ATP6V1E1

UniProt ID: P36543
Organism: Homo sapiens
Review Status: COMPLETE
📝 Provide Detailed Feedback

Gene 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.

Existing Annotations Review

GO Term Evidence Action Reason
GO:1902600 proton transmembrane transport
IBA
GO_REF:0000033 		ACCEPT
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.
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.
Supporting Evidence:
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.
GO:0046961 proton-transporting ATPase activity, rotational mechanism
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetic inference for rotational ATPase activity. The E subunit is a peripheral stalk component essential for maintaining the stator architecture during rotation.
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.
Supporting Evidence:
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.
GO:0005765 lysosomal membrane
IEA
GO_REF:0000044 		ACCEPT
Summary: UniProt subcellular location vocabulary mapping. Supported by HDA proteomics evidence (PMID:17897319) and by the established biology of V-ATPase on lysosomes.
Reason: Lysosomal membrane is the primary functional location of V-ATPase. Multiple evidence types support this localization.
GO:0016324 apical plasma membrane
IEA
GO_REF:0000044 		ACCEPT
Summary: UniProt subcellular location vocabulary mapping for apical plasma membrane. Confirmed by direct experimental evidence in kidney tubular epithelium (PMID:29993276).
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.
Supporting Evidence:
PMID:29993276
H(+)-ATPase B1 subunit localizes to thick ascending limb and distal convoluted tubule of rodent and human kidney.
GO:0030665 clathrin-coated vesicle membrane
IEA
GO_REF:0000044 		KEEP AS NON CORE
Summary: UniProt subcellular location vocabulary mapping based on ortholog data. V-ATPase acidifies clathrin-coated vesicles in the endocytic pathway.
Reason: Consistent with V-ATPase biology but non-core relative to lysosomal function.
GO:0030672 synaptic vesicle membrane
IEA
GO_REF:0000044 		KEEP AS NON CORE
Summary: UniProt subcellular location vocabulary mapping for synaptic vesicle membrane based on ortholog data.
Reason: Synaptic vesicle context is non-core for this ubiquitously expressed subunit, though V-ATPase does acidify synaptic vesicles.
GO:0033178 proton-transporting two-sector ATPase complex, catalytic domain
IEA
GO_REF:0000002 		ACCEPT
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.
Reason: The V1 sector is the catalytic (ATP-hydrolyzing) domain of the two-sector V-ATPase. Subunit E is part of this domain.
GO:0046961 proton-transporting ATPase activity, rotational mechanism
IEA
GO_REF:0000002 		ACCEPT
Summary: InterPro-based annotation for rotational ATPase activity. Consistent with IBA annotation.
Reason: Consistent with established V-ATPase biology.
GO:1902600 proton transmembrane transport
IEA
GO_REF:0000002 		ACCEPT
Summary: InterPro-based annotation for proton transmembrane transport.
Reason: Consistent with IBA and TAS annotations.
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 a large-scale human protein-protein interaction network study. Not informative for the specific function of ATP6V1E1.
Reason: Protein binding from a high-throughput interactome study is uninformative for understanding ATP6V1E1 core function.
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 the OpenCell endogenous tagging study. High-throughput; not informative.
Reason: Protein binding from high-throughput studies is uninformative for this V-ATPase subunit.
GO:0005765 lysosomal membrane
IDA
PMID:22053050
mTORC1 senses lysosomal amino acids through an inside-out me... 		ACCEPT
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.
Reason: Core localization supported by IDA evidence. The lysosomal membrane is the primary site of V-ATPase activity.
Supporting Evidence:
PMID:22053050
the v-ATPase engages in extensive amino acid-sensitive interactions with the Ragulator, a scaffolding complex that anchors the Rag GTPases to the lysosome.
