id: P38606 gene_symbol: ATP6V1A product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: 'ATP6V1A encodes the catalytic A subunit of the V1 peripheral domain of the vacuolar-type H+-ATPase (V-ATPase), the principal ATP-driven proton pump of eukaryotic cells. The V1 domain hydrolyzes ATP; subunit A forms three catalytic AB heterodimers that together with subunit B create the hexameric ring responsible for ATP hydrolysis, whose energy is transduced via a central rotor to drive proton translocation through the membrane-embedded V0 domain. V-ATPase is the primary source of organellar acidification in all eukaryotes, acidifying lysosomes, endosomes, the Golgi apparatus, and secretory vesicles; in specialized cells it is also found at the plasma membrane. ATP6V1A is expressed ubiquitously, with high expression in the skin and neurons. In neurons, V-ATPase plays additional roles in neurotransmitter loading into synaptic vesicles and in regulating synaptic transmission. Through its role in lysosomal acidification, V-ATPase (with subunit A as catalytic core) is required for activation of mTORC1 by amino acids at the lysosomal surface, for intracellular iron homeostasis via endosomal transferrin processing, and for autophagic flux. De novo heterozygous ATP6V1A mutations cause a developmental encephalopathy with epilepsy (IECEE3), while biallelic loss-of-function variants cause autosomal recessive cutis laxa type 2D (ARCL2D).' alternative_products: - name: '1' id: P38606-1 - name: '2' id: P38606-2 sequence_note: VSP_056408 existing_annotations: - term: id: GO:0005774 label: vacuolar membrane evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: The V-ATPase A subunit is active in vacuolar/lysosomal membranes where the holoenzyme acidifies these compartments. This is central to ATP6V1A function. action: ACCEPT reason: Vacuolar membrane is the primary site of V-ATPase activity; the is_active_in qualifier correctly captures that this is where ATP6V1A performs its catalytic function as part of the V-ATPase complex. supported_by: - reference_id: file:human/ATP6V1A/ATP6V1A-uniprot.txt supporting_text: Catalytic 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 reference_section_type: DATABASE_ENTRY - term: id: GO:1902600 label: proton transmembrane transport evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Proton transmembrane transport is the core biological process of V-ATPase; the catalytic A subunit is essential for this activity. action: ACCEPT reason: This is the primary biological process carried out by V-ATPase, and the A subunit is the ATP-hydrolyzing catalytic subunit that powers proton translocation. supported_by: - reference_id: PMID:33065002 supporting_text: 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. reference_section_type: ABSTRACT - term: id: GO:0046961 label: proton-transporting ATPase activity, rotational mechanism evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: summary: Proton-transporting ATPase activity by rotational mechanism is the precise molecular function of the V-ATPase complex; subunit A is the catalytic subunit. action: ACCEPT reason: This is the correct molecular function annotation for the catalytic subunit of V-ATPase, supported by extensive biochemical and structural data. supported_by: - reference_id: file:human/ATP6V1A/ATP6V1A-uniprot.txt supporting_text: Catalytic 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 reference_section_type: DATABASE_ENTRY - term: id: GO:0005524 label: ATP binding evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: The A subunit contains the ATP-binding/hydrolysis site of V-ATPase, directly supported by structural studies. action: ACCEPT reason: ATP binding is directly demonstrated at the A-B subunit interface by crystallography and cryo-EM. This is a core molecular function annotation. supported_by: - reference_id: PMID:33065002 supporting_text: We build all known protein subunits with associated N-linked glycans and identify glycolipids and phospholipids in the Vo complex. reference_section_type: ABSTRACT - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: The V1 domain including subunit A can exist in the cytoplasm as a dissociated complex during nutrient starvation; this represents the regulated V1-V0 disassembly. action: KEEP_AS_NON_CORE reason: Cytoplasmic localization reflects reversible V1-V0 disassembly, a real but non-primary functional state. The primary functional state is when V1 is assembled with V0 at organellar membranes. supported_by: - reference_id: file:human/ATP6V1A/ATP6V1A-uniprot.txt supporting_text: Cytoplasm {ECO:0000269|PubMed:29668857, ECO:0000269|PubMed:33208464}. Cytoplasm, cytosol {ECO:0000250|UniProtKB:P50516}. reference_section_type: DATABASE_ENTRY - term: id: GO:0005765 label: lysosomal membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Lysosomal membrane localization is well supported and is the primary functional compartment for V-ATPase. action: ACCEPT reason: The lysosomal membrane is where the assembled V-ATPase complex acidifies the lysosomal lumen. This is a core localization. supported_by: - reference_id: file:human/ATP6V1A/ATP6V1A-uniprot.txt supporting_text: Lysosome {ECO:0000250|UniProtKB:P50516}. reference_section_type: DATABASE_ENTRY - term: id: GO:0005829 label: cytosol evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: Cytosolic localization reflects the dissociated V1 complex under nutrient starvation. Supported by experimental evidence (HPA IDA). action: KEEP_AS_NON_CORE reason: The free V1 complex including subunit A can be cytosolic, but the functionally relevant location is membrane-associated. Valid but non-core. supported_by: - reference_id: file:human/ATP6V1A/ATP6V1A-uniprot.txt supporting_text: Cytoplasm, cytosol {ECO:0000250|UniProtKB:P50516}. reference_section_type: DATABASE_ENTRY - term: id: GO:0016887 label: ATP hydrolysis activity evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: ATP hydrolysis