# 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 "Vesicular- or vacuolar-type adenosine triphosphatases (V-ATPases) are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer. They play important roles in acidification of intracellular vesicles, organelles, and the extracellular milieu in eukaryotes."] [PMID:9442887 "The vacuolar (H+)-ATPases (or V-ATPases) function in the acidification of intracellular compartments in eukaryotic cells. The V-ATPases are multisubunit complexes composed of two functional domains. The peripheral V1 domain, a 500-kDa complex responsible for ATP hydrolysis, contains at least eight different subunits of molecular weight 70-13 (subunits A-H). The integral V0 domain, a 250-kDa complex, functions in proton translocation and contains at least five different subunits of molecular weight 100-17 (subunits a-d)."] ## 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 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"] The G subunit forms heterodimers with the E subunit, and these peripheral stalks link V1 to V0. [PMID:17360703 "This confirms that a4 and G3 are component subunits of the same proton pump and explains the observed epitope masking. This interaction was also found to be a more general feature of human H(+)-ATPases, as similar G1/a1, G3/a1, and G1/a4 interactions were also demonstrated. These interactions represent a novel link between the V(1) and V(0) domains in man, which is known to be required for H(+)-ATPase assembly and regulation."] 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 "we identify that genetic disruption of the Vacuolar H+ ATPase (V-ATPase), the key proton pump for endo-lysosomal acidification, and two previously uncharacterised V-ATPase assembly factors, TMEM199 and CCDC115, stabilise HIF1α in aerobic conditions. Rather than preventing the lysosomal degradation of HIF1α, disrupting the V-ATPase results in intracellular iron depletion, thereby impairing PHD activity and leading to HIF activation."] [PMID:28296633 "the top ranked biological process was transferrin transport and V-ATPase function, principally relating to mutagenesis of genes encoding five V-ATPase subunits: ATP6AP1, ATP6V1A, ATP6V1G1, ATP6V0A2 and ATP6V0D1"] 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 "Furthermore, the H+-ATPase B1 subunit colocalized with other H+-ATPase subunits in the TAL and DCT."] 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.