GO:0046611 lysosomal proton-transporting V-type ATPase complex
IDA
PMID:22053050
mTORC1 senses lysosomal amino acids through an inside-out me... 		ACCEPT
Summary: IDA from the Zoncu et al. (2011) study demonstrating V-ATPase complex on lysosomes; E1 subunit is part of this complex.
Reason: Well-supported by multiple evidence types.
Supporting Evidence:
PMID:22053050
the v-ATPase engages in extensive amino acid-sensitive interactions with the Ragulator, a scaffolding complex that anchors the Rag GTPases to the lysosome.
GO:0071230 cellular response to amino acid stimulus
IDA
PMID:22053050
mTORC1 senses lysosomal amino acids through an inside-out me... 		KEEP AS NON CORE
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.
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.
Supporting Evidence:
PMID:22053050
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.
GO:0160124 guanyl nucleotide exchange factor activator activity
IDA
PMID:22053050
mTORC1 senses lysosomal amino acids through an inside-out me... 		KEEP AS NON CORE
Summary: The V-ATPase complex contributes to GEF activator activity in mTORC1 signaling. V-ATPase activity facilitates Ragulator-mediated GEF activation of Rag GTPases.
Reason: This secondary function in mTORC1 signaling is genuine but not the primary role of V-ATPase or subunit E1.
Supporting Evidence:
PMID:22053050
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.
GO:1904263 positive regulation of TORC1 signaling
IDA
PMID:22053050
mTORC1 senses lysosomal amino acids through an inside-out me... 		KEEP AS NON CORE
Summary: V-ATPase is required for mTORC1 activation by amino acids.
Reason: Secondary function of V-ATPase in mTORC1 signaling; not the primary proton pump role.
GO:0016324 apical plasma membrane
EXP
PMID:29993276
H(+)-ATPase B1 subunit localizes to thick ascending limb and... 		ACCEPT
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.
Reason: Experimentally confirmed apical membrane localization in kidney is well-supported and biologically meaningful for renal acid-base homeostasis.
Supporting Evidence:
PMID:29993276
H(+)-ATPase B1 subunit localizes to thick ascending limb and distal convoluted tubule of rodent and human kidney.
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 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.
Reason: The cryo-EM structures directly confirmed the position of subunit E in the V1 domain. This is core complex membership.
Supporting Evidence:
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.
GO:0016241 regulation of macroautophagy
NAS
PMID:22982048
Lipofuscin is formed independently of macroautophagy and lys... 		MARK AS OVER ANNOTATED
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.
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.
GO:0070062 extracellular exosome
HDA
PMID:19199708
Proteomic analysis of human parotid gland exosomes by multid... 		MARK AS OVER ANNOTATED
Summary: High-throughput proteomics detection in parotid gland exosomes. Likely reflects membrane co-purification rather than a specific exosome function.
Reason: Exosome detection by proteomics is likely artifactual for a lysosomal V-ATPase subunit. Not informative for core function.
GO:0070062 extracellular exosome
HDA
PMID:19056867
Large-scale proteomics and phosphoproteomics of urinary exos... 		MARK AS OVER ANNOTATED
Summary: High-throughput proteomics detection in urinary exosomes.
Reason: Same reasoning as parotid gland exosome annotation. Not informative.
GO:0005765 lysosomal membrane
HDA
PMID:17897319
Integral and associated lysosomal membrane proteins. 		ACCEPT
Summary: Lysosomal membrane proteomics study detected ATP6V1E1. Confirms lysosomal membrane localization.
Reason: Direct proteomics evidence for lysosomal membrane localization is consistent with established V-ATPase biology.
GO:0051117 ATPase binding
IPI
PMID:20717956
Rab11b and its effector Rip11 regulate the acidosis-induced ... 		KEEP AS NON CORE
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).
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.
