Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0000221 vacuolar proton-transporting V-type ATPase, V1 domain	IBA GO_REF:0000033	ACCEPT	Summary: ATP6V1G1 is a bona fide V1 domain subunit, confirmed by cryo-EM structure. Reason: The V1 domain membership is experimentally established by mass spectrometry and cryo-EM (PMID:33065002). The IBA annotation is consistent with experimental data and reflects true V1 component status. Supporting Evidence: file:human/ATP6V1G1/ATP6V1G1-uniprot.txt Subunit of the V1 complex of vacuolar(H+)-ATPase
GO:0030672 synaptic vesicle membrane	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Synaptic vesicle membrane activity inferred by phylogenetic transfer; reflects V-ATPase role at synaptic vesicles in neurons, not core function of this ubiquitous subunit. Reason: While V-ATPases acidify synaptic vesicles in neurons, this annotation describes a non-core context for a ubiquitously expressed subunit. The specific activity is an indirect consequence of V1 participation in the overall proton pump complex rather than a dedicated synaptic function of G1.
GO:0097401 synaptic vesicle lumen acidification	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Synaptic vesicle acidification inferred by phylogenetic transfer; non-core for this ubiquitously expressed peripheral stalk subunit. Reason: Synaptic vesicle lumen acidification is a neuron-specific downstream process. This ubiquitous G1 subunit contributes to V-ATPase activity generally; synaptic vesicle context is non-core.
GO:0016324 apical plasma membrane	IEA GO_REF:0000044	ACCEPT	Summary: IEA from UniProt subcellular location vocabulary mapping; supported by experimental co-localization in kidney tubular cells. Reason: This IEA annotation is backed by experimental co-localization data showing H+-ATPase subunits including G1 at the apical membrane of kidney TAL and DCT (PMID:29993276). Supporting Evidence: PMID:29993276 the H+-ATPase B1 subunit colocalized with other H+-ATPase subunits in the TAL and DCT
GO:0016471 vacuolar proton-transporting V-type ATPase complex	IEA GO_REF:0000120	ACCEPT	Summary: Computationally inferred V-ATPase complex membership; correct and supported by structural evidence. Reason: ATP6V1G1 is a component of the assembled V-ATPase holoenzyme. IEA annotation is consistent with cryo-EM structural data (PMID:33065002).
GO:0046961 proton-transporting ATPase activity, rotational mechanism	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for rotational mechanism ATPase activity; correct at the complex level. Reason: The V-ATPase employs a rotational mechanism for proton translocation. As a peripheral stalk subunit, G1 contributes to this activity as part of the stator apparatus. The annotation is appropriate with contributes_to semantics implied.
GO:0051117 ATPase binding	IEA GO_REF:0000117	ACCEPT	Summary: IEA ARBA prediction for ATPase binding; reflects known G1 interaction with V0 subunit a documented experimentally. Reason: The G1 subunit directly interacts with V0 subunit a, constituting genuine ATPase binding within the V-ATPase complex (PMID:17360703).
GO:1902600 proton transmembrane transport	IEA GO_REF:0000002	ACCEPT	Summary: IEA from InterPro; proton transmembrane transport is the core function of the V-ATPase complex. Reason: Proton transmembrane transport is the core biological process driven by the V-ATPase. As a structural component of the complex, G1 is rightly annotated as involved in this process.
GO:0005515 protein binding	IPI PMID:16169070 A human protein-protein interaction network: a resource for ...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from high-throughput proteome-wide interaction dataset; uninformative over-annotation. Reason: This IPI annotation comes from a large-scale interactome screen. Protein binding in isolation is uninformative about G1 molecular function. The meaningful interaction is with ATP6V1E1/E2 (EG peripheral stalk) and V0 subunit a.
GO:0005515 protein binding	IPI PMID:21516116 Next-generation sequencing to generate interactome datasets.	MARK AS OVER ANNOTATED	Summary: Generic protein binding from high-throughput interaction screen; uninformative. Reason: High-throughput interactome dataset; protein binding alone does not reflect the specific structural role of G1 in the V-ATPase.
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	MARK AS OVER ANNOTATED	Summary: Generic protein binding from proteome-scale interactome network; uninformative. Reason: High-throughput interactome dataset; does not reflect specific function.
GO:0005515 protein binding	IPI PMID:30021884 Histone Interaction Landscapes Visualized by Crosslinking Ma...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from crosslinking mass spectrometry dataset; uninformative over-annotation. Reason: High-throughput dataset; uninformative for characterizing G1 function.
GO:0005515 protein binding	IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from population genetics interactome study; uninformative. Reason: High-throughput interactome dataset; does not reflect specific molecular function of G1.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: Generic protein binding from binary interactome reference map; uninformative. Reason: High-throughput interactome dataset; protein binding is an over-annotation for a subunit whose specific interactions (with E subunit and V0 subunit a) are known.
GO:0005515 protein binding	IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from OpenCell endogenous tagging study; uninformative. Reason: High-throughput dataset; protein binding does not describe the specific EG peripheral stalk assembly function.
GO:0005765 lysosomal membrane	IEA GO_REF:0000107	ACCEPT	Summary: IEA Ensembl Compara transfer; lysosomal membrane localization is consistent with HDA mass spectrometry data. Reason: Lysosomal membrane localization is supported by mass spectrometry identification in lysosome-enriched fractions (PMID:17897319) and is expected for an assembled V-ATPase subunit.
GO:0005829 cytosol	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA Ensembl Compara transfer; cytosolic localization reflects the regulated disassembly state where free V1 complex is in the cytoplasm. Reason: Cytosolic localization is a real state (free V1 complex released from membranes under regulated disassembly) but is not the primary functional location.
GO:0005886 plasma membrane	IEA GO_REF:0000107	ACCEPT	Summary: IEA transfer; plasma membrane localization is supported by experimental evidence from kidney tubular cells (apical plasma membrane) and by the G/a subunit interaction study. Reason: Plasma membrane localization is experimentally supported both by kidney apical membrane co-localization (PMID:29993276) and by the G1/a interaction study (PMID:17360703). The IEA is consistent with experimental findings.
GO:0015078 proton transmembrane transporter activity	IEA GO_REF:0000107	ACCEPT	Summary: IEA Ensembl Compara transfer; proton transmembrane transporter activity is a core V-ATPase function. Reason: Proton transmembrane transporter activity is the direct molecular function of the V-ATPase complex. The contributes_to qualifier is appropriate for a structural subunit.
GO:0033176 proton-transporting V-type ATPase complex	IEA GO_REF:0000107	ACCEPT	Summary: IEA transfer for V-ATPase complex membership; correct at the whole-complex level, but the more specific V1 domain annotation is preferred. Reason: ATP6V1G1 is a component of the entire V-ATPase holoenzyme as well as the V1 sub-complex. This whole-complex annotation is appropriate as a broader complement to the V1 domain annotation.
GO:0033180 proton-transporting V-type ATPase, V1 domain	IEA GO_REF:0000107	ACCEPT	Summary: IEA Ensembl Compara transfer; V1 domain membership is experimentally confirmed. Reason: V1 domain membership is established by cryo-EM and mass spectrometry (PMID:33065002). This IEA is consistent with experimental evidence.
GO:0097401 synaptic vesicle lumen acidification	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA Ensembl Compara transfer for synaptic vesicle lumen acidification; non-core neuronal context annotation. Reason: Neuronal synaptic vesicle acidification is a non-core context for this ubiquitously expressed subunit.
GO:0098850 extrinsic component of synaptic vesicle membrane	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA Ensembl Compara transfer; V1 domain is extrinsic to synaptic vesicle membranes in neurons. Non-core context. Reason: The V1 peripheral complex is extrinsic to vesicle membranes in neurons. This is a non-core neuronal context for a ubiquitous subunit.
GO:0016324 apical plasma membrane	EXP PMID:29993276 H(+)-ATPase B1 subunit localizes to thick ascending limb and...	ACCEPT	Summary: Experimental co-localization of G1 with other H+-ATPase subunits at the apical plasma membrane in kidney TAL and DCT. Strongly supported. Reason: Direct experimental evidence from kidney sections showing co-localization of H+-ATPase subunits including G1 at the apical plasma membrane in thick ascending limb and distal convoluted tubule. Supporting Evidence: PMID:29993276 the H+-ATPase B1 subunit colocalized with other H+-ATPase subunits in the TAL and DCT
GO:0000221 vacuolar proton-transporting V-type ATPase, V1 domain	IDA PMID:33065002 Structures of a Complete Human V-ATPase Reveal Mechanisms of...	ACCEPT	Summary: Direct experimental identification of G1 in the human V-ATPase V1 complex by cryo-EM structure determination. Reason: High-quality cryo-EM structures of the complete human V-ATPase directly identified all V1 subunits including G1 by mass spectrometry. This is the strongest possible evidence for V1 domain membership. Supporting Evidence: file:human/ATP6V1G1/ATP6V1G1-uniprot.txt The V1 complex consists of three catalytic AB heterodimers that form a heterohexamer, three peripheral stalks each consisting of EG heterodimers, one central rotor including subunits D and F, and the regulatory subunits C and H
GO:0006879 intracellular iron ion homeostasis	IMP PMID:28296633 The vacuolar-ATPase complex and assembly factors, TMEM199 an...	MARK AS OVER ANNOTATED	Summary: IMP annotation based on a genetic screen; loss of ATP6V1G1 disrupts V-ATPase proton pumping, which impairs endosomal acidification and iron release from transferrin. This is an indirect downstream consequence of impaired proton transport, not a direct iron homeostasis function. Reason: The iron homeostasis effect observed upon ATP6V1G1 knockdown is an indirect consequence of disrupted V-ATPase activity impairing endosomal acidification and therefore transferrin-mediated iron delivery. The primary molecular function is proton transport; iron homeostasis is a secondary, downstream effect. Annotating the peripheral stalk subunit to iron homeostasis overstates its direct role. Supporting Evidence: PMID:28296633 disrupting the V-ATPase results in intracellular iron depletion, thereby impairing PHD activity and leading to HIF activation PMID:28296633 principally relating to mutagenesis of genes encoding five V-ATPase subunits: ATP6AP1, ATP6V1A, ATP6V1G1, ATP6V0A2 and ATP6V0D1
GO:0036295 cellular response to increased oxygen levels	IMP PMID:28296633 The vacuolar-ATPase complex and assembly factors, TMEM199 an...	MARK AS OVER ANNOTATED	Summary: IMP annotation; HIF1alpha stabilization upon ATP6V1G1 loss is an indirect consequence of iron depletion downstream of V-ATPase disruption. Not a direct oxygen-sensing function. Reason: The cellular response to increased oxygen levels (HIF pathway) effect is downstream of iron depletion, which is itself downstream of impaired endosomal acidification. This is two steps removed from the primary proton pump function of G1. Annotating a structural peripheral stalk subunit to oxygen response conflates the primary molecular function with a distal phenotypic consequence. Supporting Evidence: PMID:28296633 disrupting the V-ATPase results in intracellular iron depletion, thereby impairing PHD activity and leading to HIF activation
GO:0016241 regulation of macroautophagy	NAS PMID:22982048 Lipofuscin is formed independently of macroautophagy and lys...	MARK AS OVER ANNOTATED	Summary: NAS annotation linking V-ATPase disruption to macroautophagy; the cited paper uses V-ATPase inhibition as a tool to block lysosomal function, not as direct evidence that G1 regulates macroautophagy. Reason: The cited paper (PMID:22982048) uses V-ATPase disruption as a tool to impair lysosomal activity and does not demonstrate that ATP6V1G1 specifically regulates macroautophagy. V-ATPase activity is required for lysosomal acidification, which is needed for autophagy completion, but this generic consequence of proton pump disruption does not justify annotating the G1 structural subunit to regulation of macroautophagy.
GO:0070062 extracellular exosome	HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos...	KEEP AS NON CORE	Summary: HDA from urinary exosome proteomics; likely contamination of exosome fraction with non-exosomal V-ATPase; not considered a core localization. Reason: Extracellular exosome identification from urinary proteomics (PMID:19056867) is likely a contaminant in the exosome-enriched fraction rather than genuine exosomal loading. Not a core localization for this cytosolic V1 peripheral stalk subunit.
GO:0005765 lysosomal membrane	HDA PMID:17897319 Integral and associated lysosomal membrane proteins.	ACCEPT	Summary: HDA from lysosomal membrane proteomics; directly supports lysosomal membrane localization as part of the assembled V-ATPase holoenzyme. Reason: Mass spectrometry identification in lysosome-enriched fractions (PMID:17897319) directly supports lysosomal membrane localization, consistent with the role of the assembled V-ATPase holoenzyme at the lysosomal membrane. Supporting Evidence: PMID:17897319 Integral and associated lysosomal membrane proteins
GO:0005829 cytosol	TAS Reactome:R-HSA-1222516	KEEP AS NON CORE	Summary: Reactome TAS annotation; cytosolic location reflects regulated disassembly state of free V1 complex. Reason: The cytosolic V1 complex is a real regulated state (disassembled from V0 under nutrient deprivation), but not the primary functional localization. Multiple Reactome entries support this non-core annotation.
GO:0005829 cytosol	TAS Reactome:R-HSA-5252133	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol; same rationale as above. Reason: Cytosolic localization in regulated disassembly context; non-core.
GO:0005829 cytosol	TAS Reactome:R-HSA-74723	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol; non-core regulated disassembly state. Reason: Cytosolic localization in regulated disassembly context; non-core.
GO:0005829 cytosol	TAS Reactome:R-HSA-917841	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol; non-core. Reason: Cytosolic localization in regulated disassembly context; non-core.
GO:0005829 cytosol	TAS Reactome:R-HSA-9639286	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol in mTORC1 signaling context; non-core. Reason: Cytosolic localization context; non-core.
GO:0005829 cytosol	TAS Reactome:R-HSA-9640167	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol; non-core. Reason: Cytosolic localization in Rag GTPase/mTORC1 signaling context; non-core.
GO:0005829 cytosol	TAS Reactome:R-HSA-9640168	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol; non-core. Reason: Cytosolic localization context; non-core.
GO:0005829 cytosol	TAS Reactome:R-HSA-9640175	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol; non-core. Reason: Cytosolic localization context; non-core.
GO:0005829 cytosol	TAS Reactome:R-HSA-9640195	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol; non-core. Reason: Cytosolic localization context; non-core.
GO:0005829 cytosol	TAS Reactome:R-HSA-9645598	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol; non-core. Reason: Cytosolic localization context; non-core.
GO:0005829 cytosol	TAS Reactome:R-HSA-9645608	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol; non-core. Reason: Cytosolic localization context; non-core.
GO:0005829 cytosol	TAS Reactome:R-HSA-9646468	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol; non-core. Reason: Cytosolic localization context; non-core.
GO:0005829 cytosol	TAS Reactome:R-HSA-9858924	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol; non-core. Reason: Cytosolic localization context; non-core.
GO:0005829 cytosol	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS manual ortholog transfer for cytosol localization; consistent with regulated disassembly producing free cytosolic V1 complex. Reason: Cytosolic localization reflects the regulated disassembly state; non-core.
GO:0005886 plasma membrane	ISS GO_REF:0000024	ACCEPT	Summary: ISS manual ortholog transfer for plasma membrane localization; consistent with experimental evidence showing G1 at apical plasma membrane in kidney and at plasma membrane in the G1/a interaction study. Reason: Plasma membrane localization is well supported experimentally (PMID:17360703, PMID:29993276). ISS is consistent with these experimental findings.
GO:0005886 plasma membrane	IDA PMID:17360703 V1 and V0 domains of the human H+-ATPase are linked by an in...	ACCEPT	Summary: Experimental plasma membrane localization from study demonstrating G1/a subunit interaction; the study demonstrated G1 at plasma membrane in the context of V0 subunit a interaction. Reason: The experimental evidence from PMID:17360703 demonstrates that G1 localizes at the plasma membrane as part of its interaction with V0 subunit a, which directly supports plasma membrane localization. Supporting Evidence: PMID:17360703 V1 and V0 domains of the human H+-ATPase are linked by an interaction between the G and a subunits
GO:0051117 ATPase binding	IPI PMID:17360703 V1 and V0 domains of the human H+-ATPase are linked by an in...	ACCEPT	Summary: Experimental IPI evidence for ATPase binding; reflects direct G1 interaction with V0 subunit a, a V-ATPase component. Reason: PMID:17360703 experimentally demonstrated direct interaction between G1 and V0 subunit a (ATP6V0A1, ATP6V0A4), supporting ATPase binding annotation as a meaningful specific interaction. Supporting Evidence: PMID:17360703 V1 and V0 domains of the human H+-ATPase are linked by an interaction between the G and a subunits