is the direct catalytic activity of subunit A in the V1 complex. Well supported. action: ACCEPT reason: ATP hydrolysis at the A-B interface is the primary molecular activity of the V1 domain, and the A subunit bears the catalytic residues. supported_by: - reference_id: file:human/ATP6V1A/ATP6V1A-uniprot.txt supporting_text: Reaction=ATP + H2O + 4 H(+)(in) = ADP + phosphate + 5 H(+)(out); EC=7.1.2.2; reference_section_type: DATABASE_ENTRY - term: id: GO:0030133 label: transport vesicle evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: V-ATPase presence on transport vesicles reflects its general role in acidifying trafficking compartments. action: KEEP_AS_NON_CORE reason: While V-ATPase is present on various vesicular compartments, this generic term is not the most informative localization for the core function of the A subunit. supported_by: - reference_id: file:human/ATP6V1A/ATP6V1A-uniprot.txt supporting_text: Cytoplasmic vesicle, clathrin-coated vesicle membrane {ECO:0000250|UniProtKB:P31404}; Peripheral membrane protein reference_section_type: DATABASE_ENTRY - term: id: GO:0030665 label: clathrin-coated vesicle membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Clathrin-coated vesicle membrane localization reflects V-ATPase role in endosomal acidification during endocytic trafficking. action: KEEP_AS_NON_CORE reason: This is a legitimate localization derived from ortholog data but is not the primary functional compartment for the core proton pump activity. - term: id: GO:0033180 label: proton-transporting V-type ATPase, V1 domain evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: part_of review: summary: ATP6V1A is definitionally a subunit of the V1 domain of V-type ATPase. action: ACCEPT reason: This is the fundamental structural annotation for the A subunit, supported by all structural and biochemical studies. supported_by: - reference_id: PMID:33065002 supporting_text: 'The V 1 ATPase is composed of three copies of subunits A, B, E, and G, and one copy of subunit C, D, F, and H' reference_section_type: INTRODUCTION - term: id: GO:0042592 label: homeostatic process evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: Homeostatic process is too broad to be an informative annotation. V-ATPase contributes to pH homeostasis but this is captured by more specific terms. action: MARK_AS_OVER_ANNOTATED reason: This ARBA annotation is too general. The specific homeostatic processes (lysosomal acidification, pH regulation) are better captured by more precise GO terms already annotated. - term: id: GO:0046034 label: ATP metabolic process evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: involved_in review: summary: ATP hydrolysis by the V1 catalytic domain is part of ATP metabolic process. However, this is a consequence of the ATP hydrolysis activity rather than the primary functional annotation. action: MARK_AS_OVER_ANNOTATED reason: While technically correct (ATP is hydrolyzed), the primary annotation should focus on the proton transport function. ATP hydrolysis by V-ATPase is energetically coupled to proton transport, not an end in itself. The more specific proton transport terms are more informative. - term: id: GO:0046961 label: proton-transporting ATPase activity, rotational mechanism evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: enables review: summary: Duplicate annotation of GO:0046961 from a different automated pipeline; same conclusion as the IBA annotation. action: ACCEPT reason: This is the core molecular function of V-ATPase and the A subunit is the catalytic component. Consistent with all evidence. - term: id: GO:0098793 label: presynapse evidence_type: IEA original_reference_id: GO_REF:0000108 qualifier: located_in review: summary: V-ATPase is expressed at high levels in neurons including presynaptic compartments, where it acidifies synaptic vesicles to enable neurotransmitter loading. action: KEEP_AS_NON_CORE reason: Presynaptic localization is real in neurons but is a specialized cell-type-specific role, not the core ubiquitous function. supported_by: - reference_id: PMID:29668857 supporting_text: the v-ATPase complex is expressed at high levels in neurons where it plays additional and unique roles in neurotransmitter loading into synaptic vesicles and in regulating synaptic transmission reference_section_type: OTHER - term: id: GO:1902600 label: proton transmembrane transport evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: involved_in review: summary: Duplicate annotation of proton transmembrane transport from a different pipeline. Core function of V-ATPase. action: ACCEPT reason: Proton transmembrane transport is the primary biological process for V-ATPase. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33208464 qualifier: enables review: summary: This protein binding annotation comes from the interaction of ATP6V1A with the Rabies virus matrix protein. Generic protein binding is uninformative. action: MARK_AS_OVER_ANNOTATED reason: Generic protein binding does not capture the relevant function. The interaction with viral M protein is a host-pathogen interaction, not a core cellular function. Protein binding as a GO term is uninformative. - term: id: GO:0005886 label: plasma membrane evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: Plasma membrane V-ATPase is present in specialized cells such as osteoclasts and renal intercalated cells. First identified in osteoclastoma (PMID:8463241). action: KEEP_AS_NON_CORE reason: Plasma membrane localization is real but cell-type-specific (osteoclasts, renal intercalated cells). Not the primary ubiquitous functional localization. supported_by: - reference_id: PMID:8463241 supporting_text: HO68 could correspond to an isoform of subunit A specific for a vacuolar-type H(+)-ATPase located in the osteoclast plasma membrane. reference_section_type: ABSTRACT - term: id: GO:0005902 label: microvillus evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: