ATP6V1G3 (V-type proton ATPase subunit G 3) is the kidney-enriched isoform of the "G" subunit of the peripheral (V1) domain of the vacuolar H+-ATPase (V-ATPase). The V-ATPase is a multisubunit rotary enzyme in which the cytosolic V1 complex hydrolyzes ATP and the membrane-integral V0 complex translocates protons, together acidifying intracellular compartments (endosomes, lysosomes, secretory vesicles) and, in specialized cells, the extracellular/luminal space. The G subunit is a component of the peripheral stalk (stator), forming an E-G heterodimer that connects the catalytic V1 head to the membrane-embedded V0 a-subunit; this stator stalk holds the catalytic AB heterohexamer stationary against the torque of the central rotor. Of the three human G paralogs (G1/G2/G3), G3 expression is restricted to and enriched in the kidney, with additional detection in inner-ear epithelium, and assembles into the tissue-specific proton pump (with a4, B1, C2, d2) that drives apical proton secretion by renal collecting-duct intercalated cells for systemic acid-base homeostasis. G3 directly binds the V0 a-subunit (a4/a1), providing a physical link between the V1 and V0 domains required for pump assembly and regulation.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000221 vacuolar proton-transporting V-type ATPase, V1 domain | IBA GO_REF:0000033 | ACCEPT | Summary: ATP6V1G3 is the G subunit of the peripheral V1 domain of the vacuolar H+-ATPase, assembling into the E-G peripheral stalk of the V1 complex. Membership in the V1 domain is a defining, core structural attribute of this gene product. Reason: Accurate core cellular-component assignment; the G subunit is an integral structural component of the V1 peripheral stalk, consistent with the UniProt subunit description. Supporting Evidence: file:human/ATP6V1G3/ATP6V1G3-uniprot.txt Subunit of the V1 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP file:human/ATP6V1G3/ATP6V1G3-uniprot.txt three peripheral stalks each consisting of EG heterodimers |
| GO:0030672 synaptic vesicle membrane | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: This synaptic vesicle membrane localization is a phylogenetic (IBA) transfer reflecting the neuronal V-ATPase context of orthologs/paralogs. ATP6V1G3 is the kidney-enriched G isoform with no evidence of neuronal/synaptic vesicle function; the ubiquitous G1 isoform underlies the neuronal context. For G3 this is not a core localization. Reason: Biologically plausible only as a generic V-ATPase property transferred across the family; not relevant to the kidney-specific function of G3, which is expressed in renal collecting-duct intercalated cells rather than neurons. The falcon deep research reinforces this isoform division of labour, noting that the brain-specific G2 (not G3) underlies the neuronal V-ATPase context. Supporting Evidence: PMID:17360703 in major organs of both mouse and man, G3 subunit expression is limited to the kidney file:human/ATP6V1G3/ATP6V1G3-uniprot.txt TISSUE SPECIFICITY: Kidney. file:human/ATP6V1G3/ATP6V1G3-deep-research-falcon.md **G3 is the kidney-specific/enriched G-subunit isoform**; by contrast **G1 is ubiquitous** and **G2 is brain-specific** |
| GO:0097401 synaptic vesicle lumen acidification | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Synaptic vesicle lumen acidification is an IBA transfer capturing the generic proton-pumping/acidification role of the V-ATPase G subunit family. The synaptic vesicle specialization is not relevant to the kidney-enriched G3 isoform, whose physiological context is renal acid secretion, not neurotransmission. Reason: The underlying acidification activity is real and family-wide, but the synaptic-vesicle qualifier is not the core biological process for G3. Retained as non-core rather than removed because it reflects a true conserved V-ATPase function. The falcon deep research likewise frames the underlying proton-pumping/acidification output as a property of the assembled holoenzyme rather than of the G subunit itself. Supporting Evidence: PMID:17360703 in major organs of both mouse and man, G3 subunit expression is limited to the kidney file:human/ATP6V1G3/ATP6V1G3-uniprot.txt V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments file:human/ATP6V1G3/ATP6V1G3-deep-research-falcon.md **Does not itself catalyze proton transfer or ATP hydrolysis**; instead it supports the activity of the V-ATPase holoenzyme |
