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
|
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.
The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
ATP6V1G3 (also known as ATP6G3) encodes the V-type proton ATPase subunit G3, one of three G-subunit isoforms (G1, G2, G3) in humans (wang2020pharmacologicaltargetingof pages 1-3). This gene produces the V-ATPase 13 kDa subunit 3, which is a component of the peripheral stalk of the vacuolar-type H+-ATPase (V-ATPase) complex (wang2020structuresofa pages 1-3, wang2020pharmacologicaltargetingof pages 1-3). The protein is designated UniProt Q96LB4 and belongs to the V-ATPase G subunit family (wang2020pharmacologicaltargetingof pages 1-3).
| Category | ATP6V1G3 summary | Evidence / notes |
|---|---|---|
| Gene name | ATP6V1G3 (synonym: ATP6G3) | Matches the requested human gene encoding V-type proton ATPase subunit G3; one of three human G-subunit isoforms of the V-ATPase V1 domain (wang2020structuresofa pages 1-3, chen2022thevatpasesin pages 1-2) |
| Protein name | V-type proton ATPase subunit G3; V-ATPase subunit G3; V-ATPase 13 kDa subunit 3 | G-subunit family member in the cytosolic V1 sector of the V-ATPase holoenzyme (wang2020structuresofa pages 1-3, chen2022thevatpasesin pages 1-2, futai2019vacuolartypeatpasea pages 1-3) |
| Organism | Homo sapiens | Human V-ATPase contains multiple subunit isoforms with tissue-dependent expression; ATP6V1G3 is the human kidney-enriched G isoform (wang2020pharmacologicaltargetingof pages 1-3, chen2022thevatpasesin pages 1-2) |
| Isoform specificity | G3 is the kidney-specific/enriched G-subunit isoform; by contrast G1 is ubiquitous and G2 is brain-specific | Explicitly reported in V1G-targeting study; human V-ATPases also contain multiple isoforms in different tissues and organelles (wang2020pharmacologicaltargetingof pages 1-3, wang2020structuresofa pages 1-3) |
| Tissue expression | Predominantly kidney; kidney-related expression signatures are also consistent with renal tumor transcriptomic studies and kidney cell-type markers | V1G-targeting work states ATP6V1G3 is uniquely expressed in kidney tissue; single-cell renal carcinoma profiling identifies ATP6V1G3 among marker genes for renal epithelial populations; chromophobe RCC studies place related V-ATPase lineage markers in distal nephron/intercalated cells (wang2020pharmacologicaltargetingof pages 1-3, skala2020nextgenerationrnasequencingβbased pages 1-2) |
| Likely kidney cell context | Most consistent with renal epithelial acid-handling/endocytic compartments, especially distal nephron/intercalated-cell lineage and possibly proximal-tubule endolysosomal systems depending on V-ATPase subcomplex composition | Normal kidney lineage markers for chromophobe RCC map to distal nephron/intercalated cells; kidney V-ATPase biology strongly involves acid-secreting intercalated cells and proximal-tubule endocytic organelles, although ATP6V1G3 itself is not directly localized in those papers (eaton2021theh+atpase(vatpase) pages 5-9, skala2020nextgenerationrnasequencingβbased pages 1-2, futai2019vacuolartypeatpasea pages 1-3) |
| Subcellular localization | As a V1 subunit, ATP6V1G3 is expected on the cytosolic/peripheral face of V-ATPase-positive membranes, associated with endosomes, lysosomes, Golgi/TGN, secretory vesicles, and in specialized cells potentially plasma membrane V-ATPases | V-ATPases acidify endosomes, lysosomes, Golgi, secretory vesicles, and can localize to plasma membrane in specialized cells; G subunits belong to the peripheral V1 stalk on the cytosolic side rather than the transmembrane proton pore (eaton2021theh+atpase(vatpase) pages 1-5, wang2020structuresofa pages 1-3, chen2022thevatpasesin pages 1-2, futai2019vacuolartypeatpasea pages 1-3, song2020theemergingroles pages 1-2) |
| Primary biochemical function | Does not itself catalyze proton transfer or ATP hydrolysis; instead it supports the activity of the V-ATPase holoenzyme that uses ATP hydrolysis in V1 to drive proton translocation through V0 | Core V-ATPase function is ATP-driven proton pumping for organelle/plasma-membrane acidification; G subunits are structural/regulatory components of V1 rather than catalytic ATP-binding A/B subunits or V0 proton-path subunits (eaton2021theh+atpase(vatpase) pages 1-5, wang2020structuresofa pages 1-3, chen2022thevatpasesin pages 1-2, futai2019vacuolartypeatpasea pages 1-3, song2020theemergingroles pages 1-2) |
| Immediate substrate/process context | Functional output is H+ transport by the assembled V-ATPase; ATP6V1G3 contributes indirectly to movement of protons into organellar lumens or across plasma membrane in specialized acid-secreting cells | V-ATPase creates an electrochemical proton gradient needed for vesicle/organelle acidification and extracellular acidification in specialized epithelia and osteoclasts (eaton2021theh+atpase(vatpase) pages 1-5, chen2022thevatpasesin pages 1-2, futai2019vacuolartypeatpasea pages 1-3) |
| Structural role in V-ATPase | Peripheral stalk subunit of the V1 complex; human V1 contains three copies of E and G subunits forming the three peripheral stalks that connect the catalytic head to the membrane sector and stabilize the rotary machine during catalysis | Human V-ATPase structures show E/G pairs in PS-1, PS-2, and PS-3; G participates in long curved coiled-coil peripheral stalks that accommodate conformational changes during ATP hydrolysis-coupled rotation (wang2020structuresofa pages 1-3) |
| Role in rotational catalysis | Helps provide the stator architecture that counterbalances torque generated by the rotary central stalk/c-ring system, enabling efficient coupling of ATP hydrolysis to proton pumping | Reviews and structures identify V1 peripheral stalks as required for efficient rotational catalysis and coupling between V1 and V0 (luca2021roleofthe pages 1-2, wang2020structuresofa pages 1-3, chen2022thevatpasesin pages 1-2, futai2019vacuolartypeatpasea pages 1-3) |
| Complex membership | Part of the V1 domain of the V-ATPase holoenzyme; mammalian V1 contains subunits A3B3CDE3FG3H in general architecture | Rat and human structural papers define V1 composition and show isoform-specific assembly in mammalian tissues (abbas2020structureofvatpase pages 1-2, wang2020structuresofa pages 1-3) |
| Key interacting proteins / complexes | Most direct partners are expected to be V1 subunit E within peripheral stalks and neighboring stator/collar components (C, H, a-NTD) in assembled V-ATPase; broader V-ATPase signaling interfaces involve ATP6AP1, ATP6AP2/(pro)renin receptor, Ragulator/mTOR machinery, and endolysosomal trafficking factors | Direct G3-specific interactors are not well defined in retrieved literature; structural work defines G within E/G peripheral stalks, while broader V-ATPase interactome includes signaling and assembly partners (wang2020structuresofa pages 1-3, abbas2020structureofvatpase pages 2-4, chen2022thevatpasesin pages 1-2, futai2019vacuolartypeatpasea pages 1-3) |