Microvillus localization from ortholog transfer; apical plasma membrane V-ATPase in specialized epithelial cells can be associated with microvilli. action: KEEP_AS_NON_CORE reason: Microvillus is a specialized apical structure; V-ATPase presence there is a context-specific localization in polarized epithelial cells. - term: id: GO:0015078 label: proton transmembrane transporter activity evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: contributes_to review: summary: The contributes_to qualifier correctly notes that the A subunit alone does not transport protons; it is part of the holoenzyme complex. This annotation is appropriate. action: ACCEPT reason: The contributes_to qualifier is correct for a subunit of a multi-subunit proton pump. The annotation captures the molecular transporter function appropriately. - term: id: GO:0016324 label: apical plasma membrane evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: Apical plasma membrane V-ATPase is found in specialized epithelial cells (intercalated cells, proximal tubule). This is a specialized non-core localization. action: KEEP_AS_NON_CORE reason: Apical plasma membrane is a real but cell-type-specific localization for V-ATPase in polarized epithelial cells. - 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: ATP6V1A is a core component of the proton-transporting V-type ATPase complex. This is a fundamental structural annotation. action: ACCEPT reason: Being part of the V-type ATPase complex is the defining structural annotation for ATP6V1A. - term: id: GO:0097401 label: synaptic vesicle lumen acidification evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: V-ATPase acidifies synaptic vesicles to enable neurotransmitter loading in neurons. This is a specialized but well-supported neuronal function. action: KEEP_AS_NON_CORE reason: Synaptic vesicle acidification is a specialized neuronal role for V-ATPase. Real and important in the nervous system but not the core ubiquitous function. supported_by: - reference_id: PMID:29668857 supporting_text: the v-ATPase complex is expressed at high levels in neurons where it plays additional and unique roles in neurotransmitter loading into synaptic vesicles and in regulating synaptic transmission reference_section_type: OTHER - term: id: GO:0071230 label: cellular response to amino acid stimulus evidence_type: IDA original_reference_id: PMID:22053050 qualifier: involved_in review: summary: V-ATPase (V1A subunit directly involved as part of the holoenzyme) mediates the cellular response to amino acid levels through mTORC1 activation at the lysosome. Supported by PMID:22053050. action: ACCEPT reason: The role of V-ATPase in amino acid sensing and mTORC1 activation is well-established. The V1 domain interacts with Ragulator in an amino acid-sensitive fashion. This is a core function of the lysosomal V-ATPase. supported_by: - reference_id: PMID:22053050 supporting_text: We found that the vacuolar H(+)-adenosine triphosphatase ATPase (v-ATPase) is necessary for amino acids to activate mTORC1. reference_section_type: ABSTRACT - reference_id: PMID:22053050 supporting_text: These results identify the v-ATPase as a component of the mTOR pathway and delineate a lysosome-associated machinery for amino acid sensing. reference_section_type: ABSTRACT - term: id: GO:0160124 label: guanyl nucleotide exchange factor activator activity evidence_type: IDA original_reference_id: PMID:22053050 qualifier: contributes_to review: summary: V-ATPase interacts with Ragulator (the GEF complex for RagA/B) and activates Rag GTPase nucleotide exchange in an amino acid-sensitive manner. The contributes_to qualifier is appropriate as this is a complex-level function. action: ACCEPT reason: The functional interaction of V-ATPase with Ragulator to activate Rag GTPases for mTORC1 translocation is well-supported. This is a distinct molecular function of the lysosomal V-ATPase. supported_by: - reference_id: PMID:22053050 supporting_text: The v-ATPase engages in extensive amino acid-sensitive interactions with the Ragulator, a scaffolding complex that anchors the Rag GTPases to the lysosome. reference_section_type: ABSTRACT - reference_id: PMID:22053050 supporting_text: amino acids regulated the interaction between the V1 domain of v-ATPase and Ragulator and Rag GTPases. reference_section_type: RESULTS - term: id: GO:0005765 label: lysosomal membrane evidence_type: IDA original_reference_id: PMID:22053050 qualifier: is_active_in review: summary: V-ATPase is active at the lysosomal membrane where it acidifies the lysosomal lumen. The is_active_in qualifier from this mTOR signaling study is correct. action: ACCEPT reason: The lysosomal membrane is the primary functional location of the assembled V-ATPase complex. supported_by: - reference_id: PMID:22053050 supporting_text: The mTOR complex 1 (mTORC1) protein kinase is a master growth regulator that is stimulated by amino acids. Amino acids activate the Rag guanosine triphosphatases (GTPases), which promote the translocation of mTORC1 to the lysosomal surface, the site of mTORC1 activation. reference_section_type: ABSTRACT - term: id: GO:0046611 label: lysosomal proton-transporting V-type ATPase complex evidence_type: IDA original_reference_id: PMID:22053050 qualifier: part_of review: summary: ATP6V1A is part of the lysosomal V-type ATPase complex as shown in the mTOR study. action: ACCEPT reason: Part of lysosomal V-ATPase complex is the most specific and accurate structural annotation for this subunit in its primary functional context. supported_by: - reference_id: PMID:22053050 supporting_text: The v-ATPase engages in extensive amino acid-sensitive interactions with the Ragulator, a scaffolding complex that anchors the Rag GTPases to the lysosome. reference_section_type: ABSTRACT - term: id: GO:1904263 label: positive regulation of TORC1 signaling evidence_type: IDA original_reference_id: PMID:22053050 qualifier: involved_in review: summary: V-ATPase is required for mTORC1 activation by amino acids. Inhibition of V-ATPase blocks mTORC1 activation. This is a well-supported function. action: ACCEPT reason: Positive regulation of TORC1 signaling by V-ATPase is directly demonstrated. This is an important regulatory function of the lysosomal V-ATPase. supported_by: - reference_id: PMID:22053050 supporting_text: We found that the vacuolar H(+)-adenosine triphosphatase ATPase (v-ATPase) is necessary for amino acids to activate mTORC1. reference_section_type: ABSTRACT - reference_id: PMID:22053050 supporting_text: these results place the v-ATPase downstream of amino acids but upstream of the regulation of nucleotide loading of the Rag GTPases reference_section_type: RESULTS - term: id: GO:0046611 label: lysosomal proton-transporting V-type ATPase complex evidence_type: IDA original_reference_id: PMID:33065002 qualifier: part_of review: summary: Cryo-EM structure of complete human V-ATPase directly confirms ATP6V1A as part of the lysosomal proton-transporting V-type ATPase complex. action: ACCEPT reason: Direct structural evidence from the complete human V-ATPase cryo-EM structure. supported_by: - reference_id: PMID:33065002 supporting_text: Here, we report cryoelectron microscopy structures of human V-ATPase in three rotational states at up to 2.9-Å resolution. reference_section_type: ABSTRACT - term: id: GO:0046961 label: proton-transporting ATPase activity, rotational mechanism evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: enables review: summary: Ortholog-transfer of the core molecular function. Consistent with all direct evidence. action: ACCEPT reason: Core molecular function annotation. Consistent with direct experimental evidence. - term: id: GO:0005829 label: cytosol evidence_type: IDA original_reference_id: GO_REF:0000052 qualifier: located_in review: summary: HPA immunofluorescence data supports cytosolic localization. This reflects the free V1 domain found in cytosol during regulated disassembly. action: KEEP_AS_NON_CORE reason: Cytosolic V1 complex is a regulated state during nutrient deprivation. Real but non-core relative to membrane-assembled V-ATPase function. - term: id: GO:0005737 label: cytoplasm evidence_type: EXP original_reference_id: PMID:29668857 qualifier: located_in review: summary: Cytoplasmic localization confirmed in the disease-variant study. Reflects the known cytoplasmic pool of V1 subunits. action: KEEP_AS_NON_CORE reason: Cytoplasmic localization is real but non-primary functional state. supported_by: - reference_id: PMID:29668857 supporting_text: both mutations caused a similar defect in neurite elongation accompanied by loss of excitatory inputs, revealing that altered lysosomal homeostasis markedly affects neurite development and synaptic connectivity reference_section_type: ABSTRACT - term: id: GO:0005737 label: cytoplasm evidence_type: EXP original_reference_id: PMID:33208464 qualifier: located_in review: summary: Cytoplasmic localization confirmed in the rabies virus study. action: KEEP_AS_NON_CORE reason: Cytoplasmic localization reflects a real but non-primary functional state of the V1 domain. - term: id: GO:0005764 label: lysosome evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in review: summary: Lysosomal localization by ortholog transfer. Consistent with the primary functional compartment. action: ACCEPT reason: Lysosomal localization is a core annotation for V-ATPase. The assembled holoenzyme is associated with lysosomal membranes. - term: id: GO:0000139 label: Golgi membrane evidence_type: NAS original_reference_id: PMID:32001091 qualifier: located_in review: summary: V-ATPase is found on Golgi membranes where it acidifies the Golgi lumen, supporting glycosylation and vesicular trafficking. action: KEEP_AS_NON_CORE reason: Golgi membrane localization is real and important for Golgi function, but it is not the primary functional localization for the core proton pump activity in the context of lysosomal degradation and mTOR signaling. supported_by: - reference_id: PMID:32001091 supporting_text: V-ATPases are the primary source of organellar acidification in all eukaryotes, making them essential for many fundamental cellular processes. reference_section_type: ABSTRACT - term: id: GO:0005765 label: lysosomal membrane evidence_type: NAS original_reference_id: PMID:32001091 qualifier: located_in review: summary: Lysosomal membrane localization supported by the review article and structural studies. action: ACCEPT reason: Lysosomal membrane is a core functional localization for V-ATPase. supported_by: - reference_id: PMID:32001091 supporting_text: V-ATPases are the primary source of organellar acidification in all eukaryotes, making them essential for many fundamental cellular processes. reference_section_type: ABSTRACT - term: id: GO:0005886 label: plasma membrane evidence_type: NAS original_reference_id: PMID:32001091 qualifier: located_in review: summary: Plasma membrane V-ATPase exists in specialized cells. Review article supports this but it is a non-core annotation. action: KEEP_AS_NON_CORE reason: Plasma membrane localization is real but cell-type-specific (osteoclasts, kidney intercalated cells). supported_by: - reference_id: PMID:32001091 supporting_text: V-ATPases are the primary source of organellar acidification in all eukaryotes, making them essential for many fundamental cellular processes reference_section_type: ABSTRACT - term: id: GO:0007035 label: vacuolar acidification evidence_type: NAS original_reference_id: PMID:32001091 qualifier: involved_in review: summary: Vacuolar acidification is the core biological process of V-ATPase. Well supported. action: ACCEPT reason: Vacuolar/lysosomal acidification is the primary biological process of V-ATPase. Core annotation. supported_by: - reference_id: PMID:32001091 supporting_text: V-ATPases are the primary source of organellar acidification in all eukaryotes, making them essential for many