational mechanism | IBA GO_REF:0000033 | ACCEPT | Summary: ATP6V0A4 contributes to rotational proton-transporting ATPase activity as part of the assembled V-ATPase, rather than acting alone. Reason: The qualifier correctly captures a complex subunit contribution: V1 hydrolyzes ATP and V0 transfers protons, requiring V1/V0 coupling. Supporting Evidence: PMID:18632794 The V0 domain contains at least five different subunits (a, c, c'', d, and e) and transports protons across the membrane PMID:18632794 Coupling of proton transport and ATP hydrolysis PMID:33065002 V-ATPases are ATP-driven proton pumps |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Plasma membrane localization is well supported for specialized V-ATPases containing ATP6V0A4, especially renal intercalated-cell apical membranes. Reason: ATP6V0A4 is a multi-pass membrane component of plasma-membrane-targeted proton pumps used for extracellular/urinary acidification. Supporting Evidence: PMID:10973252 localizes almost exclusively to the apical surface PMID:33065002 Plasma membrane V-ATPases carry out extracellular acidification file:human/ATP6V0A4/ATP6V0A4-uniprot.txt Localizes to the apical surface of alpha- |
| GO:0007035 vacuolar acidification | IBA GO_REF:0000033 | ACCEPT | Summary: Vacuolar acidification is a core V-ATPase process and is the conservative organellar-acidification term for ATP6V0A4. Reason: V-ATPases are the primary source of organellar acidification. For ATP6V0A4, this broad term is better supported than forcing a lysosome-specific projection without a4-specific lysosomal functional evidence. Supporting Evidence: PMID:32001091 primary source of organellar acidification in all eukaryotes PMID:33065002 pH homeostasis of endosomes and lysosomes file:human/ATP6V0A4/ATP6V0A4-uniprot.txt Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase) |
| GO:0051117 ATPase binding | IBA GO_REF:0000033 | ACCEPT | Summary: ATPase binding is supported by ATP6V0A4 interactions with V-ATPase V1-sector subunits and is relevant to V1/V0 coupling. Reason: The a4 subunit binds V-ATPase G subunits and participates in the same proton pump, supporting this more informative binding term. Supporting Evidence: PMID:17360703 identified a possible interaction between the G3 subunit and the a4 subunit PMID:17360703 a4 and G3 are component subunits of the same proton pump PMID:17360703 represent a novel link between the V(1) and V(0) domains |
| GO:0000220 vacuolar proton-transporting V-type ATPase, V0 domain | IEA GO_REF:0000002 | ACCEPT | Summary: vacuolar proton-transporting V-type ATPase, V0 domain is supported because ATP6V0A4 is the a4 isoform of the V0 a subunit. Reason: The a subunit is part of the membrane V0 proton-translocation sector, so V0-domain membership is a core cellular-component annotation. Supporting Evidence: file:human/ATP6V0A4/ATP6V0A4-uniprot.txt Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase) PMID:18632794 The V0 domain contains at least five different subunits (a, c, c'', d, and e) and transports protons across the membrane |
| GO:0016323 basolateral plasma membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Basolateral plasma membrane localization is plausible for beta-intercalated-cell/orthologous contexts but is not the best-supported human a4 core location. Reason: The human evidence emphasizes apical localization in alpha-intercalated and proximal tubule cells. Basolateral localization should be retained as non-core/orthology-supported context. Supporting Evidence: file:human/ATP6V0A4/ATP6V0A4-uniprot.txt Localizes to the basolateral surface of PMID:14638902 All types of intercalated cells expressed a4 |
| GO:0016324 apical plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Apical plasma membrane localization is a primary ATP6V0A4 localization in kidney proton-secreting cells. Reason: Multiple human kidney studies support apical a4 localization in alpha-intercalated cells and related nephron segments. Supporting Evidence: PMID:10973252 localizes almost exclusively to the apical surface PMID:12649290 ATP6V0A4 encodes a4, which is expressed apically PMID:14638902 a4 protein was localized by immunohistochemistry to the apical compartment PMID:15800125 co-localized with the a4 subunit in the characteristic plasma membrane-enhanced pattern |