Core Functions

ATP6V1G1 is a structural peripheral stalk subunit of the V1 domain of the V-ATPase, forming EG heterodimers with subunit E (ATP6V1E1/E2) that serve as the stator connecting the V1 catalytic hexameric ring to the V0 proton channel. It directly contacts the V0 subunit a, and the G-a interaction is required for V1-V0 assembly and integrity. As part of the assembled holoenzyme, ATP6V1G1 contributes to ATP-hydrolysis-driven proton transport across lysosomal, endosomal, and (in kidney tubular cells) apical plasma membranes.

Molecular Function:

structural molecule activity

Directly Involved In:

proton transmembrane transport

Cellular Locations:

lysosomal membrane endosome membrane apical plasma membrane

Supporting Evidence:

file:human/ATP6V1G1/ATP6V1G1-uniprot.txt
The V1 complex consists of three catalytic AB heterodimers that form a heterohexamer, three peripheral stalks each consisting of EG heterodimers, one central rotor including subunits D and F, and the regulatory subunits C and H
PMID:17360703
V1 and V0 domains of the human H+-ATPase are linked by an interaction between the G and a subunits

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:16169070

A human protein-protein interaction network: a resource for annotating the proteome.

PMID:17360703

V1 and V0 domains of the human H+-ATPase are linked by an interaction between the G and a subunits.

G1/a1, G3/a1, and G1/a4 interactions demonstrated experimentally; G and a subunit interaction is a novel link between V1 and V0 required for H+-ATPase assembly and regulation.

PMID:17897319

Integral and associated lysosomal membrane proteins.

Mass spectrometry identification of ATP6V1G1 in lysosome-enriched fractions supports lysosomal membrane localization.

PMID:19056867

Large-scale proteomics and phosphoproteomics of urinary exosomes.

Identification in urinary exosome fraction; likely contamination rather than genuine exosomal loading.

PMID:21516116

Next-generation sequencing to generate interactome datasets.

PMID:22982048

Lipofuscin is formed independently of macroautophagy and lysosomal activity in stress-induced prematurely senescent human fibroblasts.

V-ATPase disruption used as a tool to impair lysosomal activity; does not directly implicate ATP6V1G1 in macroautophagy regulation.

PMID:25416956

A proteome-scale map of the human interactome network.

PMID:28296633

The vacuolar-ATPase complex and assembly factors, TMEM199 and CCDC115, control HIF1alpha prolyl hydroxylation by regulating cellular iron levels.

ATP6V1G1 identified in genome-wide screen for HIF1alpha regulators; mechanism is indirect via iron depletion from impaired endosomal acidification leading to reduced PHD activity and HIF activation.

PMID:29993276

H(+)-ATPase B1 subunit localizes to thick ascending limb and distal convoluted tubule of rodent and human kidney.

H+-ATPase B1 subunit co-localizes with other H+-ATPase subunits at apical plasma membrane in kidney TAL and DCT.

PMID:30021884

Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei.

PMID:31515488

Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:33065002

Structures of a Complete Human V-ATPase Reveal Mechanisms of Its Assembly.

Cryo-EM structures of complete human V-ATPase directly identify all V1 subunits; V1 complex contains three peripheral EG heterodimeric stalks.

PMID:35271311

OpenCell: Endogenous tagging for the cartography of human cellular organization.

Reactome:R-HSA-1222516

Intraphagosomal pH is lowered to 5 by V-ATPase

Reactome:R-HSA-5252133

ATP6AP1 binds V-ATPase

Reactome:R-HSA-74723

Endosome acidification

Reactome:R-HSA-917841

Acidification of Tf:TfR1 containing endosome

Reactome:R-HSA-9639286

RRAGC,D exchanges GTP for GDP

Reactome:R-HSA-9640167

RRAGA,B exchanges GDP for GTP

Reactome:R-HSA-9640168

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

Reactome:R-HSA-9640175

v-ATPase:Ragulator:RagA,B:GDP:RagC,D:GDP binds SLC38A9:Arginine

Reactome:R-HSA-9640195

RRAGA,B hydrolyzes GTP

Reactome:R-HSA-9645598

RRAGC,D hydrolyzes GTP

Reactome:R-HSA-9645608

v-ATPase:Ragulator:RRAGA,B:GTP:RRAGC,D:GDP binds mTORC1

Reactome:R-HSA-9646468

mTORC1 binds RHEB:GTP

Reactome:R-HSA-9858924

MITF-M-dependent ATP6V1G1gene expression

Suggested Experiments

Experiment: Generate G1/G2/G3 paralog-specific knockout cell lines and perform functional complementation with each paralog individually to assess whether loss of G1 can be rescued by G2 or G3 with equal efficiency in lysosomal acidification and iron homeostasis assays.

Hypothesis: G1, G2, and G3 are functionally non-equivalent peripheral stalk subunits with distinct V1-V0 coupling properties.

Type: genetic complementation and lysosomal pH measurement

Experiment: Apply proximity labeling (BioID/APEX2) from G1 in nutrient-replete versus nutrient-deprived conditions to identify regulated binding partners in assembled versus disassembled states, and map G1 phosphorylation sites by quantitative phosphoproteomics.

Hypothesis: Post-translational modifications of G1 regulate V-ATPase assembly state (V1-V0 association vs. disassembly).

Type: proximity labeling proteomics and phosphoproteomics

Deep Research

Falcon

(ATP6V1G1-deep-research-falcon.md)

Comprehensive Research Report: ATP6V1G1 (V-type Proton ATPase Subunit G1) Falcon

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.

Comprehensive Research Report: ATP6V1G1 (V-type Proton ATPase Subunit G1)

Gene Identity and Overview

ATP6V1G1 (UniProt: O75348) encodes the V-type proton ATPase subunit G1, a ~13-kDa component of the peripheral V1 domain of the vacuolar H+-ATPase (V-ATPase) complex in humans (kawamura2015lossofg2 pages 1-2, smith2002molecularcloningand pages 1-2, wang2020pharmacologicaltargetingof pages 1-3). This gene represents one of three human G-subunit isoforms: ATP6V1G1 (ubiquitous), ATP6V1G2 (brain/neuron-enriched), and ATP6V1G3 (kidney-restricted) (kawamura2015lossofg2 pages 1-2, smith2002molecularcloningand pages 1-2). The G1 isoform is the predominant housekeeping G-subunit expressed across diverse tissues and cell types, distinguishing it from its tissue-specific paralogs.

Primary Function and Enzymatic Mechanism

Proton Pumping and ATP Hydrolysis

ATP6V1G1 functions as an essential structural component of the V-ATPase, a multi-subunit rotary proton pump that acidifies intracellular compartments by coupling ATP hydrolysis to proton translocation (song2020theemergingroles pages 1-2, chen2025theemergingroles pages 1-2, abbas2020structureofvatpase pages 1-2). The V-ATPase comprises two functional sectors: the peripheral V1 domain, which hydrolyzes ATP, and the membrane-embedded V0 domain, which translocates protons (abbas2020structureofvatpase pages 1-2, indrawinata2023structuralandfunctional pages 1-2). ATP6V1G1 resides in the V1 sector and participates in energy coupling between these domains.

The G subunit interacts with the E subunit to form rod-like peripheral stalks that connect the catalytic head (containing A and B subunits) to the membrane proton pore (kawamura2015lossofg2 pages 1-2, tuli2023thecytosolicnterminal pages 1-2, indrawinata2023structuralandfunctional pages 1-2). While ATP hydrolysis occurs at the A/B catalytic interface and proton translocation occurs through the V0 sector, ATP6V1G1 plays an indirect but essential role in coupling these processes by stabilizing the stator architecture that prevents futile rotation of the catalytic head (tuli2023thecytosolicnterminal pages 1-2, indrawinata2023structuralandfunctional pages 1-2).

Substrate Specificity

As a structural coupling subunit rather than a catalytic or transport subunit, ATP6V1G1 does not directly bind substrate. The transported substrate of the holoenzyme is the proton (H+), with ATP serving as the energy source. Recent structural studies using cryo-electron microscopy of mammalian brain V-ATPase have defined the enzyme's ATP:H+ stoichiometry as 3:10, providing insight into the efficiency of the proton-pumping mechanism (abbas2020structureofvatpase pages 1-2).