fundamental cellular processes. reference_section_type: ABSTRACT - term: id: GO:0007042 label: lysosomal lumen acidification evidence_type: NAS original_reference_id: PMID:32001091 qualifier: involved_in review: summary: Lysosomal lumen acidification is a core function of V-ATPase. Well supported. action: ACCEPT reason: Lysosomal acidification is central to V-ATPase function and is required for lysosomal enzyme activity, protein degradation, and multiple signaling pathways. supported_by: - reference_id: PMID:33065002 supporting_text: Vesicular and organellar V-ATPases are essential in establishing and maintaining the pH homeostasis of endosomes and lysosomes and in supporting intracellular membrane trafficking and protein degradation reference_section_type: INTRODUCTION - term: id: GO:0007042 label: lysosomal lumen acidification evidence_type: NAS original_reference_id: PMID:33065002 qualifier: involved_in review: summary: Duplicate annotation of lysosomal lumen acidification from the V-ATPase structure paper. Core function. action: ACCEPT reason: Core function annotation supported by structural and functional data. - term: id: GO:0010008 label: endosome membrane evidence_type: NAS original_reference_id: PMID:32001091 qualifier: located_in review: summary: Endosome membrane localization is well supported for V-ATPase, which acidifies early and late endosomes during endocytic trafficking. action: ACCEPT reason: Endosomal membrane is a core functional localization for V-ATPase, important for endocytic trafficking and iron release from transferrin. supported_by: - reference_id: PMID:33065002 supporting_text: Vesicular and organellar V-ATPases are essential in establishing and maintaining the pH homeostasis of endosomes and lysosomes and in supporting intracellular membrane trafficking and protein degradation reference_section_type: INTRODUCTION - term: id: GO:0016020 label: membrane evidence_type: IDA original_reference_id: PMID:33065002 qualifier: located_in review: summary: Generic membrane annotation from the cryo-EM structure paper. Too generic relative to the more specific lysosomal membrane and endosome membrane annotations. action: MARK_AS_OVER_ANNOTATED reason: The generic membrane term is less informative than the specific lysosomal membrane and endosome membrane annotations already present. The cryo-EM structure shows the holoenzyme in membrane context but should be captured by more specific terms. - term: id: GO:0033176 label: proton-transporting V-type ATPase complex evidence_type: NAS original_reference_id: PMID:33065002 qualifier: part_of review: summary: Structural annotation of ATP6V1A as part of the V-type ATPase complex, directly confirmed by cryo-EM. action: ACCEPT reason: Core structural annotation directly confirmed by the complete human V-ATPase structure. supported_by: - reference_id: PMID:33065002 supporting_text: Here, we report cryoelectron microscopy structures of human V-ATPase in three rotational states at up to 2.9-Å resolution. reference_section_type: ABSTRACT - term: id: GO:0048388 label: endosomal lumen acidification evidence_type: NAS original_reference_id: PMID:32001091 qualifier: involved_in review: summary: Endosomal lumen acidification is a core function of V-ATPase, required for endocytic trafficking, iron release from transferrin, and lysosomal enzyme activation. action: ACCEPT reason: Core function of V-ATPase; well supported. supported_by: - reference_id: PMID:33065002 supporting_text: Vesicular and organellar V-ATPases are essential in establishing and maintaining the pH homeostasis of endosomes and lysosomes and in supporting intracellular membrane trafficking and protein degradation reference_section_type: INTRODUCTION - term: id: GO:0051452 label: intracellular pH reduction evidence_type: NAS original_reference_id: PMID:32001091 qualifier: involved_in review: summary: Intracellular pH reduction is a direct consequence of V-ATPase activity. Broadly valid. action: ACCEPT reason: V-ATPase directly reduces the luminal pH of intracellular compartments. Valid annotation. - term: id: GO:0061795 label: Golgi lumen acidification evidence_type: NAS original_reference_id: PMID:32001091 qualifier: involved_in review: summary: V-ATPase acidifies the Golgi lumen, which is important for post-translational modifications and vesicular trafficking. Valid but non-primary role. action: KEEP_AS_NON_CORE reason: Golgi acidification is a real function of V-ATPase but is less central than lysosomal/endosomal acidification. supported_by: - reference_id: PMID:32001091 supporting_text: V-ATPases are the primary source of organellar acidification in all eukaryotes, making them essential for many fundamental cellular processes. reference_section_type: ABSTRACT - term: id: GO:1902600 label: proton transmembrane transport evidence_type: NAS original_reference_id: PMID:33065002 qualifier: involved_in review: summary: Duplicate annotation of proton transmembrane transport from the structure paper. Core function. action: ACCEPT reason: Core biological process annotation. - 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 cryo-EM evidence places ATP6V1A in the V1 domain of the vacuolar proton-transporting V-type ATPase. action: ACCEPT reason: Most specific and accurate structural annotation, directly confirmed by the complete human V-ATPase cryo-EM structure. supported_by: - reference_id: PMID:33065002 supporting_text: 'The V 1 ATPase is composed of three copies of subunits A, B, E, and G, and one copy of subunit C, D, F, and H' reference_section_type: INTRODUCTION - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:23035048 qualifier: enables review: summary: The interaction with WFS1 is specific and functional, but the generic protein binding term does not capture the biology. The interaction may reflect a chaperone/assembly function. action: MARK_AS_OVER_ANNOTATED reason: Protein binding is uninformative. The specific WFS1-V1A interaction in secretory