GO:0005829 cytosol
TAS
Reactome:R-HSA-1222516 		KEEP AS NON CORE
Summary: Reactome TAS annotation. The V1 peripheral sector can dissociate from V0 and exist as a soluble cytoplasmic complex during regulated disassembly.
Reason: V1 domain can be in cytosol during regulated disassembly; consistent with V-ATPase regulation biology.
GO:0005829 cytosol
TAS
Reactome:R-HSA-5252133 		KEEP AS NON CORE
Summary: Reactome TAS annotation for cytosol.
Reason: Consistent with V1 domain biology.
GO:0005829 cytosol
TAS
Reactome:R-HSA-74723 		KEEP AS NON CORE
Summary: Reactome TAS annotation for cytosol.
Reason: Consistent.
GO:0005829 cytosol
TAS
Reactome:R-HSA-917841 		KEEP AS NON CORE
Summary: Reactome TAS annotation for cytosol.
Reason: Consistent.
GO:0005829 cytosol
TAS
Reactome:R-HSA-9639286 		KEEP AS NON CORE
Summary: Reactome TAS annotation for cytosol.
Reason: Consistent.
GO:0005829 cytosol
TAS
Reactome:R-HSA-9640167 		KEEP AS NON CORE
Summary: Reactome TAS annotation for cytosol.
Reason: Consistent.
GO:0005829 cytosol
TAS
Reactome:R-HSA-9640168 		KEEP AS NON CORE
Summary: Reactome TAS annotation for cytosol.
Reason: Consistent.
GO:0005829 cytosol
TAS
Reactome:R-HSA-9640175 		KEEP AS NON CORE
Summary: Reactome TAS annotation for cytosol.
Reason: Consistent.
GO:0005829 cytosol
TAS
Reactome:R-HSA-9640195 		KEEP AS NON CORE
Summary: Reactome TAS annotation for cytosol.
Reason: Consistent.
GO:0005829 cytosol
TAS
Reactome:R-HSA-9645598 		KEEP AS NON CORE
Summary: Reactome TAS annotation for cytosol.
Reason: Consistent.
GO:0005829 cytosol
TAS
Reactome:R-HSA-9645608 		KEEP AS NON CORE
Summary: Reactome TAS annotation for cytosol.
Reason: Consistent.
GO:0005829 cytosol
TAS
Reactome:R-HSA-9646468 		KEEP AS NON CORE
Summary: Reactome TAS annotation for cytosol.
Reason: Consistent.
GO:0005829 cytosol
TAS
Reactome:R-HSA-9858923 		KEEP AS NON CORE
Summary: Reactome TAS annotation for cytosol in MITF/lysosome biogenesis context.
Reason: Consistent; relevant to MITF-regulated expression of ATP6V1E1 for lysosome biogenesis.
GO:0005515 protein binding
IPI
PMID:21784977
Zinc finger protein tristetraprolin interacts with CCL3 mRNA... 		REMOVE
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.
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.
GO:0005515 protein binding
IPI
PMID:11399750
Interaction between aldolase and vacuolar H+-ATPase: evidenc... 		MARK AS OVER ANNOTATED
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.
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.
Supporting Evidence:
PMID:11399750
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.
GO:0005768 endosome
ISS
GO_REF:0000024 		ACCEPT
Summary: Ortholog-based annotation for endosome localization. V-ATPase acidifies endosomes in the endocytic pathway.
Reason: Endosome localization is consistent with V-ATPase biology and the more specific endosome membrane annotation.
GO:0005829 cytosol
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Ortholog-based annotation for cytosol localization.
Reason: Consistent with V1 domain regulated disassembly biology.
GO:0016324 apical plasma membrane
ISS
GO_REF:0000024 		ACCEPT
Summary: Ortholog-based annotation for apical plasma membrane, consistent with the EXP evidence from PMID:29993276.
Reason: Consistent with experimental evidence for kidney apical membrane localization.
GO:0016469 proton-transporting two-sector ATPase complex
TAS
PMID:8250920
Cloning and tissue distribution of subunits C, D, and E of t... 		ACCEPT
Summary: TAS from the original cloning paper (van Hille et al. 1993). Subunit E is part of the proton-transporting V-type ATPase complex.
Reason: Historically supported complex membership confirmed by subsequent structural studies.
Supporting Evidence:
PMID:8250920
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.
GO:1902600 proton transmembrane transport
TAS
PMID:8250920
Cloning and tissue distribution of subunits C, D, and E of t... 		ACCEPT
Summary: TAS from the original cloning paper.
Reason: Historically supported core function.