Subcellular Localization

ATP6V1G1 localizes to endomembrane compartments where V-ATPase complexes function to acidify organelle lumens (song2020theemergingroles pages 1-2, chen2025theemergingroles pages 1-2, tuli2023thecytosolicnterminal pages 1-2). These include:

Lysosomes: The primary degradative compartment, maintained at pH 4.5-5.0 to enable acid hydrolase activity (chen2025theemergingroles pages 1-2, song2020theemergingroles pages 1-2)
Endosomes: Early and late endosomes that mature through progressive acidification (mulligan2024collapseoflate pages 1-4)
Synaptic vesicles: In neurons, V-ATPase generates proton gradients essential for neurotransmitter loading (kawamura2015lossofg2 pages 1-2, abbas2020structureofvatpase pages 1-2)
Secretory vesicles and Golgi apparatus: Supporting protein processing and trafficking

Recent work has shown that pH neutralization of late endosomes increases the assembly of the V1G1 subunit on endosomal membranes, linking ATP6V1G1 recruitment to stress-responsive trafficking regulation (mulligan2024collapseoflate pages 1-4). In specialized cells such as osteoclasts and kidney intercalated cells, V-ATPase can also localize to the plasma membrane to export protons extracellularly (duan2018vatpasesandosteoclasts pages 1-2).

Signaling and Biochemical Pathways

ATP6V1G1 participates in several critical cellular pathways through its role in V-ATPase function and assembly:

Pathway/Process	Role of ATP6V1G1	Molecular Mechanisms	Citations
mTORC1 nutrient sensing and activation	ATP6V1G1 functions as part of the lysosomal/endosomal V-ATPase that is required for nutrient-responsive mTORC1 signaling.	V-ATPase on lysosomal membranes acts with Ragulator/Rag signaling to support mTORC1 activation in response to amino acids; V-ATPase assembly state also changes with nutrient conditions, linking proton-pump status to lysosomal catabolic activity and mTORC1 output. Pharmacologic targeting of V1G suppresses mTORC1 signaling in multidrug-resistant cancer cells.	(wang2020pharmacologicaltargetingof pages 1-3, tuli2023thecytosolicnterminal pages 1-2, song2020theemergingroles pages 1-2)
Autophagy and lysosomal degradation	ATP6V1G1 supports lysosomal acidification needed for degradative enzyme activity and autophagic flux.	As a V1-sector subunit, ATP6V1G1 contributes to assembly/activity of the ATP-driven proton pump that lowers lysosomal lumen pH, enabling acid hydrolase function, degradation of autophagic cargo, and maintenance of proteostasis. Reduced V-ATPase function impairs substrate clearance and lysosomal homeostasis.	(chen2025theemergingroles pages 1-2, song2020theemergingroles pages 1-2, zhang2024identificationandvalidation pages 1-2)
Endosomal trafficking and late endosome maturation	ATP6V1G1 participates in late endosome function and trafficking control beyond bulk acidification.	Neutralization of late endosomal pH increases membrane assembly of V1G1-containing V-ATPase; V1G1 then helps stabilize active Rab7 through RILP, affecting tubulation and CI-M6PR recycling. This links V1G1-containing V-ATPase complexes directly to endosomal maturation and receptor recycling.	(mulligan2024collapseoflate pages 1-4)
Rab7-RILP signaling axis	ATP6V1G1 acts as a molecular bridge between organelle acidification machinery and Rab7 effector signaling.	Evidence cited in recent work indicates that Rab7, RILP, and V1G1 can form a functional complex; increased V1G1 recruitment to endosomal membranes under pH stress correlates with Rab7 hyperactivation and altered trafficking behavior.	(mulligan2024collapseoflate pages 1-4)
Intracellular pH homeostasis	ATP6V1G1 helps maintain compartment-specific acidic pH in endosomes, lysosomes, synaptic vesicles, and related organelles.	V-ATPase uses ATP hydrolysis in the V1 sector to drive proton translocation through the V0 sector; ATP6V1G1 is part of the peripheral stalk needed to couple ATP hydrolysis to proton pumping, thereby supporting acidification of intracellular organelles.	(li2020comprehensiveanalysisof pages 1-2, song2020theemergingroles pages 1-2, abbas2020structureofvatpase pages 1-2, indrawinata2023structuralandfunctional pages 1-2)
Reversible V-ATPase assembly/disassembly	ATP6V1G1 contributes to regulated assembly of V1 with V0, a core mechanism controlling pump activity.	The G subunit pairs with E subunits in rod-like peripheral stalks that stabilize the holoenzyme; regulated dissociation of V1 from V0 turns off proton transport, whereas reassembly on membranes restores acidification in response to physiological cues such as nutrient stress.	(kawamura2015lossofg2 pages 1-2, tuli2023thecytosolicnterminal pages 1-2, song2020theemergingroles pages 1-2)
Neurotransmitter vesicle loading / secretory vesicle acidification	ATP6V1G1 can support vesicular acidification in neural tissue, especially where it complements or substitutes for other G-subunit isoforms.	V-ATPase-generated proton gradients in synaptic vesicles provide the electrochemical driving force for neurotransmitter uptake. In mouse brain, loss of neuron-enriched G2 is compensated by increased G1 protein, indicating functional interchangeability of G1 in neuronal vesicle acidification contexts.	(kawamura2015lossofg2 pages 1-2, abbas2020structureofvatpase pages 1-2)
Tumor cell growth and survival signaling	ATP6V1G1 promotes pro-tumor phenotypes in several cancers by sustaining V-ATPase activity, organelle acidification, and downstream signaling.	In glioblastoma and other cancers, high ATP6V1G1 expression is associated with growth, stemness, invasion, and survival; V-ATPase inhibition or ATP6V1G1 knockdown reduces sphere formation and viability, and in some contexts suppresses stem-cell markers and signaling outputs including mTORC1 or MAPK/ERK-related programs.	(cristofori2015thevacuolarh+ pages 1-2, bertolini2018exosomessignallingin pages 1-7, zhang2024identificationandvalidation pages 1-2, wang2020pharmacologicaltargetingof pages 1-3)
Extracellular vesicle-mediated microenvironmental signaling	ATP6V1G1 may influence intercellular signaling by shaping exosome content and activity in glioma stem-like cells.	Exosomes from V1G1-high glioma neurospheres were reported to carry V-ATPase G1 and to enhance growth/motility and MAPK/ERK signaling in recipient cells; blocking V-ATPase activity reversed these effects, suggesting ATP6V1G1-dependent control of vesicle-mediated signaling.	(bertolini2018exosomessignallingin pages 1-7)

Table: This table summarizes the main signaling pathways and biological processes linked to ATP6V1G1 based on the available evidence. It highlights how ATP6V1G1 connects V-ATPase-driven acidification to nutrient sensing, trafficking, autophagy, and disease-relevant signaling.

mTORC1 Nutrient Sensing

V-ATPase functions as part of the lysosomal signaling platform that activates mTORC1 in response to amino acids (wang2020pharmacologicaltargetingof pages 1-3, tuli2023thecytosolicnterminal pages 1-2, song2020theemergingroles pages 1-2). The V-ATPase-Ragulator complex on lysosomal membranes is required for nutrient-responsive mTORC1 signaling. Pharmacological targeting of the V1G subunit with the natural product verucopeptin suppresses both V-ATPase activity and mTORC1 signaling in multidrug-resistant cancer cells, demonstrating the functional link between ATP6V1G1 and this central growth-regulatory pathway (wang2020pharmacologicaltargetingof pages 1-3).

Autophagy and Lysosomal Degradation

As a component of the proton pump that maintains lysosomal acidity, ATP6V1G1 is essential for autophagic flux and proteostasis (chen2025theemergingroles pages 1-2, song2020theemergingroles pages 1-2, zhang2024identificationandvalidation pages 1-2). Proper lysosomal acidification enables activation of cathepsins and other acid hydrolases, degradation of autophagic cargo, and recycling of cellular components. Dysfunction of V-ATPase impairs these processes, leading to accumulation of undigested materials and contributing to disease (chen2025theemergingroles pages 1-2, song2020theemergingroles pages 1-2).

Endosomal Trafficking

Recent findings reveal that ATP6V1G1 participates in late endosome function beyond bulk acidification. A 2024 study demonstrated that neutralization of late endosomal pH increases membrane assembly of V1G1-containing V-ATPase, which then stabilizes GTP-bound Rab7 through RILP, affecting tubulation and mannose-6-phosphate receptor (CI-M6PR) recycling (mulligan2024collapseoflate pages 1-4). This establishes ATP6V1G1 as a molecular bridge between organelle acidification machinery and Rab7 effector signaling.

Reversible Assembly Regulation

V-ATPase activity is regulated by reversible dissociation and reassembly of the V1 and V0 sectors (kawamura2015lossofg2 pages 1-2, tuli2023thecytosolicnterminal pages 1-2, song2020theemergingroles pages 1-2). ATP6V1G1, as part of the peripheral stalk, participates in this assembly state transition, which changes with nutrient and stress cues. During nutrient starvation, V1 domains move from the cytosol to assemble with membrane-bound V0 domains, activating proton pumping capacity (song2020theemergingroles pages 1-2).

Experimental Evidence and Structural Studies

Structural Analysis

Cryo-electron microscopy structures of mammalian V-ATPase have resolved the organization of ATP6V1G1 within the enzyme complex at near-atomic resolution (abbas2020structureofvatpase pages 1-2). These structures reveal that G subunits, together with E subunits, form the peripheral stalks that act as stators, preventing rotation of the catalytic head relative to the membrane sector and enabling productive coupling of ATP hydrolysis to proton transport (abbas2020structureofvatpase pages 1-2, indrawinata2023structuralandfunctional pages 1-2).

Functional Perturbation Studies

Experimental manipulation of ATP6V1G1 expression has demonstrated its importance for cellular fitness and disease phenotypes:

Glioblastoma: siRNA knockdown of ATP6V1G1 in glioma neurospheres reduced sphere formation ability, induced cell death, and decreased matrix invasion, effects that were not observed in differentiated glioma monolayer cultures (cristofori2015thevacuolarh+ pages 1-2)
Cancer stem cells: ATP6V1G1 expression in glioma stem cells confers proliferative advantage and is required for stem-cell maintenance (bertolini2018exosomessignallingin pages 1-7)
Multidrug-resistant cancers: Pharmacological targeting of the V1G subunit with verucopeptin demonstrated strong inhibition of both V-ATPase activity and mTORC1 signaling, leading to substantial efficacy against multidrug-resistant cell proliferation and tumor growth in vivo (wang2020pharmacologicaltargetingof pages 1-3)

Compensatory Mechanisms

Mouse studies have shown that loss of the neuron-specific G2 isoform leads to upregulation of G1 protein (without increased mRNA) in brain tissue, indicating post-translational compensation and functional interchangeability of G-subunit isoforms (kawamura2015lossofg2 pages 1-2). This demonstrates that ATP6V1G1 can support neuronal V-ATPase function when the tissue-specific isoform is absent.

Recent Developments (2023-2025)

Recent literature highlights expanding roles for ATP6V1G1 in diverse disease contexts:

Cardiovascular Disease

A 2025 review summarized emerging evidence that V-ATPase-dependent lysosomal acidification influences cardiovascular pathology, including atherosclerosis and myocardial disease (chen2025theemergingroles pages 1-2). The V1G1 subunit was noted as a recruited component of the V-ATPase machinery whose assembly state affects cellular homeostasis in cardiovascular tissues.

Hepatocellular Carcinoma

A 2024 phosphoproteomics study identified 163 ATP6V1G1-regulated phosphoproteins in hepatocellular carcinoma, with validated changes in p-RPS6, p-SQSTM1, p-PDPK1, and p-EEF2, highlighting ATP6V1G1's impact on tumor progression through altered phosphorylation signaling (zhang2024identificationandvalidation pages 1-2).

Neurotoxicity and Neurodegeneration

A 2025 study linked manganese neurotoxicity to impaired V-ATPase function through TFEB-v/p-ATPase signaling, demonstrating lysosomal dysfunction as a mechanism of parkinsonism-like symptoms, with implications for ATP6V1G1-containing complexes in neuronal homeostasis (song2020theemergingroles pages 1-2).