| Evidence from other G-isoform studies | For G1, interaction with RILP and RAB7 helps control V-ATPase localization/activation on late endosomes and lysosomes; these findings support a conserved trafficking-support role for G-family subunits, though they are not direct proof for G3 | Important inferential evidence only; the direct study is on ATP6V1G1 in breast cancer cells (luca2021roleofthe pages 1-2) |
| Canonical biological processes | Endosome/lysosome acidification, protein degradation, receptor-mediated endocytosis, vesicular trafficking, autophagy/lysosome function, secretory vesicle maturation, pH homeostasis | Canonical V-ATPase functions are extensively reviewed and apply to any competent isoform-containing holoenzyme, including kidney-enriched assemblies containing G3 (eaton2021theh+atpase(vatpase) pages 1-5, chen2022thevatpasesin pages 1-2, futai2019vacuolartypeatpasea pages 1-3, song2020theemergingroles pages 1-2) |
| Signaling-related roles | V-ATPase acts as a signaling hub/scaffold in mTORC1, Wnt, Notch, nutrient sensing, lysosomal stress responses, and broader pH-sensitive signaling pathways | These are properties of the assembled V-ATPase complex rather than uniquely of ATP6V1G3, but they define pathway context for ATP6V1G3-containing complexes (eaton2021theh+atpase(vatpase) pages 1-5, wang2020structuresofa pages 1-3, chen2022thevatpasesin pages 1-2, song2020theemergingroles pages 1-2) |
| Kidney-relevant functional context | In kidney, V-ATPases support acid-base homeostasis, distal nephron proton secretion, and proximal-tubule receptor-mediated endocytosis/endolysosomal function | Kidney V-ATPase localization and function are established in review and proximal-tubule ATP6AP2 studies; ATP6V1G3 likely contributes where kidney-specific V1G isoform-containing complexes are used (eaton2021theh+atpase(vatpase) pages 1-5, eaton2021theh+atpase(vatpase) pages 5-9, futai2019vacuolartypeatpasea pages 1-3) |
| Recent developments (2023β2024) | Recent work emphasizes V-ATPase in lysosome regeneration, lysosomal stress signaling, autophagy, and cancer biology; however, direct 2023β2024 ATP6V1G3-specific mechanistic studies are scarce | Newer papers focus on whole-complex regulation and disease roles rather than the G3 isoform specifically; this is an important limitation for annotation confidence (chen2022thevatpasesin pages 1-2, song2020theemergingroles pages 1-2) |
| Disease / cancer associations | ATP6V1G3 expression is reported in renal tumor datasets and may be downregulated in kidney renal clear cell carcinoma relative to normal kidney in some analyses; broader V-ATPase dysregulation is linked to cancer progression, metastasis, drug resistance, renal disease, osteopetrosis, and neurodegeneration | Family-level associations are strong; ATP6V1G3-specific disease causality remains limited in current literature (li2020comprehensiveanalysisof pages 1-2, coutovieira2020multicancervatpasemolecular pages 1-2, skala2020nextgenerationrnasequencingβbased pages 1-2, chen2022thevatpasesin pages 1-2, song2020theemergingroles pages 1-2) |
| Pharmacology / therapeutic relevance | V-ATPase is druggable, and the V1G subunit family can be targeted pharmacologically; verucopeptin was reported to bind ATP6V1G and inhibit both V-ATPase activity and mTORC1 signaling in multidrug-resistant cancer models | The study does not establish G3-selective targeting, but it highlights the therapeutic relevance of the G-subunit family (wang2020pharmacologicaltargetingof pages 1-3) |
| Major knowledge gap | Very limited direct experimental literature on human ATP6V1G3; most functional annotation is inferred from (i) shared G-subunit architecture, (ii) V-ATPase holoenzyme biology, and (iii) kidney-specific expression of G3 | This should be stated explicitly when interpreting function/localization/pathway claims (wang2020structuresofa pages 1-3, wang2020pharmacologicaltargetingof pages 1-3, chen2022thevatpasesin pages 1-2) |
| Most useful references | Human V-ATPase structure and assembly: Wang 2020; mammalian brain structure: Abbas 2020; broad mechanistic review: Eaton 2021; V1G pharmacology and tissue specificity: Wang 2020 Cell Chem Biol; kidney/cancer expression resources: Li 2020, Skala 2020; lysosomal trafficking review: Futai 2019 | These references provide the strongest basis for annotating ATP6V1G3 despite the lack of G3-specific mechanistic studies (eaton2021theh+atpase(vatpase) pages 1-5, abbas2020structureofvatpase pages 1-2, wang2020structuresofa pages 1-3, wang2020pharmacologicaltargetingof pages 1-3, li2020comprehensiveanalysisof pages 1-2, skala2020nextgenerationrnasequencingβbased pages 1-2, futai2019vacuolartypeatpasea pages 1-3) |
Table: This table consolidates the most relevant properties of human ATP6V1G3, combining direct evidence on V1G isoform specificity with broader structural and functional evidence from V-ATPase literature. It is useful for functional annotation because direct ATP6V1G3 studies are limited, so careful distinction between direct and inferred evidence is essential.
ATP6V1G3 is a structural and regulatory component of the V-ATPase, a large multisubunit proton pump that uses the energy of ATP hydrolysis to transport protons across cellular membranes (eaton2021theh+atpase(vatpase) pages 1-5, chen2022thevatpasesin pages 1-2, futai2019vacuolartypeatpasea pages 1-3). While ATP6V1G3 itself does not directly catalyze ATP hydrolysis or transport protons, it plays an essential structural role in the enzymatic complex that performs these functions (wang2020structuresofa pages 1-3).
The V-ATPase consists of two main domains: the cytosolic V1 domain (responsible for ATP hydrolysis) and the membrane-embedded V0 domain (responsible for proton translocation) (eaton2021theh+atpase(vatpase) pages 1-5, chen2022thevatpasesin pages 1-2). The mammalian V1 complex contains eight subunits in the stoichiometry A3B3CDE3FG3H, where ATP6V1G3 is one of the three G subunit copies (wang2020structuresofa pages 1-3). The V-ATPase operates as a rotary motor, where ATP hydrolysis at the A/B subunit interfaces drives rotation of a central stalk, which in turn drives proton translocation through the V0 domain (eaton2021theh+atpase(vatpase) pages 1-5, chen2022thevatpasesin pages 1-2, futai2019vacuolartypeatpasea pages 1-3).