Core Functions

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.

Directly Involved In:
proton transmembrane transport
Cellular Locations:
lysosomal membrane
Supporting Evidence:
  • 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.

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:
proton transmembrane transport
Cellular Locations:
apical plasma membrane
Supporting Evidence:
  • PMID:29993276
    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.

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:
proton transmembrane transport
Supporting Evidence:
  • PMID:11399750
    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,

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000024
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000044
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
PMID:11399750
Interaction between aldolase and vacuolar H+-ATPase: evidence for direct coupling of glycolysis to the ATP-hydrolyzing proton pump.
  • 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.
PMID:16169070
A human protein-protein interaction network: a resource for annotating the proteome.
  • ATP6V1E1 detected in high-throughput interactome study.
PMID:17897319
Integral and associated lysosomal membrane proteins.
  • ATP6V1E1 detected in lysosomal membrane proteomics study.
PMID:19056867
Large-scale proteomics and phosphoproteomics of urinary exosomes.
  • ATP6V1E1 detected in urinary exosomes by mass spectrometry.
PMID:19199708
Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT).
  • ATP6V1E1 detected in parotid gland exosome proteome.
PMID:20717956
Rab11b and its effector Rip11 regulate the acidosis-induced traffic of V-ATPase in salivary ducts.
  • V-ATPase E subunit interacts with RAB11B; RAB11B/Rip11 regulate acidosis-induced trafficking of V-ATPase to apical membrane in salivary duct cells.
PMID:21784977
Zinc finger protein tristetraprolin interacts with CCL3 mRNA and regulates tissue inflammation.
  • Paper concerns tristetraprolin/CCL3 mRNA regulation; no evidence for ATP6V1E1 involvement. Annotation likely a curation error.
PMID:22053050
mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase.
  • V-ATPase V1 domain (including E subunit) interacts with Ragulator on lysosomes; V-ATPase ATP hydrolysis required for amino acid-induced mTORC1 activation.
PMID:22982048
Lipofuscin is formed independently of macroautophagy and lysosomal activity in stress-induced prematurely senescent human fibroblasts.
  • V-ATPase broadly required for lysosomal-mediated macroautophagy.
PMID:28065471
Mutations in ATP6V1E1 or ATP6V1A cause autosomal-recessive cutis laxa.
  • 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.
PMID:29993276
H(+)-ATPase B1 subunit localizes to thick ascending limb and distal convoluted tubule of rodent and human kidney.
  • V-ATPase (including E subunit) localizes to apical membrane of thick ascending limb and distal convoluted tubule in human kidney.
PMID:32001091
Structure and Roles of V-type ATPases.
  • Comprehensive review of V-ATPase structure, roles in organellar acidification, and disease relevance.
PMID:33065002
Structures of a Complete Human V-ATPase Reveal Mechanisms of Its Assembly.
  • Cryo-EM structures of complete human V-ATPase; E1 subunit resolved in three peripheral stalk EG heterodimers at near-atomic resolution.
PMID:35271311
OpenCell: Endogenous tagging for the cartography of human cellular organization.
  • ATP6V1E1 localization mapped by endogenous tagging.
PMID:8250920
Cloning and tissue distribution of subunits C, D, and E of the human vacuolar H(+)-ATPase.
  • Human V-ATPase E subunit cloned from osteoclastoma; ubiquitous expression; part of the proton-transporting V-type ATPase complex.
Reactome:R-HSA-1222516
Intraphagosomal pH is lowered to 5 by V-ATPase
Reactome:R-HSA-5252133
ATP6AP1 binds V-ATPase
Reactome:R-HSA-74723
Endosome acidification
Reactome:R-HSA-917841
Acidification of Tf:TfR1 containing endosome
Reactome:R-HSA-9639286
RRAGC,D exchanges GTP for GDP
Reactome:R-HSA-9640167
RRAGA,B exchanges GDP for GTP
Reactome:R-HSA-9640168
v-ATPase:Ragulator:RRAGA,B:GTP:RRAGC,D:GDP:SLC38A9:Arginine dissociates yielding v-ATPase:Ragulator:RRAGA,B:GTP:RRAGC,D:GDP and SLC38A9:Arginine
Reactome:R-HSA-9640175
v-ATPase:Ragulator:RagA,B:GDP:RagC,D:GDP binds SLC38A9:Arginine
Reactome:R-HSA-9640195
RRAGA,B hydrolyzes GTP
Reactome:R-HSA-9645598
RRAGC,D hydrolyzes GTP
Reactome:R-HSA-9645608
v-ATPase:Ragulator:RRAGA,B:GTP:RRAGC,D:GDP binds mTORC1
Reactome:R-HSA-9646468
mTORC1 binds RHEB:GTP
Reactome:R-HSA-9858923
MITF-M-dependent ATP6V1E1 gene expression
  • MITF-M transcription factor regulates ATP6V1E1 expression in the context of lysosome biogenesis.

Suggested Questions for Experts

Q: 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?

Q: Does the aldolase-E subunit interaction regulate V-ATPase activity dynamically in response to metabolic state? Are there conditions where this coupling is disrupted?

Q: Do the three alternatively spliced isoforms of ATP6V1E1 differ in their V-ATPase complex incorporation efficiency or their subcellular targeting?

Suggested Experiments

Experiment: Cryo-EM structure determination of V-ATPase containing ATP6V1E1 variants P128L and R212W to determine how they disrupt peripheral stalk integrity and complex assembly.

Hypothesis: ATP6V1E1 cutis laxa variants (P128, W212) destabilize peripheral stalk contacts with V1 A/B subunits.

Type: structural biology

Experiment: 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.