Current Applications and Therapeutic Targeting

Disease/Application	Expression/Role	Clinical Significance	Therapeutic Strategy (if any)	Citations
Glioblastoma (GBM)	ATP6V1G1 is significantly upregulated in GBM tissues and glioma stem cell-enriched neurospheres; knockdown impairs sphere formation, induces cell death, and reduces invasion. Exosomal V1G1 from glioma stem cells is linked to MAPK/ERK activation in recipient cells.	High ATP6V1G1 expression correlates with shorter overall survival and supports cancer stem-cell maintenance and invasive behavior.	V-ATPase inhibition with bafilomycin A1 phenocopied ATP6V1G1 knockdown in GBM models, supporting proton-pump targeting as a therapeutic approach.	(cristofori2015thevacuolarh+ pages 1-2, bertolini2018exosomessignallingin pages 1-7)
Lower-grade glioma / IDH-wildtype glioma	V-ATPase subunit-expression patterns, including ATP6V1G1, stratify glioma subtypes and influence tumor growth in vivo.	Suggests value in molecular subclassification and prognosis, especially in aggressive glioma contexts.	V-ATPase proposed as a therapeutic target; pathway-level inhibition rather than ATP6V1G1-specific therapy is emphasized.	(cristofori2015thevacuolarh+ pages 1-2)
Hepatocellular carcinoma (HCC)	ATP6V1G1 is highly expressed in HCC and linked to proliferation, migration, apoptosis resistance, and altered phosphorylation signaling; phosphoproteomics identified 163 ATP6V1G1-regulated phosphoproteins, with validated changes in p-RPS6, p-SQSTM1, p-PDPK1, and p-EEF2.	Supports a pro-tumor role and nominates ATP6V1G1 as a mechanistic driver and potential biomarker in liver cancer.	No approved ATP6V1G1-directed therapy reported; findings support exploration of V-ATPase-targeted or pathway-guided interventions in HCC.	(zhang2024identificationandvalidation pages 1-2)
Renal clear cell carcinoma (KIRC/ccRCC)	Family-level analyses show lower ATP6V1G1 mRNA is associated with shorter overall survival in KIRC, indicating context-specific prognostic behavior compared with GBM/HCC.	ATP6V1G1 may contribute to prognostic stratification, though evidence is mainly bioinformatic and not yet mechanistically resolved for this subunit.	No ATP6V1G1-specific intervention established; potential value is currently as a prognostic biomarker within V-ATPase signatures.	(li2020comprehensiveanalysisof pages 1-2)
Multidrug-resistant cancers	The V1G subunit is directly targeted by the natural product verucopeptin; ATP6V1G-containing V-ATPase activity supports growth of MDR cancer cells. Target engagement inhibits both V-ATPase activity and mTORC1 signaling.	Identifies ATP6V1G subunits, including ATP6V1G1 in human systems, as actionable vulnerabilities in MDR tumors.	Verucopeptin showed antitumor efficacy in vitro and in vivo by targeting V1G and suppressing V-ATPase/mTORC1 signaling.	(wang2020pharmacologicaltargetingof pages 1-3)
Breast cancer metastasis / invasive tumor phenotypes	V-ATPase assembly and vesicular acidification promote invasive behavior broadly in cancer; ATP6V1G1 is one of the lysosomal/plasma membrane proton-pump components implicated in pH rewiring.	Highlights the translational relevance of V-ATPase-dependent acidification in metastasis and tumor microenvironment adaptation.	V-ATPase inhibition is a proposed anti-invasive strategy, although not ATP6V1G1-specific in current evidence.	(duan2018vatpasesandosteoclasts pages 1-2, song2020theemergingroles pages 1-2)
Osteoporosis / bone remodeling	Human genetics and review evidence connect ATP6V1G1 with bone mineral density and osteoclast-related V-ATPase biology.	Suggests ATP6V1G1 may be a pleiotropic determinant of bone density, though causal and cell-specific functions remain less defined than for a3 or d2 subunits.	V-ATPase inhibitors are being explored in bone disease, but isoform/subunit selectivity remains a major challenge.	(duan2018vatpasesandosteoclasts pages 1-2)
Cardiovascular disease	V-ATPase-dependent lysosomal acidification is increasingly implicated in cardiovascular homeostasis and disease; ATP6V1G1 is referenced as a recruited/interacting subunit within this machinery.	Supports indirect disease relevance through lysosomal dysfunction, autophagy defects, and altered cellular homeostasis in cardiovascular tissues.	Review literature highlights V-ATPase as a prospective therapeutic axis, but ATP6V1G1-specific cardiovascular therapies are not established.	(chen2025theemergingroles pages 1-2)
Neurodegenerative diseases	V-ATPase dysfunction impairs lysosomal acidification, autophagy, and proteostasis in neurodegeneration; ATP6V1G1 is a ubiquitous G-subunit isoform, and recent literature links altered ATP6V1G1 expression to lysosomal dysfunction and neurodegenerative contexts.	Indicates likely contribution to neuronal/endolysosomal homeostasis; evidence is stronger at the V-ATPase-complex level than for ATP6V1G1 alone.	Current strategies focus on restoring lysosomal acidification or modulating V-ATPase regulation rather than ATP6V1G1-specific targeting.	(song2020theemergingroles pages 1-2, indrawinata2023structuralandfunctional pages 1-2)
Endosomal/lysosomal trafficking disorders and pH-stress responses	Late-endosomal pH collapse increases membrane assembly of V1G1, which stabilizes GTP-bound Rab7 via RILP and alters CI-M6PR recycling/tubulation.	Provides mechanistic evidence that ATP6V1G1 participates in stress-adaptive trafficking responses with potential relevance to lysosomal storage and neurodegenerative conditions.	No direct therapy yet; suggests that modulating V-ATPase assembly or Rab7-RILP signaling could be therapeutically relevant.	(mulligan2024collapseoflate pages 1-4)
Nonalcoholic fatty liver disease / hepatic lysosomal dysfunction	ATP6V1G1 is transcriptionally induced by RORα and contributes to lysosomal acidification and autophagic flux in hepatocytes; dysregulation is implicated in fatty liver disease biology.	Positions ATP6V1G1 as a mechanistic link between transcriptional control, lysosomal pH, and hepatic metabolic disease.	RORα activation and restoration of lysosomal acidification are proposed strategies; no ATP6V1G1-specific therapy established.	(zhang2024identificationandvalidation pages 1-2)

Table: This table summarizes the current evidence linking ATP6V1G1 to human disease, prognosis, and therapeutic targeting. It is useful for identifying where evidence is strongest for biomarker development versus direct intervention.

Cancer Biomarker and Therapeutic Target

ATP6V1G1 has emerged as a prognostic biomarker and therapeutic target across multiple cancer types:

Glioblastoma: High ATP6V1G1 expression correlates with shorter overall survival and supports cancer stem-cell maintenance (cristofori2015thevacuolarh+ pages 1-2, bertolini2018exosomessignallingin pages 1-7). V-ATPase inhibition with bafilomycin A1 phenocopies ATP6V1G1 knockdown effects.
Multidrug-resistant cancers: The natural product verucopeptin directly targets the V1G subunit (including ATP6V1G1), demonstrating antitumor efficacy both in vitro and in vivo (wang2020pharmacologicaltargetingof pages 1-3). This represents a novel approach for combating chemotherapy-resistant tumors.
Hepatocellular carcinoma: ATP6V1G1 promotes proliferation, migration, and apoptosis resistance in liver cancer (zhang2024identificationandvalidation pages 1-2).
Renal clear cell carcinoma: Lower ATP6V1G1 expression associates with shorter survival in kidney cancer, suggesting context-specific prognostic value (li2020comprehensiveanalysisof pages 1-2).

V-ATPase Inhibitors

Pharmacological inhibition of V-ATPase represents a therapeutic strategy under investigation. Bafilomycin A1, a selective V-ATPase inhibitor, has shown efficacy in preclinical cancer models by suppressing stem-cell markers, invasion, and tumor growth (cristofori2015thevacuolarh+ pages 1-2). However, developing isoform-selective or subunit-specific inhibitors remains a challenge for translating V-ATPase targeting into clinical practice (duan2018vatpasesandosteoclasts pages 1-2).

Additional Disease Contexts

ATP6V1G1 has been implicated in:
- Osteoporosis: Genetic evidence links ATP6V1G1 with bone mineral density regulation (duan2018vatpasesandosteoclasts pages 1-2)
- Nonalcoholic fatty liver disease: ATP6V1G1 expression is transcriptionally regulated by RORα and contributes to hepatic lysosomal acidification and autophagic flux (zhang2024identificationandvalidation pages 1-2)

Summary

Property	Description	Key Citations
Verified identity	ATP6V1G1 encodes the human V-type proton ATPase subunit G1 (V-ATPase G1), a component of the V1/cytosolic catalytic sector of the vacuolar H+-ATPase complex. This matches the UniProt target O75348 and distinguishes it from the tissue-restricted paralogs ATP6V1G2 and ATP6V1G3.	(kawamura2015lossofg2 pages 1-2, smith2002molecularcloningand pages 1-2, wang2020pharmacologicaltargetingof pages 1-3)
Protein structure / domain organization	ATP6V1G1 is a small ~13-kDa G-subunit of the V1 sector; in mammals, G subunits are part of the peripheral stalk(s) that connect the ATP-hydrolytic head to the membrane sector. Structural work on mammalian V-ATPase places G subunits in the stator architecture that stabilizes coupling between catalytic and proton-translocating regions.	(kawamura2015lossofg2 pages 1-2, abbas2020structureofvatpase pages 1-2, indrawinata2023structuralandfunctional pages 1-2)
Molecular function	ATP6V1G1 contributes to the activity of the V-ATPase proton pump, which acidifies intracellular compartments by using the energy of ATP hydrolysis to move protons into organelle lumens. The direct transported substrate of the holoenzyme is H+; ATP6V1G1 itself is a structural/coupling subunit rather than the catalytic ATP-binding site or proton pore.	(song2020theemergingroles pages 1-2, chen2025theemergingroles pages 1-2, li2020comprehensiveanalysisof pages 1-2)
Enzymatic mechanism	V-ATPase is a rotary ATP-driven nanomotor composed of a peripheral V1 sector that hydrolyzes ATP and an integral V0/Vo sector that translocates protons. ATP hydrolysis in V1 drives rotation and conformational changes that are mechanically coupled to proton pumping through V0; ATP6V1G1 supports this coupling as part of the peripheral stalk.	(abbas2020structureofvatpase pages 1-2, tuli2023thecytosolicnterminal pages 1-2, indrawinata2023structuralandfunctional pages 1-2)
Catalytic role specificity	ATP hydrolysis occurs primarily at the A/B catalytic subunits in V1, whereas proton translocation occurs through the V0/Vo membrane sector. ATP6V1G1 therefore has an indirect but essential mechanistic role in catalysis by supporting assembly, force transmission, and stability rather than directly catalyzing ATP cleavage or forming the proton channel.	(tuli2023thecytosolicnterminal pages 1-2, indrawinata2023structuralandfunctional pages 1-2, li2020comprehensiveanalysisof pages 1-2)
Subunit interactions	The G subunit interacts with the E subunit to form a rod-like peripheral stalk structure connecting catalytic and membrane domains. This stalk architecture is important for energy coupling and for the reversible assembly/disassembly of V1 with V0, a major regulatory feature of V-ATPase.	(kawamura2015lossofg2 pages 1-2, tuli2023thecytosolicnterminal pages 1-2, indrawinata2023structuralandfunctional pages 1-2)
Complex composition context	Mammalian V-ATPase contains multiple V1 and V0 subunits; mammalian brain V-ATPase preparations included V1 subunits such as A, B2, C1, D, E1, F, G2 and low amounts of G1, alongside V0 subunits and accessory proteins. This supports ATP6V1G1 as one of several interchangeable isoform-defined structural components of the holoenzyme.	(abbas2020structureofvatpase pages 1-2, indrawinata2023structuralandfunctional pages 1-2)
Isoforms / paralogs	Mammals have three G-subunit genes: ATP6V1G1, ATP6V1G2, ATP6V1G3. G1 is ubiquitously expressed, G2 is enriched in brain/neurons, and G3 shows kidney-restricted expression. Loss of G2 in mouse brain can be compensated by increased G1 protein abundance, indicating partial functional interchangeability.	(kawamura2015lossofg2 pages 1-2, smith2002molecularcloningand pages 1-2)
Tissue distribution	ATP6V1G1 is broadly expressed across tissues and cell types, consistent with a housekeeping role in organelle acidification. In contrast, G2 and G3 show tissue specificity, reinforcing that G1 is the predominant ubiquitous G-subunit isoform in human cells.	(kawamura2015lossofg2 pages 1-2, smith2002molecularcloningand pages 1-2)
Subcellular localization	ATP6V1G1 functions as part of V-ATPase on membranes of endosomes, lysosomes, synaptic vesicles, secretory vesicles, and other endomembranes; in specialized cells, V-ATPases can also function at the plasma membrane to export protons. Its localization reflects the membrane association of assembled V-ATPase complexes.	(song2020theemergingroles pages 1-2, chen2025theemergingroles pages 1-2, tuli2023thecytosolicnterminal pages 1-2)
Functional localization in neurons	In neurons, V-ATPase-generated proton gradients energize synaptic vesicle neurotransmitter loading. Although neuron-specific G2 is prominent in brain, G1 is also present and can compensate for G2 loss, supporting a role for ATP6V1G1 in vesicle acidification and synaptic physiology when incorporated into neuronal V-ATPase complexes.	(kawamura2015lossofg2 pages 1-2, abbas2020structureofvatpase pages 1-2)
Role in lysosomal acidification	ATP6V1G1 supports lysosomal acidification, which maintains luminal pH around 4.5–5.0, enabling acid hydrolase function, autophagy, endocytosis, phagocytosis, and macromolecule degradation. Impaired V-ATPase function disrupts these processes and contributes to disease.	(chen2025theemergingroles pages 1-2, song2020theemergingroles pages 1-2)
Role in endosomal trafficking	ATP6V1G1 participates in endosomal maturation and trafficking through its role in V-ATPase assembly on endosomal membranes. A 2024 study found that pH neutralization increased V1G1 assembly on late endosomal membranes, linking V1G1 to Rab7/RILP-dependent control of endosome tubulation and CI-M6PR recycling.	(mulligan2024collapseoflate pages 1-4)
Regulatory mechanisms: reversible assembly	V-ATPase activity is regulated by reversible dissociation and reassembly of the V1 and V0 sectors. ATP6V1G1, as part of the V1 peripheral stalk, participates in this assembly state, which changes with nutrient and stress cues and directly affects proton-pumping capacity.	(tuli2023thecytosolicnterminal pages 1-2, song2020theemergingroles pages 1-2, mulligan2024collapseoflate pages 1-4)
Regulatory mechanisms: nutrient sensing and mTOR	V-ATPase functions as part of a lysosomal signaling platform that helps regulate mTORC1 and broader nutrient sensing. Because ATP6V1G1 is a V1 subunit required for assembly/activity, its regulation influences lysosomal acidification, catabolic capacity, and signaling outputs tied to nutrient sufficiency.	(song2020theemergingroles pages 1-2, tuli2023thecytosolicnterminal pages 1-2, chen2025theemergingroles pages 1-2)
Experimental functional evidence	Functional perturbation studies indicate ATP6V1G1 is important for cell fitness and disease phenotypes: siRNA knockdown in glioblastoma neurospheres reduced sphere formation, invasion, and survival; pharmacologic targeting of the V1G subunit inhibited V-ATPase activity and mTORC1 signaling in multidrug-resistant cancer cells.	(cristofori2015thevacuolarh+ pages 1-2, wang2020pharmacologicaltargetingof pages 1-3)
Disease-linked expression pattern	ATP6V1G1 is frequently studied as a cancer-associated V-ATPase subunit. It is upregulated in glioblastoma and implicated in hepatocellular carcinoma progression; altered expression of V-ATPase subunits, including ATP6V1G1, is also associated with prognosis in renal clear cell carcinoma and other tumors.	(cristofori2015thevacuolarh+ pages 1-2, zhang2024identificationandvalidation pages 1-2, li2020comprehensiveanalysisof pages 1-2)

