id: P36543 gene_symbol: ATP6V1E1 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: ATP6V1E1 encodes the E1 subunit (26 kDa) of the V1 peripheral sector of the vacuolar-type H+-ATPase (V-ATPase). Subunit E, together with subunit G, forms the three peripheral stalks of V1 that hold the catalytic head fixed against the torque of the rotating central rotor during ATP hydrolysis, enabling coupled proton translocation across organelle membranes. The V-ATPase is the primary driver of organellar acidification in eukaryotes, with key roles in lysosomal, endosomal, and Golgi pH homeostasis. In the kidney, ATP6V1E1 localizes to the apical membrane of cells in the thick ascending limb and distal convoluted tubule, where V-ATPase contributes to renal acid-base regulation. ATP6V1E1 binds aldolase (ALDOC), providing a potential coupling mechanism between glycolytic ATP supply and V-ATPase activity. Loss-of-function variants in ATP6V1E1 cause autosomal recessive cutis laxa type 2C (ARCL2C), a connective tissue disorder with skin laxity, hypotonia, and cardiovascular involvement, reflecting the ubiquitous importance of V-ATPase activity. The protein is expressed ubiquitously, with high levels in skin, and exists in three alternatively spliced isoforms. alternative_products: - name: '1' id: P36543-1 - name: '2' id: P36543-2 sequence_note: VSP_042925 - name: '3' id: P36543-3 sequence_note: VSP_044589 existing_annotations: - term: id: GO:1902600 label: proton transmembrane transport evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Phylogenetic inference that ATP6V1E1 participates in proton transmembrane transport. Well-supported by the established role of V-ATPase as the primary proton pump in eukaryotic cells. action: ACCEPT reason: Proton transmembrane transport is the core biological process of the V-ATPase, and subunit E1 is an indispensable structural component of the V1 sector required for complex function. 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. They play important roles in acidification of intracellular vesicles, organelles, and the extracellular milieu in eukaryotes. 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: Phylogenetic inference for rotational ATPase activity. The E subunit is a peripheral stalk component essential for maintaining the stator architecture during rotation. action: ACCEPT reason: The proton-transporting ATPase activity via rotational mechanism is the core molecular function of the complex. Subunit E is required for complex stability and function. 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:0005765 label: lysosomal membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: UniProt subcellular location vocabulary mapping. Supported by HDA proteomics evidence (PMID:17897319) and by the established biology of V-ATPase on lysosomes. action: ACCEPT reason: Lysosomal membrane is the primary functional location of V-ATPase. Multiple evidence types support this localization. - term: id: GO:0016324 label: apical plasma membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: UniProt subcellular location vocabulary mapping for apical plasma membrane. Confirmed by direct experimental evidence in kidney tubular epithelium (PMID:29993276). action: ACCEPT reason: Apical membrane localization of V-ATPase in kidney tubular epithelium is experimentally confirmed (PMID:29993276) and is relevant to ATP6V1E1's function in renal acid-base homeostasis. supported_by: - reference_id: PMID:29993276 supporting_text: H(+)-ATPase B1 subunit localizes to thick ascending limb and distal convoluted tubule of rodent and human kidney. reference_section_type: TITLE - term: id: GO:0030665 label: clathrin-coated vesicle membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: UniProt subcellular location vocabulary mapping based on ortholog data. V-ATPase acidifies clathrin-coated vesicles in the endocytic pathway. action: KEEP_AS_NON_CORE reason: Consistent with V-ATPase biology but non-core relative to lysosomal function. - term: id: GO:0030672 label: synaptic vesicle membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: UniProt subcellular location vocabulary mapping for synaptic vesicle membrane based on ortholog data. action: KEEP_AS_NON_CORE reason: Synaptic vesicle context is non-core for this ubiquitously expressed subunit, though V-ATPase does acidify synaptic vesicles. - term: id: GO:0033178 label: proton-transporting two-sector ATPase complex, catalytic domain evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: part_of review: summary: InterPro-based annotation placing ATP6V1E1 in the catalytic domain of the two-sector ATPase complex. The V1 sector is the catalytic domain of V-ATPase. action: ACCEPT reason: The V1 sector is the catalytic (ATP-hydrolyzing) domain of the two-sector V-ATPase. Subunit E is part of this domain. - term: id: GO:0046961 label: proton-transporting ATPase activity, rotational mechanism evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: InterPro-based annotation for rotational ATPase activity. Consistent with IBA annotation. action: ACCEPT reason: Consistent with established V-ATPase biology. - term: id: GO:1902600 label: proton transmembrane transport evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: involved_in review: summary: InterPro-based annotation for proton transmembrane transport. action: ACCEPT reason: Consistent with IBA and TAS annotations. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:16169070 qualifier: enables review: summary: Generic protein binding from a large-scale human protein-protein interaction network study. Not informative for the specific function of ATP6V1E1. action: MARK_AS_OVER_ANNOTATED reason: Protein binding from a high-throughput interactome study is uninformative for understanding ATP6V1E1 core function. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:35271311 qualifier: enables review: summary: Generic protein binding from the OpenCell endogenous tagging study. High-throughput; not informative. action: MARK_AS_OVER_ANNOTATED reason: Protein binding from high-throughput studies is uninformative for this V-ATPase subunit. - term: id: GO:0005765 label: lysosomal membrane evidence_type: IDA original_reference_id: PMID:22053050 qualifier: is_active_in review: summary: Direct experimental evidence from the Zoncu et al. (2011) mTORC1 study showing V-ATPase (including E1 subunit as part of V1 domain) is active at the lysosomal membrane. action: ACCEPT reason: Core localization supported by IDA evidence. The lysosomal membrane is the primary site of V-ATPase activity. 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:0046611 label: lysosomal proton-transporting V-type ATPase complex evidence_type: IDA original_reference_id: PMID:22053050 qualifier: part_of review: summary: IDA from the Zoncu et al. (2011) study demonstrating V-ATPase complex on lysosomes; E1 subunit is part of this complex. action: ACCEPT reason: Well-supported by multiple evidence types. 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:0071230 label: cellular response to amino acid stimulus evidence_type: IDA original_reference_id: PMID:22053050 qualifier: involved_in review: summary: The V-ATPase (with E1 as part of V1 domain) is required for mTORC1 activation in response to amino acids. This represents a genuine secondary function. action: KEEP_AS_NON_CORE reason: The cellular response to amino acid stimulus is a genuine secondary function of V-ATPase supported by direct experimental evidence, but is not the primary proton-pumping role. 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. In a cell-free system, ATP hydrolysis by the v-ATPase was necessary for amino acids to regulate the v-ATPase-Ragulator interaction and promote mTORC1 translocation. 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: The V-ATPase complex contributes to GEF activator activity in mTORC1 signaling. V-ATPase activity facilitates Ragulator-mediated GEF activation of Rag GTPases. action: KEEP_AS_NON_CORE reason: This secondary function in mTORC1 signaling is genuine but not the primary role of V-ATPase or subunit E1. supported_by: - reference_id: PMID:22053050 supporting_text: amino acids activate the Rag guanosine triphosphatases (GTPases), which promote the translocation of mTORC1 to the lysosomal surface, the site of mTORC1 activation. We found that the vacuolar H(+)-adenosine triphosphatase ATPase (v-ATPase) is necessary for amino acids to activate mTORC1. 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. action: KEEP_AS_NON_CORE reason: Secondary function of V-ATPase in mTORC1 signaling; not the primary proton pump role. - term: id: GO:0016324 label: apical plasma membrane evidence_type: EXP original_reference_id: PMID:29993276 qualifier: located_in review: summary: Experimental evidence showing V-ATPase subunit E1 at the apical membrane of kidney thick ascending limb and distal convoluted tubule epithelial cells. This is functionally relevant to renal acid excretion. action: ACCEPT reason: Experimentally confirmed apical membrane localization in kidney is well-supported and biologically meaningful for renal acid-base homeostasis. supported_by: - reference_id: PMID:29993276 supporting_text: H(+)-ATPase B1 subunit localizes to thick ascending limb and distal convoluted tubule of rodent and human kidney. reference_section_type: TITLE - 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 evidence from the cryo-EM structural study (Wang et al. 2020) confirming that E1 is a component of the V1 domain, present in three copies as part of EG peripheral stalk heterodimers. action: ACCEPT reason: The cryo-EM structures directly confirmed the position of subunit E in the V1 domain. This is core complex membership. 