| GO:0033179 proton-transporting V-type ATPase, V0 domain | IEA GO_REF:0000002 | ACCEPT | Summary: proton-transporting V-type ATPase, V0 domain is supported because ATP6V0A4 is the a4 isoform of the V0 a subunit. Reason: The a subunit is part of the membrane V0 proton-translocation sector, so V0-domain membership is a core cellular-component annotation. Supporting Evidence: file:human/ATP6V0A4/ATP6V0A4-uniprot.txt Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase) PMID:18632794 The V0 domain contains at least five different subunits (a, c, c'', d, and e) and transports protons across the membrane |
| GO:0046961 proton-transporting ATPase activity, rotational mechanism | IEA GO_REF:0000002 | ACCEPT | Summary: The activity term is biologically correct for ATP6V0A4 in the context of the assembled V-ATPase complex. Reason: Retain the term because ATP6V0A4 contributes to V-ATPase rotational proton-pump activity as a V0-sector subunit. The evidence should be interpreted in the complex-subunit context also captured by the IBA contributes_to row. Supporting Evidence: PMID:18632794 The V0 domain contains at least five different subunits (a, c, c'', d, and e) and transports protons across the membrane PMID:18632794 Coupling of proton transport and ATP hydrolysis |
| GO:1902600 proton transmembrane transport | IEA GO_REF:0000002 | ACCEPT | Summary: ATP6V0A4 supports proton transmembrane transport as part of V-ATPase-mediated proton pumping. Reason: The a4 V0-sector subunit is required for normal V-ATPase proton translocation and renal urinary acidification; retain as a core process-level annotation. Supporting Evidence: PMID:10973252 vectorial proton transport is required for urinary acidification PMID:10973252 essential role in normal vectorial acid transport into the urine by the kidney PMID:18632794 The V0 domain contains at least five different subunits (a, c, c'', d, and e) and transports protons across the membrane PMID:33065002 V-ATPases are ATP-driven proton pumps |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MARK AS OVER ANNOTATED | Summary: The underlying interaction is useful context, but GO:0005515 protein binding is too generic for ATP6V0A4 function. Reason: The interaction evidence comes from a broad neurodegenerative-disease interactome screen and does not identify a specific ATP6V0A4 molecular function. Generic protein binding is not informative for ATP6V0A4 function. Supporting Evidence: PMID:32814053 generated by systematic yeast two-hybrid interaction screening |
| GO:0005768 endosome | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Endosome localization is plausible for V-ATPase-associated ATP6V0A4 but is less central than the renal apical plasma membrane role. Reason: V-ATPases acidify endosomes and ATP6V0A4 has orthology/Reactome support in endosomal contexts, but direct human a4 evidence is stronger for kidney plasma membrane targeting. Supporting Evidence: PMID:33065002 pH homeostasis of endosomes and lysosomes Reactome:R-HSA-74723 The effect of the proton pump is to allow entry of [H+] ions into the lumen of the endosome |
| GO:0005903 brush border | IEA GO_REF:0000107 | MODIFY | Summary: Brush border is supported for proximal tubule apical localization, but brush border membrane is the more precise term for this membrane protein. Reason: ATP6V0A4 is a multi-pass membrane subunit; the direct annotation to brush border membrane is preferable to the broader brush border structure. Proposed replacements: brush border membrane Supporting Evidence: PMID:14638902 a4 protein was localized by immunohistochemistry to the apical compartment |
| GO:0016471 vacuolar proton-transporting V-type ATPase complex | IEA GO_REF:0000107 | ACCEPT | Summary: vacuolar proton-transporting V-type ATPase complex is the correct complex context for ATP6V0A4 as an a4 V0-sector subunit of V-ATPase. Reason: ATP6V0A4 is a membrane-integral component of the V0 sector of the V-ATPase holoenzyme; the complex-level annotation is a core representation of its function. Supporting Evidence: file:human/ATP6V0A4/ATP6V0A4-uniprot.txt Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase) PMID:32001091 V-ATPases are membrane-embedded protein complexes that function as ATP hydrolysis-driven proton pumps PMID:33065002 V-ATPases are ATP-driven proton pumps |