Table: This table summarizes the verified identity, structural role, biochemical function, localization, isoform context, and regulatory features of human ATP6V1G1. It is useful as a compact reference for functional annotation of this V-ATPase subunit and for distinguishing its direct role from the catalytic and proton-translocating subunits of the holoenzyme.

ATP6V1G1 encodes a ubiquitously expressed G-subunit of the V-ATPase proton pump, functioning as a structural component of the peripheral stalk that couples ATP hydrolysis to proton translocation across membranes. The protein localizes to lysosomes, endosomes, and other endomembrane compartments where it supports organelle acidification essential for proteolysis, autophagy, receptor trafficking, and cellular homeostasis. ATP6V1G1 participates in mTORC1 nutrient sensing, endosomal trafficking through Rab7-RILP signaling, and reversible V-ATPase assembly regulation.

Experimental evidence demonstrates that ATP6V1G1 is essential for cancer stem-cell maintenance, tumor invasion, and resistance to therapy, establishing it as a therapeutic target and prognostic biomarker across multiple cancer types. Recent structural studies have resolved its organization within the V-ATPase complex, while functional studies continue to reveal its roles in cardiovascular disease, neurodegeneration, and metabolic disorders. Current therapeutic strategies focus on pharmacological V-ATPase inhibition, with the natural product verucopeptin representing a V1G-targeting approach for multidrug-resistant cancers.

References

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(tuli2023thecytosolicnterminal pages 1-2): Farzana Tuli and Patricia M. Kane. The cytosolic n-terminal domain of v-atpase a-subunits is a regulatory hub targeted by multiple signals. Frontiers in Molecular Biosciences, Jun 2023. URL: https://doi.org/10.3389/fmolb.2023.1168680, doi:10.3389/fmolb.2023.1168680. This article has 10 citations.
(mulligan2024collapseoflate pages 1-4): Ryan J. Mulligan, Magdalena M. Magaj, Laura Digilio, Stefanie Redemann, Chan Choo Yap, and Bettina Winckler. Collapse of late endosomal ph elicits a rapid rab7 response via the v-atpase and rilp. Journal of Cell Science, May 2024. URL: https://doi.org/10.1242/jcs.261765, doi:10.1242/jcs.261765. This article has 16 citations and is from a domain leading 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.
(zhang2024identificationandvalidation pages 1-2): Yi Zhang, Liuyi Lu, Mingxing Chen, Jiaqi Nie, Xue Qin, and Huaping Chen. Identification and validation of atp6v1g1-regulated phosphorylated proteins in hepatocellular carcinoma. PLOS ONE, 19:e0310037, Dec 2024. URL: https://doi.org/10.1371/journal.pone.0310037, doi:10.1371/journal.pone.0310037. This article has 1 citations and is from a 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.
(cristofori2015thevacuolarh+ pages 1-2): Andrea Di Cristofori, Stefano Ferrero, Irene Bertolini, Gabriella Gaudioso, Maria Veronica Russo, Valeria Berno, Marco Vanini, Marco Locatelli, Mario Zavanone, Paolo Rampini, Thomas Vaccari, Manuela Caroli, and Valentina Vaira. The vacuolar h+ atpase is a novel therapeutic target for glioblastoma. Oncotarget, 6:17514-17531, May 2015. URL: https://doi.org/10.18632/oncotarget.4239, doi:10.18632/oncotarget.4239. This article has 89 citations.
(bertolini2018exosomessignallingin pages 1-7): IRENE BERTOLINI. Exosomes signalling in human glioma stem cells: the central role of v-atpase proton pump activity. ArXiv, Jan 2018. URL: https://doi.org/10.13130/i-bertolini_phd2018-01-24, doi:10.13130/i-bertolini_phd2018-01-24. This article has 0 citations.

📚 Additional Documentation

Notes

(ATP6V1G1-notes.md)

ATP6V1G1 Research Notes

Gene overview

ATP6V1G1 (UniProt O75348) encodes V-type proton ATPase subunit G 1, a 118 amino acid peripheral subunit (13.8 kDa) that is a component of the V1 peripheral complex of the vacuolar H+-ATPase (V-ATPase). The protein is also known as V-ATPase 13 kDa subunit 1 and Vacuolar proton pump subunit G 1.

V-ATPase complex function

V-ATPases are ATP-hydrolysis-driven proton pumps that acidify intracellular compartments across all eukaryotes.

PMID:33065002

PMID:9442887

Role of subunit G 1 specifically

Subunit G 1 is one of three G-subunit paralogs in humans (G1, G2, G3). G1 is ubiquitously expressed.

The V1 complex contains three peripheral stalks, each consisting of EG heterodimers.
PMID:33065002

The G subunit forms heterodimers with the E subunit, and these peripheral stalks link V1 to V0.
PMID:17360703

UniProt notes the G1 subunit has been directly identified by mass spectrometry in the V1 complex of the human V-ATPase structure.
[file:human/ATP6V1G1/ATP6V1G1-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 and a membrane integral complex (V0) that translocates protons"]

Role in iron homeostasis / HIF pathway

A key functional study showed that loss of ATP6V1G1 (identified in a genome-wide screen) impairs V-ATPase activity, leading to iron depletion and HIF1alpha stabilization.
PMID:28296633

PMID:28296633

This places intracellular iron homeostasis as a downstream consequence of V-ATPase activity (proton pump function needed for endosomal acidification and iron release from transferrin).

Subcellular localization

UniProt lists apical cell membrane in kidney, based on co-localization with other H+-ATPase subunits in TAL and DCT segments.
PMID:29993276

Also detected in lysosomal membrane (HDA, mass spec from lysosome-enriched fractions) and in cytosol (as component of unassembled V1 complex). Identification in extracellular exosomes is likely a contaminant in those datasets and is non-core.

Regulation of macroautophagy

A NAS annotation links V-ATPase (including ATP6V1G1) to regulation of macroautophagy. This is an indirect/downstream effect of lysosomal acidification — V-ATPase activity is required for lysosomal function and thus autophagy completion, but the G1 subunit does not directly regulate autophagy.
[PMID:22982048 "macroautophagy is responsible for the uptake of lipofuscin into the lysosomes" — here V-ATPase disruption is used to impair lysosomal activity]

Protein binding annotations

Multiple high-throughput interactome datasets contribute generic protein binding annotations (GO:0005515) for ATP6V1G1. These should all be treated as over-annotations. The specific functional interaction is with ATP6V1E1/E2 (forming G-E peripheral stalks).
[file:human/ATP6V1G1/ATP6V1G1-uniprot.txt "O75348; P36543: ATP6V1E1; NbExp=3; IntAct=EBI-711802, EBI-348639; O75348; Q96A05: ATP6V1E2; NbExp=12; IntAct=EBI-711802, EBI-8650380"]

The ATPase binding annotation (PMID:17360703) reflects the G1/a (V0 subunit a) interaction documented in that paper — this is more informative than generic protein binding.

Summary of core function

ATP6V1G1 is a structural peripheral stalk subunit of the V1 complex of the V-ATPase. Its core function is as part of the proton-transporting ATPase complex. Annotations to V1 domain membership, proton transmembrane transport, and lysosomal/endosomal membrane localization are all well-supported. The iron homeostasis and HIF pathway effects are downstream consequences of V-ATPase proton pump activity rather than direct molecular functions of the G1 subunit per se.

Falcon deep research synthesis (2026-06-21)

Falcon deep research has now completed (file:human/ATP6V1G1/ATP6V1G1-deep-research-falcon.md,
26 citations). It corroborates the G1 peripheral-stalk core above and adds isoform
and disease-context detail; no change to annotation calls.

Core confirmed. G1 pairs with subunit E to form the EG peripheral stalks
(stator) of V1, holding the A3B3 head against rotor torque; structural/regulatory,
not catalytic. G1 is the ubiquitous G isoform (vs neuronal G2 / kidney G3).
G-isoform interchangeability / post-translational compensation (Kawamura
2015). Loss of neuron-specific G2 upregulates G1 protein (without mRNA
increase) in brain, showing G1 can substitute for tissue-specific G isoforms —
relevant when interpreting isoform-restricted annotations.
Cancer / druggability (non-core). G1 supports glioma stem-cell maintenance,
proliferation and invasion (knockdown is lethal to neurospheres but not
differentiated cells); the V1G subunit is targetable pharmacologically
(verucopeptin inhibits V-ATPase + mTORC1 in multidrug-resistant tumors). HCC
phosphoproteomics and cardiovascular/neurotoxicity links are further
disease-context, non-core.

Net: no change to calls — G1 is the ubiquitous EG peripheral-stalk (stator) V1
subunit supporting V-ATPase assembly and organellar acidification.