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:0016241 label: regulation of macroautophagy evidence_type: NAS original_reference_id: PMID:22982048 qualifier: involved_in review: summary: NAS annotation from Parkinson's UK curation. V-ATPase broadly supports macroautophagy through lysosomal acidification, which is required for autophagosome-lysosome fusion and degradation. action: MARK_AS_OVER_ANNOTATED reason: Regulation of macroautophagy is an indirect, downstream consequence of V-ATPase lysosomal acidification, not a specific regulatory function of subunit E1. Overstates functional specificity. - term: id: GO:0070062 label: extracellular exosome evidence_type: HDA original_reference_id: PMID:19199708 qualifier: located_in review: summary: High-throughput proteomics detection in parotid gland exosomes. Likely reflects membrane co-purification rather than a specific exosome function. action: MARK_AS_OVER_ANNOTATED reason: Exosome detection by proteomics is likely artifactual for a lysosomal V-ATPase subunit. Not informative for core function. - term: id: GO:0070062 label: extracellular exosome evidence_type: HDA original_reference_id: PMID:19056867 qualifier: located_in review: summary: High-throughput proteomics detection in urinary exosomes. action: MARK_AS_OVER_ANNOTATED reason: Same reasoning as parotid gland exosome annotation. Not informative. - term: id: GO:0005765 label: lysosomal membrane evidence_type: HDA original_reference_id: PMID:17897319 qualifier: located_in review: summary: Lysosomal membrane proteomics study detected ATP6V1E1. Confirms lysosomal membrane localization. action: ACCEPT reason: Direct proteomics evidence for lysosomal membrane localization is consistent with established V-ATPase biology. - term: id: GO:0051117 label: ATPase binding evidence_type: IPI original_reference_id: PMID:20717956 qualifier: enables review: summary: The E subunit of V-ATPase interacts with RAB11B, as shown in the study of acidosis-induced V-ATPase trafficking in salivary ducts (PMID:20717956). The ATPase binding annotation records this as the E subunit binding to an ATPase (itself being part of the V-ATPase). action: KEEP_AS_NON_CORE reason: ATPase binding is a context-specific interaction of the E subunit with RAB11B in the context of regulated V-ATPase trafficking. This is a secondary, context-specific function. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-1222516 qualifier: located_in review: summary: Reactome TAS annotation. The V1 peripheral sector can dissociate from V0 and exist as a soluble cytoplasmic complex during regulated disassembly. action: KEEP_AS_NON_CORE reason: V1 domain can be in cytosol during regulated disassembly; consistent with V-ATPase regulation biology. - 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: Consistent with V1 domain biology. - 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: Consistent. - 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: Consistent. - 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. action: KEEP_AS_NON_CORE reason: Consistent. - 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. action: KEEP_AS_NON_CORE reason: Consistent. - 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: Consistent. - 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: Consistent. - 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: Consistent. - 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: Consistent. - 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. action: KEEP_AS_NON_CORE reason: Consistent. - 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: Consistent. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9858923 qualifier: located_in review: summary: Reactome TAS annotation for cytosol in MITF/lysosome biogenesis context. action: KEEP_AS_NON_CORE reason: Consistent; relevant to MITF-regulated expression of ATP6V1E1 for lysosome biogenesis. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:21784977 qualifier: enables review: summary: PMID:21784977 concerns tristetraprolin (ZFP36) binding to CCL3 mRNA and regulating tissue inflammation. There is no evident connection to ATP6V1E1 in this publication. This annotation appears to be a curation error. action: REMOVE reason: PMID:21784977 is about tristetraprolin/CCL3 mRNA regulation and does not contain evidence for ATP6V1E1 protein binding. This annotation is likely a curation error. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:11399750 qualifier: enables review: summary: The interaction with ALDOC (aldolase) recorded in PMID:11399750 is a specific biochemically-validated interaction of the V-ATPase E subunit with aldolase. Generic protein binding is less informative than this specific interaction. action: MARK_AS_OVER_ANNOTATED reason: The underlying biology (E subunit-aldolase interaction) is more informative than generic protein binding. The specific interaction couples glycolytic ATP supply to V-ATPase activity, which warrants a more precise annotation if a suitable GO term existed. supported_by: - reference_id: PMID:11399750 supporting_text: A screen for proteins that bind the V-ATPase E subunit using the yeast two-hybrid assay identified the cDNA clone coded for aldolase, an enzyme of the glycolytic pathway. reference_section_type: ABSTRACT - term: id: GO:0005768 label: endosome evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in review: summary: Ortholog-based annotation for endosome localization. V-ATPase acidifies endosomes in the endocytic pathway. action: ACCEPT reason: Endosome localization is consistent with V-ATPase biology and the more specific endosome membrane annotation. - term: id: GO:0005829 label: cytosol evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in review: summary: Ortholog-based annotation for cytosol localization. action: KEEP_AS_NON_CORE reason: Consistent with V1 domain regulated disassembly biology. - term: id: GO:0016324 label: apical plasma membrane evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in review: summary: Ortholog-based annotation for apical plasma membrane, consistent with the EXP evidence from PMID:29993276. action: ACCEPT reason: Consistent with experimental evidence for kidney apical membrane localization. - term: id: GO:0016469 label: proton-transporting two-sector ATPase complex evidence_type: TAS original_reference_id: PMID:8250920 qualifier: part_of review: summary: TAS from the original cloning paper (van Hille et al. 1993). Subunit E is part of the proton-transporting V-type ATPase complex. action: ACCEPT reason: Historically supported complex membership confirmed by subsequent structural studies. supported_by: - reference_id: PMID:8250920 supporting_text: The vacuolar proton ATPase (V-ATPase) translocates protons into intracellular organelles or across the plasma membrane of specialised cells such as osteoclast and renal intercalated cells. reference_section_type: ABSTRACT - term: id: GO:1902600 label: proton transmembrane transport evidence_type: TAS original_reference_id: PMID:8250920 qualifier: involved_in review: summary: TAS from the original cloning paper. action: ACCEPT reason: Historically supported core function. 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: PMID:11399750 title: 'Interaction between aldolase and vacuolar H+-ATPase: evidence for direct coupling of glycolysis to the ATP-hydrolyzing proton pump.' findings: - statement: V-ATPase E subunit directly interacts with aldolase (ALDOC); interaction confirmed by yeast two-hybrid and co-immunoprecipitation; aldolase deficiency causes V1-V0 dissociation, suggesting coupling of glycolysis to V-ATPase activity. - id: PMID:16169070 title: 'A human protein-protein interaction network: a resource for annotating the proteome.' findings: - statement: ATP6V1E1 detected in high-throughput interactome study. - id: PMID:17897319 title: Integral and associated lysosomal membrane proteins. findings: - statement: ATP6V1E1 detected in lysosomal membrane proteomics study. - id: PMID:19056867 title: Large-scale proteomics and phosphoproteomics of urinary exosomes. findings: - statement: ATP6V1E1 detected in urinary exosomes by mass spectrometry. - id: PMID:19199708 title: Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT). findings: - statement: ATP6V1E1 detected in parotid gland exosome proteome. - id: PMID:20717956 title: Rab11b and its effector Rip11 regulate the acidosis-induced traffic of V-ATPase in salivary ducts. findings: - statement: V-ATPase E subunit interacts with RAB11B; RAB11B/Rip11 regulate acidosis-induced trafficking of V-ATPase to apical membrane in salivary duct cells. - id: PMID:21784977 title: Zinc finger protein tristetraprolin interacts with CCL3 mRNA and regulates tissue inflammation. findings: - statement: Paper concerns tristetraprolin/CCL3 mRNA regulation; no evidence for ATP6V1E1 involvement. Annotation likely a curation error. - id: PMID:22053050 title: mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase. findings: - statement: V-ATPase V1 domain (including E subunit) interacts with Ragulator on lysosomes; V-ATPase ATP hydrolysis required for amino acid-induced mTORC1 activation. - id: PMID:22982048 title: Lipofuscin is formed independently of macroautophagy and lysosomal activity in stress-induced prematurely senescent human fibroblasts. findings: - statement: V-ATPase broadly required for lysosomal-mediated macroautophagy. - id: PMID:28065471 title: Mutations in ATP6V1E1 or ATP6V1A cause autosomal-recessive cutis laxa. findings: - statement: Loss-of-function variants in ATP6V1E1 cause ARCL2C; P128 and W212 variants