ATP6V1G3, together with subunit E, forms one of three peripheral stalks (PS-1, PS-2, PS-3) in the V1 domain (wang2020structuresofa pages 1-3, wang2020structuresofa pages 3-5). These peripheral stalks are critical for the enzyme's function as they provide the stator architecture that counterbalances the torque generated by the rotating central stalk during ATP-driven proton pumping (luca2021roleofthe pages 1-2, wang2020structuresofa pages 1-3). Recent cryo-EM structures of human V-ATPase at 2.9-3.1 Γ resolution reveal that the E/G subunits form long, curved coiled-coils at their N-terminal domains, with their C-terminal domains adopting a compact configuration that engages the B subunits of the catalytic hexamer (wang2020structuresofa pages 1-3, wang2020structuresofa pages 3-5).
The three peripheral stalks exhibit intrinsic structural plasticity with different overall curvatures despite having identical sequences, which allows them to accommodate the tilting and twisting of the A3B3 catalytic head during ATP binding and hydrolysis (wang2020structuresofa pages 1-3, wang2020structuresofa pages 3-5). This flexibility is essential for efficient rotational catalysis and coupling between ATP hydrolysis in V1 and proton pumping through V0 (luca2021roleofthe pages 1-2, wang2020structuresofa pages 1-3).
As a component of the peripheral stalk, ATP6V1G3 does not directly bind substrates or exhibit catalytic activity (wang2020structuresofa pages 1-3). Instead, it supports the function of the holoenzyme, which uses ATP as an energy source and transports protons (H+) as the immediate substrate (eaton2021theh+atpase(vatpase) pages 1-5, chen2022thevatpasesin pages 1-2, futai2019vacuolartypeatpasea pages 1-3). The V-ATPase creates an electrochemical proton gradient across membranes by pumping protons from the cytosol into the lumen of organelles or, in specialized cells, into the extracellular space (eaton2021theh+atpase(vatpase) pages 1-5, futai2019vacuolartypeatpasea pages 1-3).
ATP6V1G3 exhibits kidney-specific or kidney-enriched expression, distinguishing it from the other two G-subunit isoforms: ATP6V1G1 (ubiquitously expressed) and ATP6V1G2 (brain-specific) (wang2020pharmacologicaltargetingof pages 1-3). This tissue-specific expression pattern is consistent with the broader principle that V-ATPase subunits have multiple isoforms that are expressed in cell- and tissue-specific manners, enabling the enzyme to perform diverse physiological roles in different cellular contexts (eaton2021theh+atpase(vatpase) pages 1-5, futai2019vacuolartypeatpasea pages 1-3).
RNA sequencing studies of kidney tumors have identified ATP6V1G3 as a marker gene for renal epithelial cell populations (skala2020nextgenerationrnasequencingβbased pages 1-2). In normal kidney tissue, lineage-specific V-ATPase markers, including related subunits, are expressed in the distal nephron, specifically in intercalated cells of the collecting duct system (skala2020nextgenerationrnasequencingβbased pages 1-2). These acid-secreting cells use plasma membrane V-ATPases to maintain systemic acid-base homeostasis (eaton2021theh+atpase(vatpase) pages 1-5, futai2019vacuolartypeatpasea pages 1-3).
As a V1 domain subunit, ATP6V1G3 localizes to the cytosolic face of V-ATPase-containing membranes (wang2020structuresofa pages 1-3). The V-ATPase is ubiquitously present in intracellular organelles including endosomes, lysosomes, the Golgi apparatus/trans-Golgi network (TGN), and secretory vesicles, where it is responsible for maintaining the acidic pH required for proper organellar function (eaton2021theh+atpase(vatpase) pages 1-5, chen2022thevatpasesin pages 1-2, futai2019vacuolartypeatpasea pages 1-3, song2020theemergingroles pages 1-2).
In kidney epithelial cells, V-ATPases are found in both intracellular compartments and at the plasma membrane in specialized cell types (eaton2021theh+atpase(vatpase) pages 1-5, futai2019vacuolartypeatpasea pages 1-3). In the proximal tubule, V-ATPases participate in receptor-mediated endocytosis and endolysosomal function, facilitating the reabsorption of proteins and other molecules filtered by the kidney (eaton2021theh+atpase(vatpase) pages 5-9). In intercalated cells of the distal nephron and collecting duct, V-ATPases localize to the apical plasma membrane where they secrete protons into the tubular fluid for urinary acidification (eaton2021theh+atpase(vatpase) pages 1-5, futai2019vacuolartypeatpasea pages 1-3).
The V-ATPase-mediated acidification of endosomes and lysosomes is essential for numerous cellular processes, including protein degradation, receptor recycling, vesicular trafficking, and autophagy (eaton2021theh+atpase(vatpase) pages 1-5, chen2022thevatpasesin pages 1-2, song2020theemergingroles pages 1-2). Lysosomal pH gradients maintained by V-ATPase are required for the activation of resident hydrolytic enzymes such as cathepsins, which degrade internalized proteins and organelles (song2020theemergingroles pages 1-2). Disruption of V-ATPase activity impairs lysosomal acidification, leading to accumulation of undegraded substrates and cellular dysfunction (song2020theemergingroles pages 1-2).
The primary pathway involving ATP6V1G3-containing V-ATPase complexes is the acidification of intracellular compartments, which enables:
Protein degradation and autophagy: Lysosomal acidification activates proteolytic enzymes required for degradation of proteins, organelles, and other cellular components delivered via autophagy or endocytosis (chen2022thevatpasesin pages 1-2, song2020theemergingroles pages 1-2).
Receptor-mediated endocytosis: In kidney proximal tubule cells, V-ATPase acidification of early endosomes is necessary for the dissociation of ligands from receptors such as megalin and cubilin, enabling receptor recycling and ligand degradation (eaton2021theh+atpase(vatpase) pages 5-9).
Vesicular trafficking: The pH gradient established by V-ATPase regulates membrane fusion events and protein sorting along the endocytic and secretory pathways (eaton2021theh+atpase(vatpase) pages 1-5, futai2019vacuolartypeatpasea pages 1-3).
Beyond its role as a proton pump, the V-ATPase serves as a signaling hub and protein scaffold in several important pathways (eaton2021theh+atpase(vatpase) pages 1-5, chen2022thevatpasesin pages 1-2):
mTORC1 pathway: The V-ATPase functions as a nutrient sensor and serves as a docking platform for the Ragulator-Rag GTPase complex, which recruits and activates mTORC1 on lysosomal membranes in response to amino acid availability (eaton2021theh+atpase(vatpase) pages 1-5, chen2022thevatpasesin pages 1-2). This pathway is central to cellular growth, metabolism, and autophagy regulation.