Pn Notes

(ATP6V1G1-pn-notes.md)

ATP6V1G1 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: O75348
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-06
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/ATP6V1G1/ATP6V1G1-ai-review.yaml
AIGR review HTML: present - genes/human/ATP6V1G1/ATP6V1G1-ai-review.html
Gene notes: present - genes/human/ATP6V1G1/ATP6V1G1-notes.md
GOA TSV: present - genes/human/ATP6V1G1/ATP6V1G1-goa.tsv
UniProt record: present - genes/human/ATP6V1G1/ATP6V1G1-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/ATP6V1G1.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/ATP6V1G1.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

No *-deep-research*.md file found in this gene directory.

AIGR Review Snapshot

Description: ATP6V1G1 encodes V-type proton ATPase subunit G 1 (118 amino acids, 13.8 kDa), a peripheral stalk component of the V1 catalytic domain of the vacuolar-type H+-ATPase (V-ATPase). The V-ATPase is a large multi-subunit complex that couples ATP hydrolysis to proton translocation across membranes, thereby acidifying lysosomes, endosomes, and other intracellular compartments. The V1 domain (peripheral, cytosolic) contains subunits A-H and is responsible for ATP hydrolysis; it couples to the membrane-embedded V0 domain through three peripheral EG heterodimeric stalks that act as the stator. Subunit G 1 forms these EG heterodimers with subunit E (ATP6V1E1 or ATP6V1E2), directly contacts the V0 subunit a, and is essential for maintaining V1-V0 connectivity. ATP6V1G1 is ubiquitously expressed; humans also have two paralogous G subunits (G2, G3) with more restricted expression. The protein is present at lysosomal and endosomal membranes as part of the assembled holoenzyme, at the apical plasma membrane in kidney tubular epithelial cells (thick ascending limb and distal convoluted tubule), and in the cytosol as part of the free, disassembled V1 complex. V-ATPase-mediated acidification of endosomes is required for efficient iron release from transferrin; consistent with this, genetic disruption of ATP6V1G1 causes intracellular iron depletion, impaired prolyl hydroxylase (PHD) activity, and consequent HIF1alpha stabilization.
Existing/core annotation action counts: ACCEPT: 17; KEEP_AS_NON_CORE: 20; MARK_AS_OVER_ANNOTATED: 10

PN Consistency Summary

Consistency: Strong agreement. Deep-research notes, review YAML, and PN annotation all describe G1 as a V1 peripheral-stalk (EG-heterodimer) subunit acidifying lysosomes/endosomes. PN's mTORC1/Ragulator framing matches the review's Reactome mTORC1 context annotations. No contradictions.
PN story / NEW pressure: All three projected terms are VERIFIED real (OLS). GO:0033176 already in GOA/review (ACCEPT). GO:0046612 "lysosomal V1 domain" is a lysosome-specific refinement of the review's GO:0000221 vacuolar V1 / GO:0033180 generic V1 (siblings, not strictly subsumed) — defensible but a lateral re-specification, not a missing function. GO:0007042 lysosomal lumen acidification is NOT in this gene's review/GOA (it IS in the ATP6V1H review) → defensible ADD as a downstream BP of the assembled pump. Conclude: GO:0007042 = ADD candidate; GO:0046612 = already captured at function level (vacuolar/generic V1).
Evidence alignment: Divergent reference sets — PN cites review-article titles (mTORC1/V-ATPase/neurodegeneration reviews) not present as PMIDs in the review; review is anchored on primary structural/functional papers (PMID:33065002 cryo-EM, PMID:17360703 G/a interaction, PMID:28296633 iron/HIF). Same biology, different (complementary) citations; no conflict.
Verdict: Consistent. ADD GO:0007042 (lysosomal lumen acidification) to bring G1 in line with its paralog ATP6V1H; GO:0046612 already covered by existing V1-domain terms.

Full Consistency Review

UniProt: O75348 · batch: proteostasis-batch-2026-06-06 · review status: COMPLETE (thorough; notes + 40+ annotations reviewed)
PN placement: Autophagy-Lysosome Pathway two rows — …|mTORC1 pathway, upstream|Nutrient sensing|V1 lysosomal v-ATPase proton pump component and …|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification|V1 …component ; PN-node mapping: subtype→GO:0046612 (lysosomal V1 domain, mapped/ok); subtype→GO:0033176 (V-ATPase complex, mapped/ok); type→GO:0007042 (lysosomal lumen acidification, mapped/ok); class→GO:0010506 context_only/too_broad.
Consistency: Strong agreement. Deep-research notes, review YAML, and PN annotation all describe G1 as a V1 peripheral-stalk (EG-heterodimer) subunit acidifying lysosomes/endosomes. PN's mTORC1/Ragulator framing matches the review's Reactome mTORC1 context annotations. No contradictions.
PN story / NEW pressure: All three projected terms are VERIFIED real (OLS). GO:0033176 already in GOA/review (ACCEPT). GO:0046612 "lysosomal V1 domain" is a lysosome-specific refinement of the review's GO:0000221 vacuolar V1 / GO:0033180 generic V1 (siblings, not strictly subsumed) — defensible but a lateral re-specification, not a missing function. GO:0007042 lysosomal lumen acidification is NOT in this gene's review/GOA (it IS in the ATP6V1H review) → defensible ADD as a downstream BP of the assembled pump. Conclude: GO:0007042 = ADD candidate; GO:0046612 = already captured at function level (vacuolar/generic V1).
Mapping strategy: Node mapping is appropriate; subtype is correctly leaf-restricted to V1. The lysosomal-specific CC terms are narrower than the review's vacuolar terms, so no broader-than-review over-reach (contrast TOMM20/HSPA8 precedent). Scope/status correct.
Evidence alignment: Divergent reference sets — PN cites review-article titles (mTORC1/V-ATPase/neurodegeneration reviews) not present as PMIDs in the review; review is anchored on primary structural/functional papers (PMID:33065002 cryo-EM, PMID:17360703 G/a interaction, PMID:28296633 iron/HIF). Same biology, different (complementary) citations; no conflict.
Verdict: Consistent. ADD GO:0007042 (lysosomal lumen acidification) to bring G1 in line with its paralog ATP6V1H; GO:0046612 already covered by existing V1-domain terms.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-06
review_yaml: genes/human/ATP6V1G1/ATP6V1G1-ai-review.yaml
PN workbook rows: 2

PN row 1: Autophagy-Lysosome Pathway | Pre-initiation autophagy signaling | mTORC1 pathway, upstream | Nutrient sensing | V1 lysosomal v-ATPase proton pump component

UniProt: O75348
In branches: ALP
Notes: Subunit of the V1 (cytosolic) component of the lysosomal v-ATPase. The V0 and V1 components of the v-ATPase assemble during amino acid starvation creating the active v-ATPase that pumps protons into the lysosome for acidification. The v-ATPase also engages in amino acid-dependent interactions with the Ragulator complex. In the presence of amino acids, the v-ATPase-Ragulator complex undergoes a conformational change that results in Ragulator exerting its GEF activity on RAGA/B.
PN references (titles):
- Regulation of mTORC1 by amino acids - ScienceDirect
- Cells | Free Full-Text | SEA and GATOR 10 Years Later | HTML (mdpi.com)
- Eukaryotic V-ATPase: Novel structural findings and functional insights - ScienceDirect
- The emerging roles of vacuolar-type ATPase-dependent Lysosomal acidification in neurodegenerative diseases | Translational Neurodegeneration | Full Text (biomedcentral.com)
PN-node mapping records (path + ancestors):
- [subtype] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling|mTORC1 pathway, upstream|Nutrient sensing|V1 lysosomal v-ATPase proton pump component
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0046612 lysosomal proton-transporting V-type ATPase, V1 domain]
  rationale: This PN leaf is restricted to V1-sector lysosomal V-ATPase components. The GO lysosomal V1-domain component term is the direct target.
- [type] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling|mTORC1 pathway, upstream|Nutrient sensing
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a contextual PN role. The label is useful for curator triage, but by itself does not support a universal GO assertion for all member genes beyond curated ancestor or child mappings.
- [group] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling|mTORC1 pathway, upstream
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN taxonomy container. The descendants mix components, regulators, context labels, and mechanistic leaves, so propagation should come only from narrower curated nodes.
- [class] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling
  status=context_only scope=too_broad_to_propagate GO=[GO:0010506 regulation of autophagy]
  rationale: This class organizes upstream signaling inputs to autophagy initiation. Because the subtree contains generic insulin, AMPK, mTORC1, nutrient-sensing, and miscellaneous signaling components, class-level propagation to regulation of autophagy would over-annotate many genes.
- [branch] Autophagy-Lysosome Pathway
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

PN row 2: Autophagy-Lysosome Pathway | Lysosomal catabolism | Regulation of lysosomal environment | Lysosomal acidification | V1 lysosomal v-ATPase proton pump component

UniProt: O75348
In branches: ALP
Notes: Subunit of the V1 (cytosolic) component of the lysosomal v-ATPase. The V0 and V1 components of the v-ATPase assemble during amino acid starvation creating the active v-ATPase that pumps protons into the lysosome for acidification. The v-ATPase also engages in amino acid-dependent interactions with the Ragulator complex. In the presence of amino acids, the v-ATPase-Ragulator complex undergoes a conformational change that results in Ragulator exerting its GEF activity on RAGA/B.
PN references (titles):
- Regulation of mTORC1 by amino acids - ScienceDirect
- Cells | Free Full-Text | SEA and GATOR 10 Years Later | HTML (mdpi.com)
- Eukaryotic V-ATPase: Novel structural findings and functional insights - ScienceDirect
- The emerging roles of vacuolar-type ATPase-dependent Lysosomal acidification in neurodegenerative diseases | Translational Neurodegeneration | Full Text (biomedcentral.com)
PN-node mapping records (path + ancestors):
- [subtype] Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification|V1 lysosomal v-ATPase proton pump component
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0033176 proton-transporting V-type ATPase complex]
  rationale: This PN subtype denotes the V1-sector component of the lysosomal V-ATPase. In the current GO cache, the broader V-type ATPase complex is the safest validated target for this component role.
- [type] Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0007042 lysosomal lumen acidification]
  rationale: This PN group directly names the lysosomal acidification mechanism. Propagation to the GO lysosomal lumen acidification term is an exact mechanistic match.
- [group] Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN taxonomy container. The descendants mix components, regulators, context labels, and mechanistic leaves, so propagation should come only from narrower curated nodes.
- [class] Autophagy-Lysosome Pathway|Lysosomal catabolism
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad lysosomal-degradation container. The subtree includes carbohydrate, lipid, protein, nuclease, phosphatase, sulfatase, and environment-regulation roles, so mapping should occur at the enzyme or process subtype level.
- [branch] Autophagy-Lysosome Pathway
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

Projected GO annotations (3)

GO:0046612 lysosomal proton-transporting V-type ATPase, V1 domain | scope=ok_for_propagation_to_go | goa_status=more_specific_than_existing_goa | from=Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling|mTORC1 pathway, upstream|Nutrient sensing|V1 lysosomal v-ATPase proton pump component
GO:0007042 lysosomal lumen acidification | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification
GO:0033176 proton-transporting V-type ATPase complex | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification|V1 lysosomal v-ATPase proton pump component

Note

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.

📄 View Raw YAML

id: O75348
gene_symbol: ATP6V1G1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  ATP6V1G1 encodes V-type proton ATPase subunit G 1 (118 amino acids, 13.8 kDa),
  a peripheral stalk component of the V1 catalytic domain of the vacuolar-type
  H+-ATPase (V-ATPase). The V-ATPase is a large multi-subunit complex that
  couples ATP hydrolysis to proton translocation across membranes, thereby
  acidifying lysosomes, endosomes, and other intracellular compartments. The V1
  domain (peripheral, cytosolic) contains subunits A-H and is responsible for
  ATP hydrolysis; it couples to the membrane-embedded V0 domain through three
  peripheral EG heterodimeric stalks that act as the stator. Subunit G 1 forms
  these EG heterodimers with subunit E (ATP6V1E1 or ATP6V1E2), directly contacts
  the V0 subunit a, and is essential for maintaining V1-V0 connectivity. ATP6V1G1
  is ubiquitously expressed; humans also have two paralogous G subunits (G2,
  G3) with more restricted expression. The protein is present at lysosomal and
  endosomal membranes as part of the assembled holoenzyme, at the apical plasma
  membrane in kidney tubular epithelial cells (thick ascending limb and distal
  convoluted tubule), and in the cytosol as part of the free, disassembled V1
  complex. V-ATPase-mediated acidification of endosomes is required for efficient
  iron release from transferrin; consistent with this, genetic disruption of
  ATP6V1G1 causes intracellular iron depletion, impaired prolyl hydroxylase (PHD)
  activity, and consequent HIF1alpha stabilization.
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: ATP6V1G1 is a bona fide V1 domain subunit, confirmed by cryo-EM structure.
    action: ACCEPT
    reason: The V1 domain membership is experimentally established by mass spectrometry
      and cryo-EM (PMID:33065002). The IBA annotation is consistent with experimental
      data and reflects true V1 component status.
    supported_by:
    - reference_id: file:human/ATP6V1G1/ATP6V1G1-uniprot.txt
      supporting_text: "Subunit of the V1 complex of vacuolar(H+)-ATPase"

- term:
    id: GO:0030672
    label: synaptic vesicle membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Synaptic vesicle membrane activity inferred by phylogenetic transfer;
      reflects V-ATPase role at synaptic vesicles in neurons, not core function of
      this ubiquitous subunit.
    action: KEEP_AS_NON_CORE
    reason: While V-ATPases acidify synaptic vesicles in neurons, this annotation
      describes a non-core context for a ubiquitously expressed subunit. The specific
      activity is an indirect consequence of V1 participation in the overall proton
      pump complex rather than a dedicated synaptic function of G1.