| GO:0030672 synaptic vesicle membrane | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Synaptic vesicle membrane is an over-specific projection for ATP6V0A4. Reason: ATP6V0A4 has cochlear/inner-ear disease relevance, but direct evidence for synaptic vesicle membrane localization of the a4 isoform is lacking. Supporting Evidence: PMID:12414817 show ATP6V0A4 expression within the cochlea for the first time PMID:32001091 multiple isoforms that are differentially localized |
| GO:0045177 apical part of cell | IEA GO_REF:0000120 | MODIFY | Summary: Apical part of cell is true but too broad for a multi-pass V-ATPase subunit with stronger apical plasma membrane/brush-border membrane evidence. Reason: Use the more specific membrane location supported by ATP6V0A4 kidney localization studies. Proposed replacements: apical plasma membrane Supporting Evidence: PMID:14638902 a4 protein was localized by immunohistochemistry to the apical compartment PMID:10973252 localizes almost exclusively to the apical surface |
| GO:0097401 synaptic vesicle lumen acidification | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Synaptic vesicle lumen acidification is an over-specific orthology projection for ATP6V0A4. Reason: ATP6V0A4 has inner-ear expression, but the local human evidence supports renal/inner-ear specialized V-ATPases rather than a specific synaptic-vesicle acidification role for the a4 isoform. Supporting Evidence: PMID:12414817 show ATP6V0A4 expression within the cochlea for the first time PMID:32001091 multiple isoforms that are differentially localized |
| GO:0005886 plasma membrane | NAS PMID:32001091 Structure and Roles of V-type ATPases. | ACCEPT | Summary: Plasma membrane localization is well supported for specialized V-ATPases containing ATP6V0A4, especially renal intercalated-cell apical membranes. Reason: ATP6V0A4 is a multi-pass membrane component of plasma-membrane-targeted proton pumps used for extracellular/urinary acidification. Supporting Evidence: PMID:10973252 localizes almost exclusively to the apical surface PMID:33065002 Plasma membrane V-ATPases carry out extracellular acidification file:human/ATP6V0A4/ATP6V0A4-uniprot.txt Localizes to the apical surface of alpha- |
| GO:0033176 proton-transporting V-type ATPase complex | NAS PMID:33065002 Structures of a Complete Human V-ATPase Reveal Mechanisms of... | ACCEPT | Summary: proton-transporting V-type ATPase complex is the correct complex context for ATP6V0A4 as an a4 V0-sector subunit of V-ATPase. Reason: ATP6V0A4 is a membrane-integral component of the V0 sector of the V-ATPase holoenzyme; the complex-level annotation is a core representation of its function. Supporting Evidence: file:human/ATP6V0A4/ATP6V0A4-uniprot.txt Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase) PMID:32001091 V-ATPases are membrane-embedded protein complexes that function as ATP hydrolysis-driven proton pumps PMID:33065002 V-ATPases are ATP-driven proton pumps |
| GO:0051452 intracellular pH reduction | NAS PMID:32001091 Structure and Roles of V-type ATPases. | MODIFY | Summary: Intracellular pH reduction captures the general V-ATPase effect but is less precise than vacuolar acidification and proton transport. Reason: The relevant mechanism is proton translocation by the V-ATPase into membrane-bounded compartments, not an undifferentiated reduction of intracellular pH. Proposed replacements: vacuolar acidification proton transmembrane transport Supporting Evidence: PMID:32001091 primary source of organellar acidification in all eukaryotes PMID:33065002 pH homeostasis of endosomes and lysosomes |
| GO:1902600 proton transmembrane transport | NAS PMID:33065002 Structures of a Complete Human V-ATPase Reveal Mechanisms of... | ACCEPT | Summary: ATP6V0A4 supports proton transmembrane transport as part of V-ATPase-mediated proton pumping. Reason: The a4 V0-sector subunit is required for normal V-ATPase proton translocation and renal urinary acidification; retain as a core process-level annotation. Supporting Evidence: PMID:10973252 vectorial proton transport is required for urinary acidification PMID:10973252 essential role in normal vectorial acid transport into the urine by the kidney PMID:18632794 The V0 domain contains at least five different subunits (a, c, c'', d, and e) and transports protons across the membrane PMID:33065002 V-ATPases are ATP-driven proton pumps |