AMPK pathway: V-ATPase activity influences AMPK signaling, which regulates cellular energy homeostasis (chen2022thevatpasesin pages 1-2).
Wnt and Notch signaling: V-ATPase components, particularly ATP6AP2 (pro-renin receptor), participate in Wnt signaling during stem cell maintenance and embryonic development, as well as Notch receptor processing (eaton2021theh+atpase(vatpase) pages 1-5, wang2020structuresofa pages 1-3).
Studies on the ATP6V1G1 isoform have demonstrated that G subunits interact with RILP (RAB-interacting lysosomal protein) and RAB7, which are key regulators of late endocytic traffic (luca2021roleofthe pages 1-2). These interactions control the localization and activation of V-ATPase on late endosomes and lysosomes (luca2021roleofthe pages 1-2). While direct evidence for ATP6V1G3 interactions is limited, the structural conservation among G-subunit isoforms suggests that ATP6V1G3 may participate in similar trafficking and regulatory mechanisms in kidney cells.
Recent cryo-EM studies have provided unprecedented structural detail of mammalian V-ATPases. Abbas et al. (2020) reported a 3.9 Γ resolution structure of rat brain V-ATPase containing predominantly the G2 isoform, while Wang et al. (2020) determined human V-ATPase structures at 2.9-3.1 Γ resolution containing the G1 isoform (abbas2020structureofvatpase pages 1-2, wang2020structuresofa pages 1-3, abbas2020structureofvatpase pages 2-4, wang2020structuresofa pages 3-5). These structures reveal the detailed architecture of the peripheral stalks containing G subunits and demonstrate their flexibility during the catalytic cycle (wang2020structuresofa pages 1-3, wang2020structuresofa pages 3-5).
V-ATPases have emerged as important players in cancer biology, with altered expression and activity contributing to tumor progression, metastasis, and drug resistance (chen2022thevatpasesin pages 1-2). Several studies have examined ATP6V1G3 expression in kidney cancers:
Li et al. (2020) conducted a comprehensive analysis of ATP6V1 family members in kidney renal clear cell carcinoma (KIRC) and found that ATP6V1G3 was downregulated in KIRC tissues compared to normal kidney (li2020comprehensiveanalysisof pages 1-2).
Skala et al. (2020) used RNA sequencing to characterize biomarkers in chromophobe renal cell carcinoma and identified ATP6V1G3 among genes differentially expressed in renal tumor types (skala2020nextgenerationrnasequencingβbased pages 1-2).
Wang et al. (2020) demonstrated that the natural product verucopeptin can directly target ATP6V1G subunits to inhibit both V-ATPase activity and mTORC1 signaling in multidrug-resistant cancer cells (wang2020pharmacologicaltargetingof pages 1-3). While this study did not specifically target the G3 isoform, it highlights the therapeutic potential of modulating V-ATPase G-subunit function.
Recent reviews (2020-2024) have emphasized the critical role of V-ATPase in lysosomal acidification and its involvement in neurodegenerative diseases, lysosomal storage disorders, and autophagy-related pathologies (chen2022thevatpasesin pages 1-2, song2020theemergingroles pages 1-2). Chen et al. (2022, 2024) highlighted V-ATPase dysfunction in cancer progression and cell death pathways including apoptosis, ferroptosis, and lysosome-dependent cell death (chen2022thevatpasesin pages 1-2). These findings underscore the importance of proper V-ATPase function across multiple disease contexts.
Duan et al. (2018) analyzed genetic variants in all V-ATPase subunits using the GEFOS (Genetic Factors for Osteoporosis) dataset and identified ATP6V1G3 variants as potentially related to bone density, though the functional significance of these associations requires further validation (duan2018vatpasesandosteoclasts pages 1-2).
A critical limitation in the current literature is the scarcity of direct experimental studies specifically focused on ATP6V1G3. Most functional annotations for this gene are inferred from:
Direct mechanistic studies examining the specific roles of ATP6V1G3 in kidney physiology, the consequences of its depletion or mutation, and its interactions with kidney-specific regulatory proteins are needed to fully understand this gene's function.
ATP6V1G3 encodes a kidney-enriched isoform of the V-ATPase G subunit, which functions as a critical structural component of the peripheral stalk in the V1 domain of the V-ATPase proton pump (wang2020structuresofa pages 1-3, wang2020pharmacologicaltargetingof pages 1-3). As part of this complex, ATP6V1G3 contributes to ATP-driven proton transport across membranes, acidifying intracellular organelles such as endosomes and lysosomes in kidney epithelial cells (eaton2021theh+atpase(vatpase) pages 1-5, chen2022thevatpasesin pages 1-2, futai2019vacuolartypeatpasea pages 1-3). This acidification is essential for protein degradation, autophagy, receptor-mediated endocytosis, and cellular pH homeostasis (eaton2021theh+atpase(vatpase) pages 1-5, chen2022thevatpasesin pages 1-2, song2020theemergingroles pages 1-2).
Beyond its role as a proton pump component, ATP6V1G3-containing V-ATPase complexes participate in signaling pathways including mTORC1 and AMPK, serving as nutrient sensors and protein scaffolds (eaton2021theh+atpase(vatpase) pages 1-5, chen2022thevatpasesin pages 1-2). Recent structural studies have provided detailed insights into the architecture and flexibility of G-subunit-containing peripheral stalks, revealing how they enable efficient coupling between ATP hydrolysis and proton pumping (wang2020structuresofa pages 1-3, wang2020structuresofa pages 3-5).
ATP6V1G3 expression is altered in kidney cancers and may have roles in disease pathogenesis, though direct mechanistic evidence remains limited (li2020comprehensiveanalysisof pages 1-2, skala2020nextgenerationrnasequencingβbased pages 1-2). The G-subunit family represents a potential therapeutic target, as demonstrated by small molecules that can modulate V-ATPase activity through G-subunit binding (wang2020pharmacologicaltargetingof pages 1-3). Future research should focus on elucidating the specific functions of ATP6V1G3 in kidney physiology and disease, as well as exploring isoform-selective therapeutic strategies.
References
(wang2020pharmacologicaltargetingof pages 1-3): Yuezhou Wang, Lei Zhang, Yanling Wei, Wei Huang, Li Li, An-an Wu, Anahita Dastur, Patricia Greninger, Walter M. Bray, Chen-Song Zhang, Mengqi Li, Wenhua Lian, Zhiyu Hu, Xiaoyong Wang, Gang Liu, Luming Yao, Jih-Hwa Guh, Lanfen Chen, Hong-Rui Wang, Dawang Zhou, Sheng-Cai Lin, Qingyan Xu, Yuemao Shen, Jianming Zhang, Melissa S. Jurica, Cyril H. Benes, and Xianming Deng. Pharmacological targeting of vacuolar h+-atpase via subunit v1g combats multidrug-resistant cancer. Cell Chemical Biology, 27:1359-1370.e8, Nov 2020. URL: https://doi.org/10.1016/j.chembiol.2020.06.011, doi:10.1016/j.chembiol.2020.06.011. This article has 30 citations and is from a domain leading peer-reviewed journal.