identified; high expression in skin; disease mechanism involves V-ATPase dysfunction affecting connective tissue. - id: PMID:29993276 title: H(+)-ATPase B1 subunit localizes to thick ascending limb and distal convoluted tubule of rodent and human kidney. findings: - statement: V-ATPase (including E subunit) localizes to apical membrane of thick ascending limb and distal convoluted tubule in human kidney. - id: PMID:32001091 title: Structure and Roles of V-type ATPases. findings: - statement: Comprehensive review of V-ATPase structure, roles in organellar acidification, and disease relevance. - 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; E1 subunit resolved in three peripheral stalk EG heterodimers at near-atomic resolution. - id: PMID:35271311 title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.' findings: - statement: ATP6V1E1 localization mapped by endogenous tagging. - id: PMID:8250920 title: Cloning and tissue distribution of subunits C, D, and E of the human vacuolar H(+)-ATPase. findings: - statement: Human V-ATPase E subunit cloned from osteoclastoma; ubiquitous expression; part of the proton-transporting V-type ATPase complex. - 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-9858923 title: MITF-M-dependent ATP6V1E1 gene expression findings: - statement: MITF-M transcription factor regulates ATP6V1E1 expression in the context of lysosome biogenesis. core_functions: - description: Peripheral stalk (EG heterodimer) component of the V1 sector of the vacuolar-type H+-ATPase. Forms three EG heterodimers that serve as the stator, keeping the catalytic A3B3 hexamer fixed against the torque generated during ATP hydrolysis-driven rotation of the central DF rotor. Essential for proton pumping into lysosomes, endosomes, Golgi, and other organelles. contributes_to_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 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 - description: Apical membrane V-ATPase function in kidney tubular epithelium (thick ascending limb and distal convoluted tubule). Contributes to urinary acidification and renal acid-base homeostasis. directly_involved_in: - id: GO:1902600 label: proton transmembrane transport locations: - id: GO:0016324 label: apical plasma membrane supported_by: - reference_id: PMID:29993276 supporting_text: Abundant H + -ATPase B1 subunit immunoreactivity was observed in the human kidney. As expected, intercalated cells showed the strongest signal, but significant signal was also observed in apical membrane domains of the distal nephron, including TAL, macula densa, and DCT. reference_section_type: RESULTS - description: Interaction with aldolase (ALDOC) providing a mechanism for coupling glycolytic ATP generation to V-ATPase proton pumping activity. Aldolase deficiency causes V1-V0 dissociation, implicating this interaction in V-ATPase assembly/regulation. directly_involved_in: - id: GO:1902600 label: proton transmembrane transport supported_by: - reference_id: PMID:11399750 supporting_text: In yeast cells deficient in aldolase, the peripheral V(1) domain of V-ATPase was found to dissociate from the integral membrane V(0) domain, reference_section_type: RESULTS suggested_questions: - question: What is the structural basis for how ATP6V1E1 variants (Pro-128, Trp-212) cause cutis laxa? Are these variants at the EG peripheral stalk interface with A/B subunits? experts: [] - question: Does the aldolase-E subunit interaction regulate V-ATPase activity dynamically in response to metabolic state? Are there conditions where this coupling is disrupted? experts: [] - question: Do the three alternatively spliced isoforms of ATP6V1E1 differ in their V-ATPase complex incorporation efficiency or their subcellular targeting? experts: [] suggested_experiments: - hypothesis: ATP6V1E1 cutis laxa variants (P128, W212) destabilize peripheral stalk contacts with V1 A/B subunits. description: Cryo-EM structure determination of V-ATPase containing ATP6V1E1 variants P128L and R212W to determine how they disrupt peripheral stalk integrity and complex assembly. experiment_type: structural biology - hypothesis: Aldolase binding to the V-ATPase E subunit dynamically modulates V-ATPase assembly or activity in response to glycolytic flux. description: Biochemical reconstitution of the aldolase-V-ATPase interaction to determine whether aldolase binding modulates V-ATPase assembly or proton pumping activity under varying glycolytic conditions. experiment_type: in vitro biochemical assay - hypothesis: ATP6V1E1 isoforms differ in V-ATPase complex incorporation or subcellular targeting. description: Comparative proteomics of V-ATPase complexes immunoprecipitated with isoform-specific antibodies to determine if isoform switching affects subunit composition or organelle targeting. experiment_type: immunoprecipitation proteomics