| GO:0016323 basolateral plasma membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Basolateral plasma membrane localization is plausible for beta-intercalated-cell/orthologous contexts but is not the best-supported human a4 core location. Reason: The human evidence emphasizes apical localization in alpha-intercalated and proximal tubule cells. Basolateral localization should be retained as non-core/orthology-supported context. Supporting Evidence: file:human/ATP6V0A4/ATP6V0A4-uniprot.txt Localizes to the basolateral surface of PMID:14638902 All types of intercalated cells expressed a4 |
| GO:0097254 renal tubular secretion | IMP PMID:12414817 Novel ATP6V1B1 and ATP6V0A4 mutations in autosomal recessive... | ACCEPT | Summary: Renal tubular secretion is supported by the disease-defining role of ATP6V0A4 in vectorial acid transport into urine. Reason: Although broad, the term reflects a primary tissue-level ATP6V0A4 function in renal intercalated-cell acid secretion. Supporting Evidence: PMID:10973252 essential role in normal vectorial acid transport into the urine by the kidney PMID:14638902 a4 is regulated by trafficking but not protein expression |
| GO:0016471 vacuolar proton-transporting V-type ATPase complex | IDA PMID:10973252 Mutations in ATP6N1B, encoding a new kidney vacuolar proton ... | ACCEPT | Summary: vacuolar proton-transporting V-type ATPase complex is the correct complex context for ATP6V0A4 as an a4 V0-sector subunit of V-ATPase. Reason: ATP6V0A4 is a membrane-integral component of the V0 sector of the V-ATPase holoenzyme; the complex-level annotation is a core representation of its function. Supporting Evidence: file:human/ATP6V0A4/ATP6V0A4-uniprot.txt Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase) PMID:32001091 V-ATPases are membrane-embedded protein complexes that function as ATP hydrolysis-driven proton pumps PMID:33065002 V-ATPases are ATP-driven proton pumps |
| GO:0070062 extracellular exosome | HDA PMID:19199708 Proteomic analysis of human parotid gland exosomes by multid... | KEEP AS NON CORE | Summary: Extracellular exosome localization is retained as a non-core high-throughput vesicle-proteomics observation. Reason: Parotid exosome detection is a high-throughput extracellular-vesicle context and should not drive core functional interpretation. Supporting Evidence: PMID:19199708 we catalogued 491 proteins in the exosome fraction of human parotid saliva PMID:19199708 membrane-bound vesicles of endosomal origin within multivesicular endosomes |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: Extracellular exosome localization is retained as a non-core high-throughput vesicle-proteomics observation. Reason: Urinary exosome detection is relevant to renal epithelial membranes but remains a high-throughput vesicle-location observation, not a core ATP6V0A4 function. Supporting Evidence: PMID:19056867 Normal human urine contains large numbers of exosomes |
| GO:0005765 lysosomal membrane | HDA PMID:17897319 Integral and associated lysosomal membrane proteins. | KEEP AS NON CORE | Summary: Lysosomal membrane is supported by high-throughput lysosomal membrane proteomics and general V-ATPase biology, but it should be treated cautiously for the a4 isoform. Reason: The PN projection asks whether ATP6V0A4 should be treated as a lysosomal V-ATPase component. Existing evidence supports possible lysosomal membrane presence, but not a direct a4-specific lysosomal lumen acidification role. Supporting Evidence: PMID:17897319 In membranes purified from placental lysosomes, we identified 58 proteins PMID:33065002 pH homeostasis of endosomes and lysosomes PMID:32001091 multiple isoforms that are differentially localized |