| GO:0016471 vacuolar proton-transporting V-type ATPase complex | IEA GO_REF:0000002 | ACCEPT | Summary: ATP6V1G3 is a bona fide subunit of the vacuolar H+-ATPase holoenzyme (V1+V0). Complex membership is supported by the UniProt subunit composition and by direct experimental demonstration that G3 binds the V0 a-subunit, confirming both are components of the same proton pump. Reason: Core, well-supported cellular-component annotation; the G subunit is an integral part of the assembled V-ATPase complex. Supporting Evidence: PMID:17360703 This confirms that a4 and G3 are component subunits of the same proton pump file:human/ATP6V1G3/ATP6V1G3-uniprot.txt V-ATPase is a heteromultimeric enzyme made up of two complexes |
| GO:0046961 proton-transporting ATPase activity, rotational mechanism | IEA GO_REF:0000120 | ACCEPT | Summary: This molecular function describes the rotary ATP-hydrolysis-driven proton transport activity of the assembled V-ATPase. As a peripheral-stalk subunit, G3 contributes to (rather than independently enables) this activity, which is the central function of the holoenzyme. The annotation correctly captures the core molecular function of the complex to which G3 belongs. Reason: Appropriate core molecular-function annotation for a V-ATPase subunit; the activity is enabled by the assembled complex of which G3 is a structural component. Supporting Evidence: file:human/ATP6V1G3/ATP6V1G3-uniprot.txt a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons |
| GO:0051117 ATPase binding | IEA GO_REF:0000117 | ACCEPT | Summary: This IEA-derived ATPase binding annotation is the electronic counterpart of the experimentally supported G3-a interaction. The same binding function is directly demonstrated by the IPI annotation from PMID:17360703 (G3 binding the V0 a4/a1 subunit), so this annotation is accepted as a correct, if redundant, prediction. Reason: Electronic prediction that is corroborated by the experimental IPI annotation to the same term; the specific G3-a-subunit binding is genuine and informative. Supporting Evidence: PMID:17360703 purified, immobilized full-length G3 to pull down the a4 subunit from human kidney membrane preparations |
| GO:1902600 proton transmembrane transport | IEA GO_REF:0000002 | ACCEPT | Summary: Proton transmembrane transport is the central biological process of the V-ATPase to which G3 contributes as a peripheral-stalk subunit. This is a core, accurate process annotation reflecting the ATP-hydrolysis-driven translocation of protons across membranes. Reason: Core biological-process annotation directly consistent with V-ATPase function and with the renal proton-secretion role of the G3-containing pump. Supporting Evidence: file:human/ATP6V1G3/ATP6V1G3-uniprot.txt a membrane integral complex (V0) that translocates protons |
| GO:0005829 cytosol | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Cytosolic localization reflects the peripheral (cytoplasmic) nature of the V1 domain and the pool of free/disassembled V1 subcomplex. While accurate, it is not the core functional location of the assembled membrane-bound pump and is captured redundantly across many electronic and Reactome annotations. Reason: Real but non-core localization; the V1 G subunit is cytosolic when not assembled into the membrane holoenzyme, but the functionally important location is the membrane-associated V-ATPase. Supporting Evidence: file:human/ATP6V1G3/ATP6V1G3-uniprot.txt a peripheral complex (V1) that hydrolyzes ATP |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Plasma membrane localization reflects the plasma-membrane-targeted V-ATPase of specialized acid-secreting cells. For the kidney-enriched G3, the relevant context is the apical plasma membrane of collecting-duct intercalated cells, where the tissue-specific pump mediates proton secretion. This is supported experimentally by the IDA annotation from PMID:17360703. Reason: Plasma membrane is a functionally relevant location for the G3-containing tissue-specific V-ATPase in renal acid-handling cells; supported by both electronic and direct experimental evidence. Supporting Evidence: file:human/ATP6V1G3/ATP6V1G3-uniprot.txt in some cell types, is targeted to the plasma membrane, where it is responsible for acidifying the extracellular environment |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1222516 | KEEP AS NON CORE | Summary: Reactome TAS cytosol annotation, one of many duplicate cytosol localizations from pathway reactions. Accurate for the peripheral V1 pool but non-core relative to the assembled membrane pump. Reason: Duplicate cytosol localization derived from a Reactome pathway reaction; real but not the core functional location. Supporting Evidence: file:human/ATP6V1G3/ATP6V1G3-uniprot.txt a peripheral complex (V1) that hydrolyzes ATP |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5252133 | KEEP AS NON CORE | Summary: Reactome TAS cytosol annotation duplicating the V1 peripheral localization. Real but non-core. Reason: Duplicate cytosol localization from a Reactome pathway reaction. Supporting Evidence: file:human/ATP6V1G3/ATP6V1G3-uniprot.txt a peripheral complex (V1) that hydrolyzes ATP |
| GO:0005829 cytosol | TAS Reactome:R-HSA-74723 | KEEP AS NON CORE | Summary: Reactome TAS cytosol annotation duplicating the V1 peripheral localization. Real but non-core. Reason: Duplicate cytosol localization from a Reactome pathway reaction. Supporting Evidence: file:human/ATP6V1G3/ATP6V1G3-uniprot.txt a peripheral complex (V1) that hydrolyzes ATP |
| GO:0005829 cytosol | TAS Reactome:R-HSA-917841 | KEEP AS NON CORE | Summary: Reactome TAS cytosol annotation duplicating the V1 peripheral localization. Real but non-core. Reason: Duplicate cytosol localization from a Reactome pathway reaction. Supporting Evidence: file:human/ATP6V1G3/ATP6V1G3-uniprot.txt a peripheral complex (V1) that hydrolyzes ATP |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9639286 | KEEP AS NON CORE | Summary: Reactome TAS cytosol annotation duplicating the V1 peripheral localization (mTORC1 amino-acid signaling context). Real but non-core. Reason: Duplicate cytosol localization from a Reactome pathway reaction. Supporting Evidence: file:human/ATP6V1G3/ATP6V1G3-uniprot.txt a peripheral complex (V1) that hydrolyzes ATP |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9640167 | KEEP AS NON CORE | Summary: Reactome TAS cytosol annotation duplicating the V1 peripheral localization (mTORC1 amino-acid signaling context). Real but non-core. Reason: Duplicate cytosol localization from a Reactome pathway reaction. Supporting Evidence: file:human/ATP6V1G3/ATP6V1G3-uniprot.txt a peripheral complex (V1) that hydrolyzes ATP |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9640168 | KEEP AS NON CORE | Summary: Reactome TAS cytosol annotation duplicating the V1 peripheral localization (mTORC1 amino-acid signaling context). Real but non-core. Reason: Duplicate cytosol localization from a Reactome pathway reaction. Supporting Evidence: file:human/ATP6V1G3/ATP6V1G3-uniprot.txt a peripheral complex (V1) that hydrolyzes ATP |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9640175 | KEEP AS NON CORE | Summary: Reactome TAS cytosol annotation duplicating the V1 peripheral localization (mTORC1 amino-acid signaling context). Real but non-core. Reason: Duplicate cytosol localization from a Reactome pathway reaction. Supporting Evidence: file:human/ATP6V1G3/ATP6V1G3-uniprot.txt a peripheral complex (V1) that hydrolyzes ATP |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9640195 | KEEP AS NON CORE | Summary: Reactome TAS cytosol annotation duplicating the V1 peripheral localization (mTORC1 amino-acid signaling context). Real but non-core. Reason: Duplicate cytosol localization from a Reactome pathway reaction. Supporting Evidence: file:human/ATP6V1G3/ATP6V1G3-uniprot.txt a peripheral complex (V1) that hydrolyzes ATP |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9645598 | KEEP AS NON CORE | Summary: Reactome TAS cytosol annotation duplicating the V1 peripheral localization (mTORC1 amino-acid signaling context). Real but non-core. Reason: Duplicate cytosol localization from a Reactome pathway reaction. Supporting Evidence: file:human/ATP6V1G3/ATP6V1G3-uniprot.txt a peripheral complex (V1) that hydrolyzes ATP |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9645608 | KEEP AS NON CORE | Summary: Reactome TAS cytosol annotation duplicating the V1 peripheral localization (mTORC1 amino-acid signaling context). Real but non-core. Reason: Duplicate cytosol localization from a Reactome pathway reaction. Supporting Evidence: file:human/ATP6V1G3/ATP6V1G3-uniprot.txt a peripheral complex (V1) that hydrolyzes ATP |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9646468 | KEEP AS NON CORE | Summary: Reactome TAS cytosol annotation duplicating the V1 peripheral localization (mTORC1 amino-acid signaling context). Real but non-core. Reason: Duplicate cytosol localization from a Reactome pathway reaction. Supporting Evidence: file:human/ATP6V1G3/ATP6V1G3-uniprot.txt a peripheral complex (V1) that hydrolyzes ATP |