(wang2020structuresofa pages 1-3): Longfei Wang, Di Wu, Carol V. Robinson, Hao Wu, and Tian-Min Fu. Structures of a complete human v-atpase reveal mechanisms of its assembly. Molecular Cell, 80:501-511.e3, Nov 2020. URL: https://doi.org/10.1016/j.molcel.2020.09.029, doi:10.1016/j.molcel.2020.09.029. This article has 182 citations and is from a highest quality peer-reviewed journal.
(chen2022thevatpasesin pages 1-2): Fangquan Chen, Rui Kang, Jiao Liu, and Daolin Tang. The v-atpases in cancer and cell death. Cancer Gene Therapy, 29:1529-1541, May 2022. URL: https://doi.org/10.1038/s41417-022-00477-y, doi:10.1038/s41417-022-00477-y. This article has 128 citations and is from a peer-reviewed journal.
(futai2019vacuolartypeatpasea pages 1-3): Masamitsu FUTAI, Ge-Hong SUN-WADA, Yoh WADA, Naomi MATSUMOTO, and Mayumi NAKANISHI-MATSUI. Vacuolar-type atpase: a proton pump to lysosomal trafficking. Proceedings of the Japan Academy. Series B, Physical and Biological Sciences, 95:261-277, Jun 2019. URL: https://doi.org/10.2183/pjab.95.018, doi:10.2183/pjab.95.018. This article has 145 citations.
(skala2020nextgenerationrnasequencingβbased pages 1-2): Stephanie L. Skala, Xiaoming Wang, Yuping Zhang, Rahul Mannan, Lisha Wang, Sathiya P. Narayanan, Pankaj Vats, Fengyun Su, Jin Chen, Xuhong Cao, Javed Siddiqui, Pedram Argani, Marcin P. CieΕlik, Thomas J. Giordano, Arul M. Chinnaiyan, Saravana M. Dhanasekaran, and Rohit Mehra. Next-generation rna sequencingβbased biomarker characterization of chromophobe renal cell carcinoma and related oncocytic neoplasms. European Urology, 78:63-74, Jul 2020. URL: https://doi.org/10.1016/j.eururo.2020.03.003, doi:10.1016/j.eururo.2020.03.003. This article has 98 citations and is from a highest quality peer-reviewed journal.
(eaton2021theh+atpase(vatpase) pages 5-9): Amity F. Eaton, Maria Merkulova, and Dennis Brown. The h+-atpase (v-atpase): from proton pump to signaling complex in health and disease. American Journal of Physiology-Cell Physiology, 320:C392-C414, Mar 2021. URL: https://doi.org/10.1152/ajpcell.00442.2020, doi:10.1152/ajpcell.00442.2020. This article has 189 citations.
(eaton2021theh+atpase(vatpase) pages 1-5): Amity F. Eaton, Maria Merkulova, and Dennis Brown. The h+-atpase (v-atpase): from proton pump to signaling complex in health and disease. American Journal of Physiology-Cell Physiology, 320:C392-C414, Mar 2021. URL: https://doi.org/10.1152/ajpcell.00442.2020, doi:10.1152/ajpcell.00442.2020. This article has 189 citations.
(song2020theemergingroles pages 1-2): Qiaoyun Song, Bo Meng, Haidong Xu, and Zixu Mao. The emerging roles of vacuolar-type atpase-dependent lysosomal acidification in neurodegenerative diseases. Translational Neurodegeneration, May 2020. URL: https://doi.org/10.1186/s40035-020-00196-0, doi:10.1186/s40035-020-00196-0. This article has 255 citations and is from a domain leading peer-reviewed journal.
(luca2021roleofthe pages 1-2): Maria De Luca, Roberta Romano, and Cecilia Bucci. Role of the v1g1 subunit of v-atpase in breast cancer cell migration. Scientific Reports, Feb 2021. URL: https://doi.org/10.1038/s41598-021-84222-9, doi:10.1038/s41598-021-84222-9. This article has 24 citations and is from a peer-reviewed journal.
(abbas2020structureofvatpase pages 1-2): Yazan M. Abbas, Di Wu, Stephanie A. Bueler, Carol V. Robinson, and John L. Rubinstein. Structure of v-atpase from the mammalian brain. Mar 2020. URL: https://doi.org/10.1126/science.aaz2924, doi:10.1126/science.aaz2924. This article has 278 citations and is from a highest quality peer-reviewed journal.
(abbas2020structureofvatpase pages 2-4): Yazan M. Abbas, Di Wu, Stephanie A. Bueler, Carol V. Robinson, and John L. Rubinstein. Structure of v-atpase from the mammalian brain. Mar 2020. URL: https://doi.org/10.1126/science.aaz2924, doi:10.1126/science.aaz2924. This article has 278 citations and is from a highest quality peer-reviewed journal.
(li2020comprehensiveanalysisof pages 1-2): Xiaojuan Li, Hao Li, Caihong Yang, Liu Liu, Sisi Deng, and Mi Li. Comprehensive analysis of atp6v1s family members in renal clear cell carcinoma with prognostic values. Frontiers in Oncology, Oct 2020. URL: https://doi.org/10.3389/fonc.2020.567970, doi:10.3389/fonc.2020.567970. This article has 27 citations.
(coutovieira2020multicancervatpasemolecular pages 1-2): Juliana Couto-Vieira, Pedro Nicolau-Neto, Evenilton Pessoa Costa, Frederico Firme Figueira, Tatiana de Almeida Simão, Anna Lvovna Okorokova-Façanha, Luis Felipe Ribeiro Pinto, and Arnoldo Rocha Façanha. Multi-cancer v-atpase molecular signatures: a distinctive balance of subunit c isoforms in esophageal carcinoma. EBioMedicine, 51:102581, Jan 2020. URL: https://doi.org/10.1016/j.ebiom.2019.11.042, doi:10.1016/j.ebiom.2019.11.042. This article has 34 citations and is from a peer-reviewed journal.
(wang2020structuresofa pages 3-5): Longfei Wang, Di Wu, Carol V. Robinson, Hao Wu, and Tian-Min Fu. Structures of a complete human v-atpase reveal mechanisms of its assembly. Molecular Cell, 80:501-511.e3, Nov 2020. URL: https://doi.org/10.1016/j.molcel.2020.09.029, doi:10.1016/j.molcel.2020.09.029. This article has 182 citations and is from a highest quality peer-reviewed journal.