| GO:0030670 phagocytic vesicle membrane | TAS Reactome:R-HSA-1222516 | MARK AS OVER ANNOTATED | Summary: Phagocytic vesicle membrane is a generic Reactome V-ATPase projection and is not well supported for ATP6V0A4 specifically. Reason: The Reactome event describes V-ATPase proton pumping in phagosomes generally; the a4 isoform is best supported in renal and inner-ear specialized pumps. Supporting Evidence: Reactome:R-HSA-1222516 ATP hydrolysis drives a 120 degree rotation of the rotor PMID:32001091 multiple isoforms that are differentially localized |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-5252133 | KEEP AS NON CORE | Summary: Endosome membrane is retained as a supported V-ATPase context but not the defining ATP6V0A4 localization. Reason: Reactome events capture V-ATPase-mediated endosome acidification; ATP6V0A4-specific human evidence is stronger for renal apical membranes. Supporting Evidence: Reactome:R-HSA-74723 The effect of the proton pump is to allow entry of [H+] ions into the lumen of the endosome PMID:33065002 pH homeostasis of endosomes and lysosomes |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-74723 | KEEP AS NON CORE | Summary: Endosome membrane is retained as a supported V-ATPase context but not the defining ATP6V0A4 localization. Reason: Reactome events capture V-ATPase-mediated endosome acidification; ATP6V0A4-specific human evidence is stronger for renal apical membranes. Supporting Evidence: Reactome:R-HSA-74723 The effect of the proton pump is to allow entry of [H+] ions into the lumen of the endosome PMID:33065002 pH homeostasis of endosomes and lysosomes |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-917841 | KEEP AS NON CORE | Summary: Endosome membrane is retained as a supported V-ATPase context but not the defining ATP6V0A4 localization. Reason: Reactome events capture V-ATPase-mediated endosome acidification; ATP6V0A4-specific human evidence is stronger for renal apical membranes. Supporting Evidence: Reactome:R-HSA-74723 The effect of the proton pump is to allow entry of [H+] ions into the lumen of the endosome PMID:33065002 pH homeostasis of endosomes and lysosomes |
| GO:0045177 apical part of cell | IDA PMID:14675051 Comparative ontogeny, processing, and segmental distribution... | MODIFY | Summary: Apical part of cell is true but too broad for a multi-pass V-ATPase subunit with stronger apical plasma membrane/brush-border membrane evidence. Reason: Use the more specific membrane location supported by ATP6V0A4 kidney localization studies. Proposed replacements: apical plasma membrane Supporting Evidence: PMID:14638902 a4 protein was localized by immunohistochemistry to the apical compartment PMID:10973252 localizes almost exclusively to the apical surface |
| GO:0005768 endosome | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Endosome localization is plausible for V-ATPase-associated ATP6V0A4 but is less central than the renal apical plasma membrane role. Reason: V-ATPases acidify endosomes and ATP6V0A4 has orthology/Reactome support in endosomal contexts, but direct human a4 evidence is stronger for kidney plasma membrane targeting. Supporting Evidence: PMID:33065002 pH homeostasis of endosomes and lysosomes Reactome:R-HSA-74723 The effect of the proton pump is to allow entry of [H+] ions into the lumen of the endosome |
| GO:0016324 apical plasma membrane | IDA PMID:15800125 Vacuolar H+-ATPase d2 subunit: molecular characterization, d... | ACCEPT | Summary: Apical plasma membrane localization is a primary ATP6V0A4 localization in kidney proton-secreting cells. Reason: Multiple human kidney studies support apical a4 localization in alpha-intercalated cells and related nephron segments. Supporting Evidence: PMID:10973252 localizes almost exclusively to the apical surface PMID:12649290 ATP6V0A4 encodes a4, which is expressed apically PMID:14638902 a4 protein was localized by immunohistochemistry to the apical compartment PMID:15800125 co-localized with the a4 subunit in the characteristic plasma membrane-enhanced pattern |
| GO:0005886 plasma membrane | IDA PMID:17360703 V1 and V0 domains of the human H+-ATPase are linked by an in... | ACCEPT | Summary: Plasma membrane localization is well supported for specialized V-ATPases containing ATP6V0A4, especially renal intercalated-cell apical membranes. Reason: ATP6V0A4 is a multi-pass membrane component of plasma-membrane-targeted proton pumps used for extracellular/urinary acidification. Supporting Evidence: PMID:10973252 localizes almost exclusively to the apical surface PMID:33065002 Plasma membrane V-ATPases carry out extracellular acidification file:human/ATP6V0A4/ATP6V0A4-uniprot.txt Localizes to the apical surface of alpha- |