Hypothesis: Aldolase binding to the V-ATPase E subunit dynamically modulates V-ATPase assembly or activity in response to glycolytic flux.

Type: in vitro biochemical assay

Experiment: Comparative proteomics of V-ATPase complexes immunoprecipitated with isoform-specific antibodies to determine if isoform switching affects subunit composition or organelle targeting.

Hypothesis: ATP6V1E1 isoforms differ in V-ATPase complex incorporation or subcellular targeting.

Type: immunoprecipitation proteomics

Deep Research

Falcon

(ATP6V1E1-deep-research-falcon.md)
Comprehensive Research Report: ATP6V1E1 (V-type Proton ATPase Subunit E1) Falcon

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Comprehensive Research Report: ATP6V1E1 (V-type Proton ATPase Subunit E1)

Gene and Protein Identity

ATP6V1E1 (UniProt: P36543) encodes the E1 subunit of the V-type proton ATPase (V-ATPase) in Homo sapiens, a member of the V-ATPase E subunit family containing the vATP-synt_E domain (pottie2021lossofzebrafish pages 1-2). This gene product is an essential component of the vacuolar-type H+-ATPase, a large multisubunit protein complex that functions as an ATP-driven rotary proton pump (chen2024vatpaseincancer pages 1-3, falace2024vatpasedysfunctionin pages 1-3).

Molecular Structure and Function of V-ATPase

Overall Architecture

The V-ATPase is composed of two main domains: the cytosolic V1 domain and the membrane-embedded V0 domain (chen2024vatpaseincancer pages 1-3, eaton2021theh+atpase(vatpase) pages 1-5). The V1 domain consists of eight subunits arranged as A3B3CDE3FG3H, where subunits A and B form a catalytic hexamer responsible for ATP hydrolysis (chen2024vatpaseincancer pages 1-3, chen2022thevatpasesin pages 1-2). The V0 domain, comprising subunits a, c, d, and e, is responsible for proton translocation across the membrane (chen2024vatpaseincancer pages 1-3, abbas2020structureofvatpase pages 1-2).

Role of the E Subunit in V-ATPase Structure

ATP6V1E1 encodes one of three copies of the E subunit present in the V1 domain (chen2024vatpaseincancer pages 1-3). The E subunits form heterodimers with G subunits (E:G), creating three peripheral stalk structures that connect the V1 and V0 domains (chen2024vatpaseincancer pages 1-3, vasanthakumar2019structuralcomparisonof pages 1-2, colinatenorio2018theperipheralstalk pages 1-2). These peripheral stalks serve as stators—structural elements that counteract the rotational torque generated during ATP hydrolysis, preventing the catalytic A3B3 hexamer from rotating along with the central rotor complex (wang2020structuresofa pages 1-3, colinatenorio2018theperipheralstalk pages 1-2, colinatenorio2018theperipheralstalk pages 2-3).

The peripheral stalks exhibit right-handed coiling of their helices, which provides rigidity in the direction of rotation while allowing flexibility perpendicular to accommodate conformational changes in the catalytic core (colinatenorio2018theperipheralstalk pages 1-2, colinatenorio2018theperipheralstalk pages 2-3). This structural arrangement is essential for efficient mechanochemical coupling—linking ATP hydrolysis in the V1 domain to proton translocation through the V0 domain (chen2024vatpaseincancer pages 1-3, vasanthakumar2019structuralcomparisonof pages 1-2).

Catalytic Mechanism

While ATP6V1E1 itself does not directly hydrolyze ATP, it is indispensable for the overall function of the V-ATPase complex (chen2024vatpaseincancer pages 1-3). ATP hydrolysis occurs at the interfaces between A and B subunits in the A3B3 hexamer (chen2022thevatpasesin pages 1-2). The energy released drives rotation of a central stalk complex (comprising D, F, and d subunits), which is connected to a ring of c subunits (the c-ring) in the V0 domain (chen2024vatpaseincancer pages 1-3, abbas2020structureofvatpase pages 1-2, colinatenorio2018theperipheralstalk pages 1-2). This rotation drives proton translocation through hemichannels in subunit a, creating an electrochemical proton gradient across the membrane (abbas2020structureofvatpase pages 1-2, indrawinata2023structuralandfunctional pages 1-2).