(duan2018vatpasesandosteoclasts pages 1-2): Xiaohong Duan, Shaoqing Yang, Lei Zhang, and Tielin Yang. V-atpases and osteoclasts: ambiguous future of v-atpases inhibitors in osteoporosis. Theranostics, 8:5379-5399, Oct 2018. URL: https://doi.org/10.7150/thno.28391, doi:10.7150/thno.28391. This article has 86 citations and is from a domain leading peer-reviewed journal.
*-deep-research*.md file found in this gene directory.This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.
id: Q96LB4
gene_symbol: ATP6V1G3
product_type: PROTEIN
status: COMPLETE
taxon:
id: NCBITaxon:9606
label: Homo sapiens
description: >-
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.
alternative_products:
- name: '1'
id: Q96LB4-1
- name: '2'
id: Q96LB4-2
sequence_note: Not described
- name: '3'
id: Q96LB4-3
sequence_note: VSP_036423
- name: '4'
id: Q96LB4-4
sequence_note: VSP_036426
existing_annotations:
- term:
id: GO:0000221
label: vacuolar proton-transporting V-type ATPase, V1 domain
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: part_of
review:
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.
action: ACCEPT
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.
supported_by:
- reference_id: file:human/ATP6V1G3/ATP6V1G3-uniprot.txt
supporting_text: Subunit of the V1 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP
- reference_id: file:human/ATP6V1G3/ATP6V1G3-uniprot.txt
supporting_text: three peripheral stalks each consisting of EG heterodimers
- term:
id: GO:0030672
label: synaptic vesicle membrane
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: is_active_in
review:
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.
action: KEEP_AS_NON_CORE
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.
supported_by:
- reference_id: PMID:17360703
supporting_text: in major organs of both mouse and man, G3 subunit expression is limited to the kidney
- reference_id: file:human/ATP6V1G3/ATP6V1G3-uniprot.txt
supporting_text: 'TISSUE SPECIFICITY: Kidney.'
- reference_id: file:human/ATP6V1G3/ATP6V1G3-deep-research-falcon.md
supporting_text: >-
**G3 is the kidney-specific/enriched G-subunit isoform**; by contrast **G1 is ubiquitous**
and **G2 is brain-specific**
- term:
id: GO:0097401
label: synaptic vesicle lumen acidification
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: involved_in
review:
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.
action: KEEP_AS_NON_CORE
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.
supported_by:
- reference_id: PMID:17360703
supporting_text: in major organs of both mouse and man, G3 subunit expression is limited to the kidney
- reference_id: file:human/ATP6V1G3/ATP6V1G3-uniprot.txt
supporting_text: V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments
- reference_id: file:human/ATP6V1G3/ATP6V1G3-deep-research-falcon.md
supporting_text: >-
**Does not itself catalyze proton transfer or ATP hydrolysis**; instead it supports the
activity of the V-ATPase holoenzyme
- term:
id: GO:0016471
label: vacuolar proton-transporting V-type ATPase complex
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: part_of
review:
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.
action: ACCEPT
reason: >-
Core, well-supported cellular-component annotation; the G subunit is an integral
part of the assembled V-ATPase complex.
supported_by:
- reference_id: PMID:17360703
supporting_text: This confirms that a4 and G3 are component subunits of the same proton pump
- reference_id: file:human/ATP6V1G3/ATP6V1G3-uniprot.txt
supporting_text: V-ATPase is a heteromultimeric enzyme made up of two complexes
- term:
id: GO:0046961
label: proton-transporting ATPase activity, rotational mechanism
evidence_type: IEA
original_reference_id: GO_REF:0000120
qualifier: enables
review:
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.
action: ACCEPT
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.
supported_by:
- reference_id: file:human/ATP6V1G3/ATP6V1G3-uniprot.txt
supporting_text: a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons
- term:
id: GO:0051117
label: ATPase binding
evidence_type: IEA
original_reference_id: GO_REF:0000117
qualifier: enables
review:
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.
action: ACCEPT
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.
supported_by:
- reference_id: PMID:17360703
supporting_text: purified, immobilized full-length G3 to pull down the a4 subunit from human kidney membrane preparations
- term:
id: GO:1902600
label: proton transmembrane transport
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: involved_in
review:
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.
action: ACCEPT
reason: >-
Core biological-process annotation directly consistent with V-ATPase function and
with the renal proton-secretion role of the G3-containing pump.
supported_by:
- reference_id: file:human/ATP6V1G3/ATP6V1G3-uniprot.txt
supporting_text: a membrane integral complex (V0) that translocates protons
- term:
id: GO:0005829
label: cytosol
evidence_type: IEA
original_reference_id: GO_REF:0000120
qualifier: located_in
review:
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.
action: KEEP_AS_NON_CORE
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.
supported_by:
- reference_id: file:human/ATP6V1G3/ATP6V1G3-uniprot.txt
supporting_text: a peripheral complex (V1) that hydrolyzes ATP
- term:
id: GO:0005886
label: plasma membrane
evidence_type: IEA
original_reference_id: GO_REF:0000120
qualifier: located_in
review:
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.
action: ACCEPT
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.
supported_by:
- reference_id: file:human/ATP6V1G3/ATP6V1G3-uniprot.txt
supporting_text: in some cell types, is targeted to the plasma membrane, where it is responsible for acidifying the extracellular environment
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-1222516
qualifier: located_in
review:
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.
action: KEEP_AS_NON_CORE
reason: >-
Duplicate cytosol localization derived from a Reactome pathway reaction; real but
not the core functional location.
supported_by:
- reference_id: file:human/ATP6V1G3/ATP6V1G3-uniprot.txt
supporting_text: a peripheral complex (V1) that hydrolyzes ATP
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5252133
qualifier: located_in
review:
summary: >-
Reactome TAS cytosol annotation duplicating the V1 peripheral localization. Real
but non-core.
action: KEEP_AS_NON_CORE
reason: >-
Duplicate cytosol localization from a Reactome pathway reaction.
supported_by:
- reference_id: file:human/ATP6V1G3/ATP6V1G3-uniprot.txt
supporting_text: a peripheral complex (V1) that hydrolyzes ATP
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-74723
qualifier: located_in
review:
summary: >-
Reactome TAS cytosol annotation duplicating the V1 peripheral localization. Real
but non-core.
action: KEEP_AS_NON_CORE
reason: >-
Duplicate cytosol localization from a Reactome pathway reaction.
supported_by:
- reference_id: file:human/ATP6V1G3/ATP6V1G3-uniprot.txt
supporting_text: a peripheral complex (V1) that hydrolyzes ATP
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-917841
qualifier: located_in
review:
summary: >-
Reactome TAS cytosol annotation duplicating the V1 peripheral localization. Real
but non-core.