| GO:0016324 apical plasma membrane | IDA PMID:12649290 The a-subunit of the V-type H+-ATPase interacts with phospho... | ACCEPT | Summary: Apical plasma membrane localization is a primary ATP6V0A4 localization in kidney proton-secreting cells. Reason: Multiple human kidney studies support apical a4 localization in alpha-intercalated cells and related nephron segments. Supporting Evidence: PMID:10973252 localizes almost exclusively to the apical surface PMID:12649290 ATP6V0A4 encodes a4, which is expressed apically PMID:14638902 a4 protein was localized by immunohistochemistry to the apical compartment PMID:15800125 co-localized with the a4 subunit in the characteristic plasma membrane-enhanced pattern |
| GO:0051117 ATPase binding | IPI PMID:17360703 V1 and V0 domains of the human H+-ATPase are linked by an in... | ACCEPT | Summary: ATPase binding is supported by ATP6V0A4 interactions with V-ATPase V1-sector subunits and is relevant to V1/V0 coupling. Reason: The a4 subunit binds V-ATPase G subunits and participates in the same proton pump, supporting this more informative binding term. Supporting Evidence: PMID:17360703 identified a possible interaction between the G3 subunit and the a4 subunit PMID:17360703 a4 and G3 are component subunits of the same proton pump PMID:17360703 represent a novel link between the V(1) and V(0) domains |
| GO:0005515 protein binding | IPI PMID:18632794 Human H+ATPase a4 subunit mutations causing renal tubular ac... | MARK AS OVER ANNOTATED | Summary: The underlying interaction is useful context, but GO:0005515 protein binding is too generic for ATP6V0A4 function. Reason: The PFK-1 interaction is real and functionally relevant to pump coupling, but GO:0005515 is too generic and should not be treated as a core molecular function. Supporting Evidence: PMID:18632794 PFK-1 in normal proton pump function PMID:12649290 co-immunoprecipitation of a4 with PFK-1 from solubilized human kidney membrane proteins |
| GO:1902600 proton transmembrane transport | IMP PMID:10973252 Mutations in ATP6N1B, encoding a new kidney vacuolar proton ... | ACCEPT | Summary: ATP6V0A4 supports proton transmembrane transport as part of V-ATPase-mediated proton pumping. Reason: The a4 V0-sector subunit is required for normal V-ATPase proton translocation and renal urinary acidification; retain as a core process-level annotation. Supporting Evidence: PMID:10973252 vectorial proton transport is required for urinary acidification PMID:10973252 essential role in normal vectorial acid transport into the urine by the kidney PMID:18632794 The V0 domain contains at least five different subunits (a, c, c'', d, and e) and transports protons across the membrane PMID:33065002 V-ATPases are ATP-driven proton pumps |
| GO:0001503 ossification | IMP PMID:10973252 Mutations in ATP6N1B, encoding a new kidney vacuolar proton ... | MARK AS OVER ANNOTATED | Summary: Ossification phenotypes in distal renal tubular acidosis are downstream systemic consequences, not evidence that ATP6V0A4 directly participates in ossification. Reason: The cited disease paper mentions disturbed bone physiology and growth as consequences of renal tubular acidosis. ATP6V0A4 is not the osteoclast a-subunit and this annotation overprojects a clinical consequence. Supporting Evidence: PMID:10973252 essential role in normal vectorial acid transport into the urine by the kidney |
| GO:0005515 protein binding | IPI PMID:12649290 The a-subunit of the V-type H+-ATPase interacts with phospho... | MARK AS OVER ANNOTATED | Summary: The underlying interaction is useful context, but GO:0005515 protein binding is too generic for ATP6V0A4 function. Reason: The cited study supports a4 interaction with PFK-1, but generic protein binding is an uninformative over-annotation relative to the mechanistic V-ATPase coupling role. Supporting Evidence: PMID:12649290 co-immunoprecipitation of a4 with PFK-1 from solubilized human kidney membrane proteins PMID:12649290 direct link between V-type H+-ATPases and glycolysis |
| GO:0006885 regulation of pH | IMP PMID:10973252 Mutations in ATP6N1B, encoding a new kidney vacuolar proton ... | MODIFY | Summary: Regulation of pH is supported by ATP6V0A4 disease and renal acidification evidence but is too broad for the mechanistic annotation. Reason: The literature supports vectorial proton transport and urinary acidification; proton transmembrane transport is the more informative GO process. Proposed replacements: proton transmembrane transport Supporting Evidence: PMID:10973252 vectorial proton transport is required for urinary acidification PMID:10973252 essential role in normal vectorial acid transport into the urine by the kidney |
