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.
| 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 |
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Download this section (compressed HTML)Q: 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?
Suggested experts: Blake-Palmer KG, Karet FE
Q: 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?
Suggested experts: Forgac M
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
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