action: KEEP_AS_NON_CORE
reason: >-
Duplicate cytosol localization from a Reactome pathway reaction.
supported_by:
- reference_id: file:human/ATP6V1G3/ATP6V1G3-uniprot.txt
supporting_text: a peripheral complex (V1) that hydrolyzes ATP
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9639286
qualifier: located_in
review:
summary: >-
Reactome TAS cytosol annotation duplicating the V1 peripheral localization (mTORC1
amino-acid signaling context). Real but non-core.
action: KEEP_AS_NON_CORE
reason: >-
Duplicate cytosol localization from a Reactome pathway reaction.
supported_by:
- reference_id: file:human/ATP6V1G3/ATP6V1G3-uniprot.txt
supporting_text: a peripheral complex (V1) that hydrolyzes ATP
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9640167
qualifier: located_in
review:
summary: >-
Reactome TAS cytosol annotation duplicating the V1 peripheral localization (mTORC1
amino-acid signaling context). Real but non-core.
action: KEEP_AS_NON_CORE
reason: >-
Duplicate cytosol localization from a Reactome pathway reaction.
supported_by:
- reference_id: file:human/ATP6V1G3/ATP6V1G3-uniprot.txt
supporting_text: a peripheral complex (V1) that hydrolyzes ATP
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9640168
qualifier: located_in
review:
summary: >-
Reactome TAS cytosol annotation duplicating the V1 peripheral localization (mTORC1
amino-acid signaling context). Real but non-core.
action: KEEP_AS_NON_CORE
reason: >-
Duplicate cytosol localization from a Reactome pathway reaction.
supported_by:
- reference_id: file:human/ATP6V1G3/ATP6V1G3-uniprot.txt
supporting_text: a peripheral complex (V1) that hydrolyzes ATP
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9640175
qualifier: located_in
review:
summary: >-
Reactome TAS cytosol annotation duplicating the V1 peripheral localization (mTORC1
amino-acid signaling context). Real but non-core.
action: KEEP_AS_NON_CORE
reason: >-
Duplicate cytosol localization from a Reactome pathway reaction.
supported_by:
- reference_id: file:human/ATP6V1G3/ATP6V1G3-uniprot.txt
supporting_text: a peripheral complex (V1) that hydrolyzes ATP
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9640195
qualifier: located_in
review:
summary: >-
Reactome TAS cytosol annotation duplicating the V1 peripheral localization (mTORC1
amino-acid signaling context). Real but non-core.
action: KEEP_AS_NON_CORE
reason: >-
Duplicate cytosol localization from a Reactome pathway reaction.
supported_by:
- reference_id: file:human/ATP6V1G3/ATP6V1G3-uniprot.txt
supporting_text: a peripheral complex (V1) that hydrolyzes ATP
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9645598
qualifier: located_in
review:
summary: >-
Reactome TAS cytosol annotation duplicating the V1 peripheral localization (mTORC1
amino-acid signaling context). Real but non-core.
action: KEEP_AS_NON_CORE
reason: >-
Duplicate cytosol localization from a Reactome pathway reaction.
supported_by:
- reference_id: file:human/ATP6V1G3/ATP6V1G3-uniprot.txt
supporting_text: a peripheral complex (V1) that hydrolyzes ATP
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9645608
qualifier: located_in
review:
summary: >-
Reactome TAS cytosol annotation duplicating the V1 peripheral localization (mTORC1
amino-acid signaling context). Real but non-core.
action: KEEP_AS_NON_CORE
reason: >-
Duplicate cytosol localization from a Reactome pathway reaction.
supported_by:
- reference_id: file:human/ATP6V1G3/ATP6V1G3-uniprot.txt
supporting_text: a peripheral complex (V1) that hydrolyzes ATP
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9646468
qualifier: located_in
review:
summary: >-
Reactome TAS cytosol annotation duplicating the V1 peripheral localization (mTORC1
amino-acid signaling context). Real but non-core.
action: KEEP_AS_NON_CORE
reason: >-
Duplicate cytosol localization from a Reactome pathway reaction.
supported_by:
- reference_id: file:human/ATP6V1G3/ATP6V1G3-uniprot.txt
supporting_text: a peripheral complex (V1) that hydrolyzes ATP
- term:
id: GO:0005829
label: cytosol
evidence_type: IDA
original_reference_id: PMID:17360703
qualifier: located_in
review:
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.
action: KEEP_AS_NON_CORE
reason: >-
Experimentally observed but non-core localization; reflects the cytosolic pool of
the V1 peripheral subunit rather than the functional membrane-associated holoenzyme.
supported_by:
- reference_id: PMID:17360703
supporting_text: in the kidney, C2, d2, and G3 as well. These subunits replace the ubiquitously expressed forms
- term:
id: GO:0005886
label: plasma membrane
evidence_type: IDA
original_reference_id: PMID:17360703
qualifier: located_in
review:
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.
action: ACCEPT
reason: >-
Experimentally supported, functionally relevant plasma-membrane localization for the
tissue-specific acid-secreting V-ATPase in kidney.
supported_by:
- reference_id: PMID:17360703
supporting_text: purified, immobilized full-length G3 to pull down the a4 subunit from human kidney membrane preparations
- reference_id: file:human/ATP6V1G3/ATP6V1G3-uniprot.txt
supporting_text: is targeted to the plasma membrane, where it is responsible for acidifying the extracellular environment
- term:
id: GO:0051117
label: ATPase binding
evidence_type: IPI
original_reference_id: PMID:17360703
qualifier: enables
review:
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).
action: ACCEPT
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.
supported_by:
- reference_id: PMID:17360703
supporting_text: identified a possible interaction between the G3 subunit and the a4 subunit of the H(+)-ATPase
- reference_id: PMID:17360703
supporting_text: 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
core_functions:
- description: >-
Structural subunit of the peripheral stalk (stator) of the vacuolar H+-ATPase V1
domain, forming the E-G heterodimer that holds the catalytic AB head stationary and
couples ATP hydrolysis to proton translocation by the holoenzyme.
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:0000221
label: vacuolar proton-transporting V-type ATPase, V1 domain
supported_by:
- reference_id: file:human/ATP6V1G3/ATP6V1G3-uniprot.txt
supporting_text: three peripheral stalks each consisting of EG heterodimers
- reference_id: file:human/ATP6V1G3/ATP6V1G3-uniprot.txt
supporting_text: a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons
- description: >-
Physically links the V1 and V0 domains by binding the membrane-embedded a-subunit
(a4/a1), an interaction required for assembly and regulation of the kidney-specific
proton pump that drives luminal acid secretion in renal intercalated cells.
molecular_function:
id: GO:0051117
label: ATPase binding
directly_involved_in:
- id: GO:1902600
label: proton transmembrane transport
locations:
- id: GO:0005886
label: plasma membrane
supported_by:
- reference_id: PMID:17360703
supporting_text: This confirms that a4 and G3 are component subunits of the same proton pump
- reference_id: PMID:17360703
supporting_text: 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
proposed_new_terms: []
suggested_questions:
- question: >-
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?