- 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 acidification inferred by phylogenetic transfer; non-core
      for this ubiquitously expressed peripheral stalk subunit.
    action: KEEP_AS_NON_CORE
    reason: Synaptic vesicle lumen acidification is a neuron-specific downstream process.
      This ubiquitous G1 subunit contributes to V-ATPase activity generally; synaptic
      vesicle context is non-core.

- term:
    id: GO:0016324
    label: apical plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: IEA from UniProt subcellular location vocabulary mapping; supported by
      experimental co-localization in kidney tubular cells.
    action: ACCEPT
    reason: This IEA annotation is backed by experimental co-localization data showing
      H+-ATPase subunits including G1 at the apical membrane of kidney TAL and DCT
      (PMID:29993276).
    supported_by:
    - reference_id: PMID:29993276
      supporting_text: the H+-ATPase B1 subunit colocalized with other H+-ATPase subunits
        in the TAL and DCT

- term:
    id: GO:0016471
    label: vacuolar proton-transporting V-type ATPase complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: part_of
  review:
    summary: Computationally inferred V-ATPase complex membership; correct and supported
      by structural evidence.
    action: ACCEPT
    reason: ATP6V1G1 is a component of the assembled V-ATPase holoenzyme. IEA annotation
      is consistent with cryo-EM structural data (PMID:33065002).

- term:
    id: GO:0046961
    label: proton-transporting ATPase activity, rotational mechanism
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: IEA annotation for rotational mechanism ATPase activity; correct at the
      complex level.
    action: ACCEPT
    reason: The V-ATPase employs a rotational mechanism for proton translocation.
      As a peripheral stalk subunit, G1 contributes to this activity as part of the
      stator apparatus. The annotation is appropriate with contributes_to semantics
      implied.

- term:
    id: GO:0051117
    label: ATPase binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: enables
  review:
    summary: IEA ARBA prediction for ATPase binding; reflects known G1 interaction
      with V0 subunit a documented experimentally.
    action: ACCEPT
    reason: The G1 subunit directly interacts with V0 subunit a, constituting genuine
      ATPase binding within the V-ATPase complex (PMID:17360703).

- term:
    id: GO:1902600
    label: proton transmembrane transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: IEA from InterPro; proton transmembrane transport is the core function
      of the V-ATPase complex.
    action: ACCEPT
    reason: Proton transmembrane transport is the core biological process driven by
      the V-ATPase. As a structural component of the complex, G1 is rightly annotated
      as involved in this process.

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16169070
  qualifier: enables
  review:
    summary: Generic protein binding from high-throughput proteome-wide interaction
      dataset; uninformative over-annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: This IPI annotation comes from a large-scale interactome screen. Protein
      binding in isolation is uninformative about G1 molecular function. The meaningful
      interaction is with ATP6V1E1/E2 (EG peripheral stalk) and V0 subunit a.

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21516116
  qualifier: enables
  review:
    summary: Generic protein binding from high-throughput interaction screen; uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput interactome dataset; protein binding alone does not reflect
      the specific structural role of G1 in the V-ATPase.

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: Generic protein binding from proteome-scale interactome network; uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput interactome dataset; does not reflect specific function.

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30021884
  qualifier: enables
  review:
    summary: Generic protein binding from crosslinking mass spectrometry dataset;
      uninformative over-annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput dataset; uninformative for characterizing G1 function.

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31515488
  qualifier: enables
  review:
    summary: Generic protein binding from population genetics interactome study; uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput interactome dataset; does not reflect specific molecular
      function of G1.

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Generic protein binding from binary interactome reference map; uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput interactome dataset; protein binding is an over-annotation
      for a subunit whose specific interactions (with E subunit and V0 subunit a)
      are known.

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  qualifier: enables
  review:
    summary: Generic protein binding from OpenCell endogenous tagging study; uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput dataset; protein binding does not describe the specific
      EG peripheral stalk assembly function.

- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: IEA Ensembl Compara transfer; lysosomal membrane localization is consistent
      with HDA mass spectrometry data.
    action: ACCEPT
    reason: Lysosomal membrane localization is supported by mass spectrometry identification
      in lysosome-enriched fractions (PMID:17897319) and is expected for an assembled
      V-ATPase subunit.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: IEA Ensembl Compara transfer; cytosolic localization reflects the regulated
      disassembly state where free V1 complex is in the cytoplasm.
    action: KEEP_AS_NON_CORE
    reason: Cytosolic localization is a real state (free V1 complex released from
      membranes under regulated disassembly) but is not the primary functional location.

- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: IEA transfer; plasma membrane localization is supported by experimental
      evidence from kidney tubular cells (apical plasma membrane) and by the G/a
      subunit interaction study.
    action: ACCEPT
    reason: Plasma membrane localization is experimentally supported both by kidney
      apical membrane co-localization (PMID:29993276) and by the G1/a interaction
      study (PMID:17360703). The IEA is consistent with experimental findings.

- term:
    id: GO:0015078
    label: proton transmembrane transporter activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: contributes_to
  review:
    summary: IEA Ensembl Compara transfer; proton transmembrane transporter activity
      is a core V-ATPase function.
    action: ACCEPT
    reason: Proton transmembrane transporter activity is the direct molecular function
      of the V-ATPase complex. The contributes_to qualifier is appropriate for a
      structural subunit.

- term:
    id: GO:0033176
    label: proton-transporting V-type ATPase complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: part_of
  review:
    summary: IEA transfer for V-ATPase complex membership; correct at the whole-complex
      level, but the more specific V1 domain annotation is preferred.
    action: ACCEPT
    reason: ATP6V1G1 is a component of the entire V-ATPase holoenzyme as well as
      the V1 sub-complex. This whole-complex annotation is appropriate as a broader
      complement to the V1 domain annotation.

- term:
    id: GO:0033180
    label: proton-transporting V-type ATPase, V1 domain
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: part_of
  review:
    summary: IEA Ensembl Compara transfer; V1 domain membership is experimentally
      confirmed.
    action: ACCEPT
    reason: V1 domain membership is established by cryo-EM and mass spectrometry
      (PMID:33065002). This IEA is consistent with experimental evidence.

- term:
    id: GO:0097401
    label: synaptic vesicle lumen acidification
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: IEA Ensembl Compara transfer for synaptic vesicle lumen acidification;
      non-core neuronal context annotation.
    action: KEEP_AS_NON_CORE
    reason: Neuronal synaptic vesicle acidification is a non-core context for this
      ubiquitously expressed subunit.

- term:
    id: GO:0098850
    label: extrinsic component of synaptic vesicle membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: IEA Ensembl Compara transfer; V1 domain is extrinsic to synaptic vesicle
      membranes in neurons. Non-core context.
    action: KEEP_AS_NON_CORE
    reason: The V1 peripheral complex is extrinsic to vesicle membranes in neurons.
      This is a non-core neuronal context for a ubiquitous subunit.

- term:
    id: GO:0016324
    label: apical plasma membrane
  evidence_type: EXP
  original_reference_id: PMID:29993276
  qualifier: located_in
  review:
    summary: Experimental co-localization of G1 with other H+-ATPase subunits at
      the apical plasma membrane in kidney TAL and DCT. Strongly supported.
    action: ACCEPT
    reason: Direct experimental evidence from kidney sections showing co-localization
      of H+-ATPase subunits including G1 at the apical plasma membrane in thick
      ascending limb and distal convoluted tubule.
    supported_by:
    - reference_id: PMID:29993276
      supporting_text: the H+-ATPase B1 subunit colocalized with other H+-ATPase subunits
        in the TAL and DCT

- term:
    id: GO:0000221
    label: vacuolar proton-transporting V-type ATPase, V1 domain
  evidence_type: IDA
  original_reference_id: PMID:33065002
  qualifier: part_of
  review:
    summary: Direct experimental identification of G1 in the human V-ATPase V1 complex
      by cryo-EM structure determination.
    action: ACCEPT
    reason: High-quality cryo-EM structures of the complete human V-ATPase directly
      identified all V1 subunits including G1 by mass spectrometry. This is the strongest
      possible evidence for V1 domain membership.
    supported_by:
    - reference_id: file:human/ATP6V1G1/ATP6V1G1-uniprot.txt
      supporting_text: "The V1 complex consists of three catalytic AB heterodimers that
        form a heterohexamer, three peripheral stalks each consisting of EG heterodimers,
        one central rotor including subunits D and F, and the regulatory subunits C
        and H"

- term:
    id: GO:0006879
    label: intracellular iron ion homeostasis
  evidence_type: IMP
  original_reference_id: PMID:28296633
  qualifier: involved_in
  review:
    summary: IMP annotation based on a genetic screen; loss of ATP6V1G1 disrupts
      V-ATPase proton pumping, which impairs endosomal acidification and iron release
      from transferrin. This is an indirect downstream consequence of impaired proton
      transport, not a direct iron homeostasis function.
    action: MARK_AS_OVER_ANNOTATED
    reason: The iron homeostasis effect observed upon ATP6V1G1 knockdown is an indirect
      consequence of disrupted V-ATPase activity impairing endosomal acidification
      and therefore transferrin-mediated iron delivery. The primary molecular function
      is proton transport; iron homeostasis is a secondary, downstream effect. Annotating
      the peripheral stalk subunit to iron homeostasis overstates its direct role.
    supported_by:
    - reference_id: PMID:28296633
      supporting_text: disrupting the V-ATPase results in intracellular iron depletion,
        thereby impairing PHD activity and leading to HIF activation
    - reference_id: PMID:28296633
      supporting_text: 'principally relating to mutagenesis of genes encoding five V-ATPase
        subunits: ATP6AP1, ATP6V1A, ATP6V1G1, ATP6V0A2 and ATP6V0D1'

- term:
    id: GO:0036295
    label: cellular response to increased oxygen levels
  evidence_type: IMP
  original_reference_id: PMID:28296633
  qualifier: involved_in
  review:
    summary: IMP annotation; HIF1alpha stabilization upon ATP6V1G1 loss is an indirect
      consequence of iron depletion downstream of V-ATPase disruption. Not a direct
      oxygen-sensing function.
    action: MARK_AS_OVER_ANNOTATED
    reason: The cellular response to increased oxygen levels (HIF pathway) effect
      is downstream of iron depletion, which is itself downstream of impaired endosomal
      acidification. This is two steps removed from the primary proton pump function
      of G1. Annotating a structural peripheral stalk subunit to oxygen response
      conflates the primary molecular function with a distal phenotypic consequence.
    supported_by:
    - reference_id: PMID:28296633
      supporting_text: disrupting the V-ATPase results in intracellular iron depletion,
        thereby impairing PHD activity and leading to HIF activation

- term:
    id: GO:0016241
    label: regulation of macroautophagy
  evidence_type: NAS
  original_reference_id: PMID:22982048
  qualifier: involved_in
  review:
    summary: NAS annotation linking V-ATPase disruption to macroautophagy; the cited
      paper uses V-ATPase inhibition as a tool to block lysosomal function, not as
      direct evidence that G1 regulates macroautophagy.
    action: MARK_AS_OVER_ANNOTATED
    reason: The cited paper (PMID:22982048) uses V-ATPase disruption as a tool to
      impair lysosomal activity and does not demonstrate that ATP6V1G1 specifically
      regulates macroautophagy. V-ATPase activity is required for lysosomal acidification,
      which is needed for autophagy completion, but this generic consequence of
      proton pump disruption does not justify annotating the G1 structural subunit
      to regulation of macroautophagy.

- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  qualifier: located_in
  review:
    summary: HDA from urinary exosome proteomics; likely contamination of exosome
      fraction with non-exosomal V-ATPase; not considered a core localization.
    action: KEEP_AS_NON_CORE
    reason: Extracellular exosome identification from urinary proteomics (PMID:19056867)
      is likely a contaminant in the exosome-enriched fraction rather than genuine
      exosomal loading. Not a core localization for this cytosolic V1 peripheral
      stalk subunit.

- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: HDA
  original_reference_id: PMID:17897319
  qualifier: located_in
  review:
    summary: HDA from lysosomal membrane proteomics; directly supports lysosomal
      membrane localization as part of the assembled V-ATPase holoenzyme.
    action: ACCEPT
    reason: Mass spectrometry identification in lysosome-enriched fractions (PMID:17897319)
      directly supports lysosomal membrane localization, consistent with the role
      of the assembled V-ATPase holoenzyme at the lysosomal membrane.
    supported_by:
    - reference_id: PMID:17897319
      supporting_text: Integral and associated lysosomal membrane proteins

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1222516
  qualifier: located_in
  review:
    summary: Reactome TAS annotation; cytosolic location reflects regulated disassembly
      state of free V1 complex.
    action: KEEP_AS_NON_CORE
    reason: The cytosolic V1 complex is a real regulated state (disassembled from
      V0 under nutrient deprivation), but not the primary functional localization.
      Multiple Reactome entries support this non-core annotation.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5252133
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol; same rationale as above.
    action: KEEP_AS_NON_CORE
    reason: Cytosolic localization in regulated disassembly context; non-core.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-74723
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol; non-core regulated disassembly
      state.
    action: KEEP_AS_NON_CORE
    reason: Cytosolic localization in regulated disassembly context; non-core.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-917841
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol; non-core.
    action: KEEP_AS_NON_CORE
    reason: Cytosolic localization in regulated disassembly context; non-core.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9639286
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol in mTORC1 signaling context; non-core.
    action: KEEP_AS_NON_CORE
    reason: Cytosolic localization context; non-core.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9640167
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol; non-core.
    action: KEEP_AS_NON_CORE
    reason: Cytosolic localization in Rag GTPase/mTORC1 signaling context; non-core.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9640168
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol; non-core.
    action: KEEP_AS_NON_CORE
    reason: Cytosolic localization context; non-core.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9640175
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol; non-core.
    action: KEEP_AS_NON_CORE
    reason: Cytosolic localization context; non-core.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9640195
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol; non-core.
    action: KEEP_AS_NON_CORE
    reason: Cytosolic localization context; non-core.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9645598
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol; non-core.
    action: KEEP_AS_NON_CORE
    reason: Cytosolic localization context; non-core.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9645608
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol; non-core.
    action: KEEP_AS_NON_CORE
    reason: Cytosolic localization context; non-core.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9646468
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol; non-core.
    action: KEEP_AS_NON_CORE
    reason: Cytosolic localization context; non-core.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9858924
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol; non-core.
    action: KEEP_AS_NON_CORE
    reason: Cytosolic localization context; non-core.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: ISS manual ortholog transfer for cytosol localization; consistent with
      regulated disassembly producing free cytosolic V1 complex.
    action: KEEP_AS_NON_CORE
    reason: Cytosolic localization reflects the regulated disassembly state; non-core.

- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: ISS manual ortholog transfer for plasma membrane localization; consistent
      with experimental evidence showing G1 at apical plasma membrane in kidney and
      at plasma membrane in the G1/a interaction study.
    action: ACCEPT
    reason: Plasma membrane localization is well supported experimentally (PMID:17360703,
      PMID:29993276). ISS is consistent with these experimental findings.

- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:17360703
  qualifier: located_in
  review:
    summary: Experimental plasma membrane localization from study demonstrating G1/a
      subunit interaction; the study demonstrated G1 at plasma membrane in the context
      of V0 subunit a interaction.
    action: ACCEPT
    reason: The experimental evidence from PMID:17360703 demonstrates that G1 localizes
      at the plasma membrane as part of its interaction with V0 subunit a, which
      directly supports plasma membrane localization.
    supported_by:
    - reference_id: PMID:17360703
      supporting_text: V1 and V0 domains of the human H+-ATPase are linked by an interaction
        between the G and a subunits

- term:
    id: GO:0051117
    label: ATPase binding
  evidence_type: IPI
  original_reference_id: PMID:17360703
  qualifier: enables
  review:
    summary: Experimental IPI evidence for ATPase binding; reflects direct G1 interaction
      with V0 subunit a, a V-ATPase component.
    action: ACCEPT
    reason: PMID:17360703 experimentally demonstrated direct interaction between G1
      and V0 subunit a (ATP6V0A1, ATP6V0A4), supporting ATPase binding annotation
      as a meaningful specific interaction.
    supported_by:
    - reference_id: PMID:17360703
      supporting_text: V1 and V0 domains of the human H+-ATPase are linked by an interaction
        between the G and a subunits

references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: 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:16169070
  title: 'A human protein-protein interaction network: a resource for annotating the
    proteome.'
  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: G1/a1, G3/a1, and G1/a4 interactions demonstrated experimentally;
      G and a subunit interaction is a novel link between V1 and V0 required for
      H+-ATPase assembly and regulation.
- id: PMID:17897319
  title: Integral and associated lysosomal membrane proteins.
  findings:
  - statement: Mass spectrometry identification of ATP6V1G1 in lysosome-enriched
      fractions supports lysosomal membrane localization.
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  findings:
  - statement: Identification in urinary exosome fraction; likely contamination
      rather than genuine exosomal loading.
- id: PMID:21516116
  title: Next-generation sequencing to generate interactome datasets.
  findings: []
- id: PMID:22982048
  title: Lipofuscin is formed independently of macroautophagy and lysosomal activity
    in stress-induced prematurely senescent human fibroblasts.
  findings:
  - statement: V-ATPase disruption used as a tool to impair lysosomal activity;
      does not directly implicate ATP6V1G1 in macroautophagy regulation.
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
- id: PMID:28296633
  title: The vacuolar-ATPase complex and assembly factors, TMEM199 and CCDC115, control
    HIF1alpha prolyl hydroxylation by regulating cellular iron levels.
  findings:
  - statement: ATP6V1G1 identified in genome-wide screen for HIF1alpha regulators;
      mechanism is indirect via iron depletion from impaired endosomal acidification
      leading to reduced PHD activity and HIF activation.
- id: PMID:29993276
  title: H(+)-ATPase B1 subunit localizes to thick ascending limb and distal convoluted
    tubule of rodent and human kidney.
  findings:
  - statement: H+-ATPase B1 subunit co-localizes with other H+-ATPase subunits
      at apical plasma membrane in kidney TAL and DCT.
- id: PMID:30021884
  title: Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry
    in Intact Cell Nuclei.
  findings: []
- id: PMID:31515488
  title: Extensive disruption of protein interactions by genetic variants across the
    allele frequency spectrum in human populations.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:33065002
  title: Structures of a Complete Human V-ATPase Reveal Mechanisms of Its Assembly.
  findings:
  - statement: Cryo-EM structures of complete human V-ATPase directly identify
      all V1 subunits; V1 complex contains three peripheral EG heterodimeric stalks.
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings: []
- id: Reactome:R-HSA-1222516
  title: Intraphagosomal pH is lowered to 5 by V-ATPase
  findings: []
- id: Reactome:R-HSA-5252133
  title: ATP6AP1 binds V-ATPase
  findings: []
- id: Reactome:R-HSA-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: []
- id: Reactome:R-HSA-9858924
  title: MITF-M-dependent ATP6V1G1gene expression
  findings: []

core_functions:
- description: >-
    ATP6V1G1 is a structural peripheral stalk subunit of the V1 domain of the
    V-ATPase, forming EG heterodimers with subunit E (ATP6V1E1/E2) that serve as
    the stator connecting the V1 catalytic hexameric ring to the V0 proton channel.
    It directly contacts the V0 subunit a, and the G-a interaction is required for
    V1-V0 assembly and integrity. As part of the assembled holoenzyme, ATP6V1G1
    contributes to ATP-hydrolysis-driven proton transport across lysosomal, endosomal,
    and (in kidney tubular cells) apical plasma membranes.
  contributes_to_molecular_function:
    id: GO:0046961
    label: proton-transporting ATPase activity, rotational mechanism
  molecular_function:
    id: GO:0005198
    label: structural molecule activity
  directly_involved_in:
  - id: GO:1902600
    label: proton transmembrane transport
  locations:
  - id: GO:0005765
    label: lysosomal membrane
  - id: GO:0010008
    label: endosome membrane
  - id: GO:0016324
    label: apical plasma membrane
  supported_by:
  - reference_id: file:human/ATP6V1G1/ATP6V1G1-uniprot.txt
    supporting_text: "The V1 complex consists of three catalytic AB heterodimers that
      form a heterohexamer, three peripheral stalks each consisting of EG heterodimers,
      one central rotor including subunits D and F, and the regulatory subunits C
      and H"
  - reference_id: PMID:17360703
    supporting_text: V1 and V0 domains of the human H+-ATPase are linked by an interaction
      between the G and a subunits

suggested_questions:
- question: Are the three human G subunit paralogs (G1, G2, G3) fully interchangeable
    in the peripheral stalk, or does G1 have distinct V-ATPase assembly or localization
    properties compared with G2 and G3?
  experts:
  - Blake-Palmer KG
  - Karet FE
- question: Does regulated disassembly of V1 from V0 under nutrient deprivation
    preferentially affect V-ATPase complexes containing a particular G subunit paralog,
    and what determines the cytosolic versus membrane-bound distribution of G1?
  experts:
  - Forgac M

suggested_experiments:
- hypothesis: G1, G2, and G3 are functionally non-equivalent peripheral stalk subunits
    with distinct V1-V0 coupling properties.
  description: >-
    Generate G1/G2/G3 paralog-specific knockout cell lines and perform functional
    complementation with each paralog individually to assess whether loss of G1
    can be rescued by G2 or G3 with equal efficiency in lysosomal acidification
    and iron homeostasis assays.
  experiment_type: genetic complementation and lysosomal pH measurement
- hypothesis: Post-translational modifications of G1 regulate V-ATPase assembly
    state (V1-V0 association vs. disassembly).
  description: >-
    Apply proximity labeling (BioID/APEX2) from G1 in nutrient-replete versus
    nutrient-deprived conditions to identify regulated binding partners in assembled
    versus disassembled states, and map G1 phosphorylation sites by quantitative
    phosphoproteomics.
  experiment_type: proximity labeling proteomics and phosphoproteomics

ATP6V1G1

Gene Description

Existing Annotations Review

Core Functions

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Comprehensive Research Report: ATP6V1G1 (V-type Proton ATPase Subunit G1)

Gene Identity and Overview

Primary Function and Enzymatic Mechanism

Proton Pumping and ATP Hydrolysis

Substrate Specificity

Subcellular Localization

Signaling and Biochemical Pathways

mTORC1 Nutrient Sensing

Autophagy and Lysosomal Degradation

Endosomal Trafficking

Reversible Assembly Regulation

Experimental Evidence and Structural Studies

Structural Analysis

Functional Perturbation Studies

Compensatory Mechanisms

Recent Developments (2023-2025)

Cardiovascular Disease

Hepatocellular Carcinoma

Neurotoxicity and Neurodegeneration

Current Applications and Therapeutic Targeting

Cancer Biomarker and Therapeutic Target

V-ATPase Inhibitors

Additional Disease Contexts

Summary

📚 Additional Documentation

Notes

ATP6V1G1 Research Notes

Gene overview

V-ATPase complex function

Role of subunit G 1 specifically

Role in iron homeostasis / HIF pathway

Subcellular localization

Regulation of macroautophagy

Protein binding annotations

Summary of core function

Falcon deep research synthesis (2026-06-21)

Pn Notes

ATP6V1G1 PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

PN row 1: Autophagy-Lysosome Pathway | Pre-initiation autophagy signaling | mTORC1 pathway, upstream | Nutrient sensing | V1 lysosomal v-ATPase proton pump component

PN row 2: Autophagy-Lysosome Pathway | Lysosomal catabolism | Regulation of lysosomal environment | Lysosomal acidification | V1 lysosomal v-ATPase proton pump component

Projected GO annotations (3)

Note

📄 View Raw YAML