| GO:0007605 sensory perception of sound | IMP PMID:12414817 Novel ATP6V1B1 and ATP6V0A4 mutations in autosomal recessive... | KEEP AS NON CORE | Summary: Sensorineural hearing loss in ATP6V0A4 disease and cochlear expression support an inner-ear role, but this is secondary to the renal acidification core function. Reason: Retain as a non-core tissue phenotype/process because ATP6V0A4 is expressed in the human cochlea and some mutation carriers develop hearing loss. Supporting Evidence: PMID:12414817 several patients with ATP6V0A4 mutations have developed hearing loss PMID:12414817 show ATP6V0A4 expression within the cochlea for the first time file:human/ATP6V0A4/ATP6V0A4-uniprot.txt Found in the inner ear |
| GO:0016324 apical plasma membrane | IDA PMID:10973252 Mutations in ATP6N1B, encoding a new kidney vacuolar proton ... | ACCEPT | Summary: Apical plasma membrane localization is a primary ATP6V0A4 localization in kidney proton-secreting cells. Reason: Multiple human kidney studies support apical a4 localization in alpha-intercalated cells and related nephron segments. Supporting Evidence: PMID:10973252 localizes almost exclusively to the apical surface PMID:12649290 ATP6V0A4 encodes a4, which is expressed apically PMID:14638902 a4 protein was localized by immunohistochemistry to the apical compartment PMID:15800125 co-localized with the a4 subunit in the characteristic plasma membrane-enhanced pattern |
| GO:0031526 brush border membrane | IDA PMID:14638902 Localization and regulation of the ATP6V0A4 (a4) vacuolar H+... | ACCEPT | Summary: Brush border membrane localization is supported for ATP6V0A4 in proximal tubule apical compartments. Reason: This is a specific membrane localization consistent with the JASN a4 localization study. Supporting Evidence: PMID:14638902 a4 protein was localized by immunohistochemistry to the apical compartment |
| GO:0045177 apical part of cell | IDA PMID:14638902 Localization and regulation of the ATP6V0A4 (a4) vacuolar H+... | MODIFY | Summary: Apical part of cell is true but too broad for a multi-pass V-ATPase subunit with stronger apical plasma membrane/brush-border membrane evidence. Reason: Use the more specific membrane location supported by ATP6V0A4 kidney localization studies. Proposed replacements: apical plasma membrane Supporting Evidence: PMID:14638902 a4 protein was localized by immunohistochemistry to the apical compartment PMID:10973252 localizes almost exclusively to the apical surface |
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Download this section (compressed HTML)Q: Should ATP6V0A4 be annotated to GO:0007042 lysosomal lumen acidification or GO:0046610 lysosomal proton-transporting V-type ATPase, V0 domain in human, or should those PN projections be limited to V-ATPase a-subunit isoforms with stronger lysosomal evidence? Existing ATP6V0A4 evidence supports V0 membership, broad organellar/vacuolar acidification, and high-throughput lysosomal membrane detection, but its best-supported isoform-specific biology is renal apical plasma membrane acid secretion.
Suggested experts: Karet FE, Wagner CA, Rubinstein JL
Experiment: Use endogenous tagging or isoform-specific antibodies in human kidney intercalated-cell models and inner-ear-relevant cells, combined with LAMP1/RAB7 colocalization and lysosomal pH reporters, to distinguish lysosomal ATP6V0A4 from apical plasma membrane pools.
Hypothesis: ATP6V0A4 has a context-specific lysosomal role only in cell types where the a4 isoform is targeted to endolysosomal membranes.
Type: cell localization and lysosomal pH assay
Experiment: Compare wild-type ATP6V0A4 and PFK-binding-defective disease variants in a human epithelial rescue system, measuring V-ATPase assembly, membrane targeting, ATPase activity, and proton transport separately.
Hypothesis: PFK-1 binding modulates ATP6V0A4-containing V-ATPase proton transport by affecting V1/V0 coupling rather than complex targeting.
Type: structure-function rescue assay
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