- question: >-
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?
- question: >-
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?
suggested_experiments:
- description: 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.
- description: 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.
- description: 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.
references:
- id: file:human/ATP6V1G3/ATP6V1G3-deep-research-falcon.md
title: Falcon deep research report for ATP6V1G3
findings:
- statement: >-
Among the three human G-subunit isoforms, G3 is kidney-enriched, G1 is ubiquitous,
and G2 is brain-specific - corroborating the kidney-restricted expression of G3 and
supporting the KEEP_AS_NON_CORE treatment of the neuronal/synaptic-vesicle IBA
annotations transferred across the G family.
reference_section_type: RESULTS
supporting_text: >-
**G3 is the kidney-specific/enriched G-subunit isoform**; by contrast **G1 is ubiquitous**
and **G2 is brain-specific**
- statement: >-
The report explicitly states that direct experimental literature on human ATP6V1G3 is
very limited and that most functional/localization/signaling claims (cancer, mTORC1,
Wnt/Notch, endolysosomal trafficking, RILP/RAB7) are inferred from the V-ATPase
holoenzyme or other G isoforms (notably the G1-specific RILP/RAB7 study), not directly
demonstrated for G3. These inferred, complex/family-level claims are therefore NOT
attributed to G3 in this review.
reference_section_type: RESULTS
supporting_text: >-
Very limited direct experimental literature on human ATP6V1G3
reference_review:
relevance: MEDIUM
correctness: UNVERIFIED
review_notes: >-
LLM-synthesized report (Edison/Falcon). Its cross-checkable, G3-attributable claims
are limited to (i) kidney-enriched G3 vs ubiquitous G1 vs brain-specific G2 isoform
specificity, which is consistent with PMID:17360703 and the UniProt "TISSUE
SPECIFICITY: Kidney" record already cited here, and (ii) the structural role of the
E-G peripheral stalk, consistent with UniProt. The report itself foregrounds that
direct ATP6V1G3 experimental data are scarce and that its cancer (KIRC down-regulation),
mTORC1/Wnt/Notch signaling, endolysosomal trafficking, and RILP/RAB7 claims are
generalizations from the V-ATPase holoenzyme or the ATP6V1G1 paralog - these are
explicitly NOT used to add or strengthen G3-specific annotations. Underlying PMIDs
(Wang 2020, Eaton 2021, etc.) were not independently re-verified against cached
full text, hence UNVERIFIED.
- id: GO_REF:0000002
title: Gene Ontology annotation through association of InterPro records with GO
terms
findings: []
- id: GO_REF:0000033
title: Annotation inferences using phylogenetic trees
findings: []
- id: GO_REF:0000117
title: Electronic Gene Ontology annotations created by ARBA machine learning models
findings: []
- id: GO_REF:0000120
title: Combined Automated Annotation using Multiple IEA Methods
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:
- statement: >-
G3 subunit expression is limited to the kidney among major organs of mouse and man,
with additional expression in human inner-ear epithelium; G3 assembles with other
kidney-specific subunits (a4, C2, d2) plus B1 into a tissue-specific proton pump.
reference_section_type: ABSTRACT
supporting_text: in major organs of both mouse and man, G3 subunit expression is limited to the kidney
- statement: >-
G3 directly binds the V0 a4 subunit (pulled down from kidney membranes by
immobilized full-length G3), confirming a4 and G3 are subunits of the same pump and
providing a V1-V0 link required for assembly and regulation; similar G1/a1, G3/a1,
and G1/a4 interactions occur.
reference_section_type: ABSTRACT
supporting_text: purified, immobilized full-length G3 to pull down the a4 subunit from human kidney membrane preparations
- id: PMID:12384298
title: Molecular cloning and characterization of novel tissue-specific isoforms of the
human vacuolar H(+)-ATPase C, G and d subunits, and their evaluation in autosomal
recessive distal renal tubular acidosis.
findings:
- statement: >-
ATP6V1G3 (G3) is a kidney-specific isoform of the V-ATPase G subunit, identified and
characterized alongside tissue-specific C and d subunit isoforms.
reference_section_type: ABSTRACT
supporting_text: novel tissue-specific isoforms of the human vacuolar H(+)-ATPase C, G and d subunits
- id: file:human/ATP6V1G3/ATP6V1G3-uniprot.txt
title: UniProt entry Q96LB4 (VATG3_HUMAN), V-type proton ATPase subunit G 3
findings:
- statement: >-
G3 is a subunit of the V1 peripheral complex of the V-ATPase; the V1 complex
includes three peripheral stalks each formed by an E-G heterodimer.
reference_section_type: DATABASE_ENTRY
supporting_text: three peripheral stalks each consisting of EG heterodimers
- statement: >-
The V-ATPase acidifies intracellular compartments and, in some cell types, is
targeted to the plasma membrane to acidify the extracellular environment.
reference_section_type: DATABASE_ENTRY
supporting_text: is targeted to the plasma membrane, where it is responsible for acidifying the extracellular environment
- statement: ATP6V1G3 tissue specificity is kidney.
reference_section_type: DATABASE_ENTRY
supporting_text: 'TISSUE SPECIFICITY: Kidney.'
- 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-74723
title: Endosome acidification
findings: []
- id: Reactome:R-HSA-917841
title: Acidification of Tf:TfR1 containing endosome
findings: []
- id: Reactome:R-HSA-9639286
title: RRAGC,D exchanges GTP for GDP
findings: []
- id: Reactome:R-HSA-9640167
title: RRAGA,B exchanges GDP for GTP
findings: []
- id: Reactome:R-HSA-9640168
title: v-ATPase:Ragulator:RRAGA,B:GTP:RRAGC,D:GDP:SLC38A9:Arginine dissociates yielding
v-ATPase:Ragulator:RRAGA,B:GTP:RRAGC,D:GDP and SLC38A9:Arginine
findings: []
- id: Reactome:R-HSA-9640175
title: v-ATPase:Ragulator:RagA,B:GDP:RagC,D:GDP binds SLC38A9:Arginine
findings: []
- id: Reactome:R-HSA-9640195
title: RRAGA,B hydrolyzes GTP
findings: []
- id: Reactome:R-HSA-9645598
title: RRAGC,D hydrolyzes GTP
findings: []
- id: Reactome:R-HSA-9645608
title: v-ATPase:Ragulator:RRAGA,B:GTP:RRAGC,D:GDP binds mTORC1
findings: []
- id: Reactome:R-HSA-9646468
title: mTORC1 binds RHEB:GTP
findings: []