| GO:0005829 cytosol | IDA PMID:17360703 V1 and V0 domains of the human H+-ATPase are linked by an in... | KEEP AS NON CORE | Summary: Direct experimental (IDA) cytosol localization of G3 from kidney, consistent with the peripheral V1 pool. Although experimentally observed, cytosol is not the core functional location of the assembled membrane-bound pump. Reason: Experimentally observed but non-core localization; reflects the cytosolic pool of the V1 peripheral subunit rather than the functional membrane-associated holoenzyme. Supporting Evidence: PMID:17360703 in the kidney, C2, d2, and G3 as well. These subunits replace the ubiquitously expressed forms |
| GO:0005886 plasma membrane | IDA PMID:17360703 V1 and V0 domains of the human H+-ATPase are linked by an in... | ACCEPT | Summary: Direct experimental (IDA) plasma membrane localization of G3 from kidney, consistent with the apical plasma-membrane V-ATPase of renal collecting-duct intercalated cells that mediates proton secretion. This is a functionally relevant location for the kidney-specific G3-containing pump. Reason: Experimentally supported, functionally relevant plasma-membrane localization for the tissue-specific acid-secreting V-ATPase in kidney. Supporting Evidence: PMID:17360703 purified, immobilized full-length G3 to pull down the a4 subunit from human kidney membrane preparations file:human/ATP6V1G3/ATP6V1G3-uniprot.txt is targeted to the plasma membrane, where it is responsible for acidifying the extracellular environment |
| GO:0051117 ATPase binding | IPI PMID:17360703 V1 and V0 domains of the human H+-ATPase are linked by an in... | ACCEPT | Summary: G3 directly and specifically binds the V0 a-subunit (a4/ATP6V0A4 and a1/ATP6V0A1), demonstrated by phage display, ELISA, and pull-down of a4 from kidney membranes by immobilized full-length G3. This G-a interaction physically links the V1 and V0 domains and is required for V-ATPase assembly and regulation. Because the binding partner is a specific named ATPase subunit (not a generic "protein binding"), this is an informative, core molecular-function annotation. The IPI WITH/FROM evidence cites UniProtKB:Q93050 (ATP6V0A1) and UniProtKB:Q9HBG4 (ATP6V0A4). Reason: Specific, experimentally demonstrated interaction with a defined V-ATPase a-subunit; this is the mechanistically informative function of G3 (V1-V0 linkage), not an uninformative generic binding annotation. Supporting Evidence: PMID:17360703 identified a possible interaction between the G3 subunit and the a4 subunit of the H(+)-ATPase PMID:17360703 These interactions represent a novel link between the V(1) and V(0) domains in man, which is known to be required for H(+)-ATPase assembly and regulation |
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Download this section (compressed HTML)Q: Does the kidney-specific G3-containing V-ATPase (with a4, B1, C2, d2) have distinct assembly, trafficking, or regulatory properties compared with the ubiquitous G1-containing pump in intercalated cells?
Q: What is the functional significance of the inner-ear expression of G3, and does it contribute to endolymph acidification or other otic ion-handling processes?
Q: Do isoform 3 (VSP_036423) and isoform 4 (VSP_036426), which alter the C-terminal coiled-coil region, retain the ability to form the E-G heterodimer and bind the a-subunit, or do they represent non-functional/regulatory variants?
Experiment: Cryo-EM or crystallographic structure of the kidney-specific human V-ATPase containing G3, a4, B1, C2, and d2 to define how the G3 peripheral stalk engages the a4 subunit.
Experiment: Conditional knockout or knock-in of Atp6v1g3 in mouse renal intercalated cells with assessment of urinary acidification and systemic acid-base balance to test the physiological requirement of the G3 isoform.
Experiment: Co-immunoprecipitation and proximity-labeling in renal intercalated cells to map the full G3 interactome and confirm preferential incorporation of G3 into the tissue-specific pump over G1.
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