granules/ER context is better described as a specific assembly/regulatory interaction, but there is no more specific GO term available in the current annotations. supported_by: - reference_id: PMID:23035048 supporting_text: We demonstrated a novel interaction between WFS1 and the V1A subunit of the H(+) V-ATPase (proton pump) by co-immunoprecipitation in human embryonic kidney (HEK) 293 cells and with endogenous proteins in human neuroblastoma cells. reference_section_type: ABSTRACT - term: id: GO:0030141 label: secretory granule evidence_type: IDA original_reference_id: PMID:23035048 qualifier: located_in review: summary: Co-localization of ATP6V1A with WFS1 in secretory granules in neuroblastoma cells is experimentally demonstrated. action: KEEP_AS_NON_CORE reason: Secretory granule localization is real but cell-type-specific (neuroblastoma/pancreatic beta cells). Not the core ubiquitous localization. supported_by: - reference_id: PMID:23035048 supporting_text: Wolfram syndrome is an autosomal recessive disorder characterized by neurodegeneration and diabetes mellitus. The gene responsible for the syndrome (WFS1) encodes an endoplasmic reticulum (ER)-resident transmembrane protein that also localizes to secretory granules in pancreatic beta cells. reference_section_type: ABSTRACT - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: PMID:8463241 qualifier: located_in review: summary: Original identification of an osteoclastoma-specific V-ATPase A subunit isoform at the plasma membrane. Cell-type-specific localization. action: KEEP_AS_NON_CORE reason: Plasma membrane localization is real in osteoclasts and other specialized cells, but this is not the primary functional localization in most cell types. supported_by: - reference_id: PMID:8463241 supporting_text: HO68 could correspond to an isoform of subunit A specific for a vacuolar-type H(+)-ATPase located in the osteoclast plasma membrane. reference_section_type: ABSTRACT - term: id: GO:0006879 label: intracellular iron ion homeostasis evidence_type: IMP original_reference_id: PMID:28296633 qualifier: involved_in review: summary: V-ATPase loss of function leads to intracellular iron depletion through impaired transferrin/iron recycling in endosomes. Experimental evidence from CRISPR screen directly implicates ATP6V1A. action: KEEP_AS_NON_CORE reason: Iron homeostasis is an important secondary consequence of V-ATPase endosomal function, but it is not the primary proton pump function. The mechanism is indirect via endosomal acidification affecting transferrin-iron cycling. 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_section_type: ABSTRACT - reference_id: PMID:28296633 supporting_text: 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. reference_section_type: ABSTRACT - term: id: GO:0036295 label: cellular response to increased oxygen levels evidence_type: IMP original_reference_id: PMID:28296633 qualifier: involved_in review: summary: This annotation follows from the iron homeostasis finding - V-ATPase disruption leads to iron depletion which impairs PHD activity, causing HIF1A stabilization even under normoxia. This is an indirect effect. action: MARK_AS_OVER_ANNOTATED reason: Cellular response to increased oxygen levels is an over-annotation; V-ATPase does not directly sense or respond to oxygen. The effect on HIF1A is indirect via iron homeostasis. The intracellular iron ion homeostasis annotation (GO:0006879) better captures the relevant biology. supported_by: - reference_id: PMID:28296633 supporting_text: 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. reference_section_type: ABSTRACT - term: id: GO:0016241 label: regulation of macroautophagy evidence_type: NAS original_reference_id: PMID:22982048 qualifier: involved_in review: summary: V-ATPase acidification of lysosomes is required for autophagic flux. The reference (PMID:22982048) studied lipofuscin in senescent fibroblasts and used V-ATPase inhibitors as experimental tools. The annotation is an indirect inference. action: KEEP_AS_NON_CORE reason: V-ATPase does regulate macroautophagy by acidifying lysosomes required for autophagic degradation. However, this is an indirect downstream consequence of the core proton pump function, not a direct regulatory activity of ATP6V1A per se. supported_by: - reference_id: PMID:22982048 supporting_text: Lipofuscin is formed independently of macroautophagy and lysosomal activity in stress-induced prematurely senescent human fibroblasts. reference_section_type: TITLE - term: id: GO:0070062 label: extracellular exosome evidence_type: HDA original_reference_id: PMID:23533145 qualifier: located_in review: summary: V-ATPase subunit A detected in exosome proteomics studies. These HDA annotations reflect mass spectrometry detection and may include contamination. action: MARK_AS_OVER_ANNOTATED reason: Exosome proteomics HDA annotations for V-ATPase subunits likely reflect contamination or non-specific co-purification rather than a genuine exosomal localization or function. V-ATPase is a lysosomal/endosomal enzyme; detection in exosomes is not supported as a primary functional localization. - term: id: GO:0070062 label: extracellular exosome evidence_type: HDA original_reference_id: PMID:19199708 qualifier: located_in review: summary: Same as above - mass spectrometry detection in parotid exosomes. action: MARK_AS_OVER_ANNOTATED reason: High-throughput proteomics exosome annotation; not a primary functional localization for V-ATPase. - term: id: GO:0070062 label: extracellular exosome evidence_type: HDA original_reference_id: PMID:19056867 qualifier: located_in review: summary: Mass spectrometry detection in urinary exosomes. action: MARK_AS_OVER_ANNOTATED reason: High-throughput proteomics exosome annotation; not a primary functional localization for V-ATPase. - term: id: GO:0005765 label: lysosomal membrane evidence_type: HDA original_reference_id: PMID:17897319 qualifier: located_in review: summary: Large-scale proteomics study of lysosomal membrane proteins identifies V-ATPase subunit A. Supports lysosomal membrane localization. action: ACCEPT reason: Proteomics study of lysosomal membranes directly confirms V-ATPase subunit A at the lysosomal membrane. - term: id: GO:0070062 label: extracellular exosome evidence_type: HDA original_reference_id: PMID:20458337 qualifier: located_in review: summary: Mass spectrometry detection in B-cell exosomes. action: MARK_AS_OVER_ANNOTATED reason: High-throughput proteomics exosome annotation; not a primary functional localization for V-ATPase. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-1222516 qualifier: located_in review: summary: Multiple Reactome TAS annotations for cytosol reflect V-ATPase participation in various Reactome pathway reactions. action: KEEP_AS_NON_CORE reason: The V1 domain can be cytosolic during regulated disassembly. Valid but non-primary functional state. - 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. action: KEEP_AS_NON_CORE reason: Non-primary functional state. - 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. action: KEEP_AS_NON_CORE reason: Non-primary functional state. - 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. action: KEEP_AS_NON_CORE reason: Non-primary functional state. - 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 context of mTOR/Rag GTPase pathway. action: KEEP_AS_NON_CORE reason: Non-primary functional state. - 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 in context of mTOR pathway. action: KEEP_AS_NON_CORE reason: Non-primary functional state. - 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. action: KEEP_AS_NON_CORE reason: Non-primary functional state. - 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. action: KEEP_AS_NON_CORE reason: Non-primary functional state. - 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. action: KEEP_AS_NON_CORE reason: Non-primary functional state. - 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. action: KEEP_AS_NON_CORE reason: Non-primary functional state. - 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 in context of mTORC1 recruitment. action: KEEP_AS_NON_CORE reason: Non-primary functional state. - 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. action: KEEP_AS_NON_CORE reason: Non-primary functional state. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9858928 qualifier: located_in review: summary: Reactome TAS annotation for cytosol in context of MITF-M regulation of ATP6V1A. action: KEEP_AS_NON_CORE reason: Non-primary functional state. - term: id: GO:0005829 label: cytosol evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in review: summary: Ortholog-based cytosol annotation. action: KEEP_AS_NON_CORE reason: Non-primary functional state. - term: id: GO:0005886 label: plasma membrane evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in review: summary: Ortholog-based plasma membrane annotation. Consistent with osteoclast/renal cell specialization. action: KEEP_AS_NON_CORE reason: Cell-type-specific localization; non-core for the ubiquitous function. - term: id: GO:0016469 label: proton-transporting two-sector ATPase complex evidence_type: TAS original_reference_id: PMID:8463241 qualifier: part_of review: summary: Original paper from osteoclastoma identifies ATP6V1A as part of the proton-transporting two-sector ATPase complex. Valid structural annotation. action: ACCEPT reason: This structural annotation correctly identifies ATP6V1A as part of the two-sector V-type ATPase complex. supported_by: - reference_id: PMID:8463241 supporting_text: Subunit A is thought to be the main component of the catalytic site of the vacuolar-type H(+)-ATPase. reference_section_type: ABSTRACT core_functions: - description: ATP6V1A is the catalytic A subunit of the V1 domain of V-ATPase, directly hydrolyzing ATP to power proton translocation across organellar membranes. Three copies of subunit A form catalytic AB heterodimers in the V1 hexameric ring. molecular_function: id: GO:0046961 label: proton-transporting ATPase activity, rotational mechanism directly_involved_in: - id: GO:1902600 label: proton transmembrane transport locations: - id: GO:0005765 label: lysosomal membrane in_complex: id: GO:0046611 label: lysosomal proton-transporting V-type ATPase complex - description: As the catalytic ATPase subunit, ATP6V1A powers acidification of lysosomal and endosomal lumens, which is essential for protein degradation, receptor-mediated endocytosis, and lysosomal enzyme function. molecular_function: id: GO:0046961 label: proton-transporting ATPase activity, rotational mechanism directly_involved_in: - id: GO:0007042 label: lysosomal lumen acidification - id: GO:0048388 label: endosomal lumen acidification locations: - id: GO:0005765 label: lysosomal membrane - description: The lysosomal V-ATPase complex, through the V1 domain, engages Ragulator in an amino acid-sensitive fashion to activate Rag GTPase-mediated mTORC1 recruitment and activation at the lysosomal surface. molecular_function: id: GO:0160124 label: guanyl nucleotide exchange factor activator activity directly_involved_in: - id: GO:1904263 label: positive regulation of TORC1 signaling locations: - id: GO:0005765 label: lysosomal membrane suggested_questions: - question: Does ATP6V1A isoform 2 (lacking the first 33 amino acids) have altered V-ATPase activity or localization compared to isoform 1? - question: What is the mechanism by which de novo ATP6V1A mutations cause IECEE3 specifically rather than ARCL2D? Is it a dominant-negative effect or haploinsufficiency? - question: Are there cell-type-specific expression differences between isoforms 1 and 2 that could explain differential disease phenotypes? - question: How does AMPK phosphorylation of Ser-384 regulate V-ATPase activity in vivo, and does this affect mTORC1 signaling? suggested_experiments: - description: Cryo-EM structure of V-ATPase with disease-variant A subunits to determine structural basis of gain-of-function vs loss-of-function mutations. hypothesis: Disease variants alter V-ATPase assembly or catalytic mechanism in structurally distinct ways that explain gain vs loss of function. - description: Isoform-selective knockdown and overexpression experiments to determine the functional distinction between ATP6V1A isoforms 1 and 2. hypothesis: Isoform 2 (lacking first 33 amino acids) has altered assembly kinetics or localization preference compared to isoform 1. - description: Mass spectrometry-based measurement of V1-V0 assembly ratio in cells expressing IECEE3 vs ARCL2D mutations to distinguish pathomechanisms. hypothesis: IECEE3 mutations alter assembly dynamics differently from ARCL2D biallelic loss-of-function mutations. - description: In vivo lysosomal pH measurement with genetically-encoded sensors in neurons expressing disease-linked ATP6V1A variants. hypothesis: De novo IECEE3 mutations alter lysosomal pH differently than loss-of-function ARCL2D mutations, explaining the distinct neurological phenotype. 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:0000052 title: Gene Ontology annotation based on curation of immunofluorescence data findings: [] - id: GO_REF:0000107 title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara findings: [] - id: GO_REF:0000108 title: Automatic assignment of GO terms using logical inference, based on on inter-ontology links 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:17897319 title: Integral and associated lysosomal membrane proteins. findings: - statement: Large-scale proteomics of lysosomal membrane fraction confirms V-ATPase subunit A (ATP6V1A) presence at lysosomal membrane. - id: PMID:19056867 title: Large-scale proteomics and phosphoproteomics of urinary exosomes. findings: - statement: Mass spectrometry-based detection of ATP6V1A in urinary exosome fraction; likely a contaminant/non-specific co-purification. - id: PMID:19199708 title: Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT). findings: - statement: Mass spectrometry detection of ATP6V1A in parotid gland exosomes; likely a contaminant. - id: PMID:20458337 title: MHC class II-associated proteins in B-cell exosomes and potential functional implications for exosome biogenesis. findings: - statement: Mass spectrometry detection in B-cell exosomes; context is contamination or non-specific. - id: PMID:22053050 title: mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase. findings: - statement: V-ATPase (V1A subunit confirmed to co-immunoprecipitate with Ragulator) is required for amino acid-induced mTORC1 activation at the lysosome. - statement: V1 domain interacts with Ragulator in an amino acid-sensitive manner. - statement: ATP hydrolysis by V-ATPase is required for the amino acid signaling but the proton gradient itself is not. - id: PMID:22982048 title: Lipofuscin is formed independently of macroautophagy and lysosomal activity in stress-induced prematurely senescent human fibroblasts. findings: - statement: Used V-ATPase inhibitors to block lysosomal activity; demonstrates V-ATPase dependence of macroautophagy, but not a primary study of ATP6V1A function. - id: PMID:23035048 title: Vacuolar-type H+-ATPase V1A subunit is a molecular partner of Wolfram syndrome 1 (WFS1) protein, which regulates its expression and stability. findings: - statement: ATP6V1A directly interacts with WFS1 in neuroblastoma cells and HEK293 cells. - statement: WFS1 regulates V1A expression and stability; V1A co-localizes with WFS1 in secretory granules. - id: PMID:23533145 title: In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine. findings: - statement: Mass spectrometry detection of ATP6V1A in urinary exosomes. - id: PMID:28296633 title: The vacuolar-ATPase complex and assembly factors, TMEM199 and CCDC115, control HIF1α prolyl hydroxylation by regulating cellular iron levels. findings: - statement: ATP6V1A depletion by CRISPR stabilizes HIF1α under aerobic conditions. - statement: Mechanism is via intracellular iron depletion impairing PHD activity, not direct lysosomal degradation of HIF1α. - id: PMID:29668857 title: De novo mutations of the ATP6V1A gene cause developmental encephalopathy with epilepsy. findings: - statement: Four de novo heterozygous ATP6V1A mutations cause IECEE3. - statement: Mutations disrupt lysosomal homeostasis and neuronal development. - statement: V-ATPase plays specific roles in neurotransmitter loading and synaptic connectivity. - id: PMID:32001091 title: Structure and Roles of V-type ATPases. findings: - statement: Comprehensive review of V-ATPase structure, function, and disease associations. - statement: V-ATPase is the primary organellar acidification system in eukaryotes. - id: PMID:33065002 title: Structures of a Complete Human V-ATPase Reveal Mechanisms of Its Assembly. findings: - statement: First complete human V-ATPase cryo-EM structure at 2.9 Angstrom resolution. - statement: ATP6V1A is the catalytic A subunit; three copies form the catalytic AB hexameric ring. - statement: Identifies mechanisms of V-ATPase assembly involving ATP6AP1, glycans, and lipids. - id: PMID:33208464 title: The ATPase ATP6V1A facilitates rabies virus replication by promoting virion uncoating and interacting with the viral matrix protein. findings: - statement: ATP6V1A interacts with Rabies virus M protein and facilitates viral uncoating in endosomes. - statement: This is a host-pathogen interaction exploiting V-ATPase endosomal acidification function. - id: PMID:8463241 title: Identification of two subunit A isoforms of the vacuolar H(+)-ATPase in human osteoclastoma. findings: - statement: First identification of two A subunit isoforms; ubiquitous VA68 (isoform 1) and osteoclastoma-specific HO68. - statement: A subunit is the main catalytic component of V-ATPase. - 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-9858928 title: MITF-M-dependent ATP6V1A gene expression findings: []