The peripheral stalks formed by E:G heterodimers are crucial for coupling this rotary mechanism, as they prevent dissipation of the torque by holding the catalytic domain stationary relative to the rotating central stalk (chen2024vatpaseincancer pages 1-3, colinatenorio2018theperipheralstalk pages 1-2). Without functional E subunits, the coupling between ATP hydrolysis and proton pumping would be compromised.

Subcellular Localization

ATP6V1E1 is localized to multiple intracellular membrane compartments as an integral component of V-ATPase complexes (pottie2021lossofzebrafish pages 1-2, eaton2021theh+atpase(vatpase) pages 1-5). Primary sites of function include:

  1. Lysosomes: V-ATPases maintain the acidic pH (approximately 4.5-5.0) required for hydrolytic enzyme activity and degradation of macromolecules (falace2024vatpasedysfunctionin pages 1-3, eaton2021theh+atpase(vatpase) pages 1-5, chen2022thevatpasesin pages 1-2, ye2023tauoverloadassociated pages 1-5).

  2. Endosomes: V-ATPases acidify early and late endosomes, supporting receptor-mediated endocytosis, protein sorting, and membrane trafficking (pottie2021lossofzebrafish pages 1-2, eaton2021theh+atpase(vatpase) pages 1-5, pottie2021lossofzebrafish pages 5-7).

  3. Golgi apparatus and trans-Golgi network: V-ATPases regulate pH in the Golgi, which is critical for proper function of glycosyltransferases and other enzymes involved in protein modification and glycosylation (pottie2021lossofzebrafish pages 1-2, vogt2021expandingtheclinical pages 1-5, pottie2021lossofzebrafish pages 5-7, pottie2021lossofzebrafish pages 3-5, hu2024correlationbetweeninitial pages 1-2).

  4. Secretory vesicles and synaptic vesicles: In neurons, V-ATPases create the proton gradient necessary for neurotransmitter loading into synaptic vesicles (abbas2020structureofvatpase pages 1-2, eaton2021theh+atpase(vatpase) pages 1-5).

  5. Plasma membrane (specialized cells): In certain cell types such as osteoclasts and renal intercalated cells, V-ATPases localize to the plasma membrane to acidify the extracellular environment (chen2024vatpaseincancer pages 1-3, eaton2021theh+atpase(vatpase) pages 1-5).

Biological Processes and Signaling Pathways

pH Homeostasis and Organelle Acidification

The primary function of ATP6V1E1-containing V-ATPases is to establish and maintain pH gradients across cellular membranes (chen2024vatpaseincancer pages 1-3, falace2024vatpasedysfunctionin pages 1-3, eaton2021theh+atpase(vatpase) pages 1-5). This acidification is fundamental to numerous cellular processes:

  • Lysosomal degradation: The acidic pH activates hydrolytic enzymes (cathepsins, proteases, lipases, nucleases) that degrade cellular waste, damaged organelles, and engulfed pathogens (falace2024vatpasedysfunctionin pages 1-3, chen2022thevatpasesin pages 1-2, ye2023tauoverloadassociated pages 1-5).

  • Autophagy: V-ATPase-mediated acidification is essential for autophagosome-lysosome fusion and subsequent degradation of autophagosomal contents (falace2024vatpasedysfunctionin pages 1-3, indrawinata2023structuralandfunctional pages 1-2, chen2022thevatpasesin pages 1-2, ye2023tauoverloadassociated pages 1-5).

  • Endocytic trafficking: Acidification of endosomal compartments regulates receptor recycling, protein sorting, and cargo delivery (pottie2021lossofzebrafish pages 1-2, eaton2021theh+atpase(vatpase) pages 1-5, pottie2021lossofzebrafish pages 5-7).

Golgi Function and Glycosylation

V-ATPases play a critical role in maintaining the appropriate pH gradient across the Golgi apparatus, which is essential for the activity of glycosyltransferases and other modifying enzymes (pottie2021lossofzebrafish pages 1-2, vogt2021expandingtheclinical pages 1-5, pottie2021lossofzebrafish pages 5-7, hu2024correlationbetweeninitial pages 1-2). Loss of ATP6V1E1 function leads to:

  • Golgi fragmentation and dilation (pottie2021lossofzebrafish pages 1-2, pottie2021lossofzebrafish pages 5-7)
  • Altered N-glycosylation patterns, including increased oligomannose glycans (pottie2021lossofzebrafish pages 1-2, pottie2021lossofzebrafish pages 5-7, pottie2021lossofzebrafish pages 3-5)
  • Impaired protein trafficking and secretion (pottie2021lossofzebrafish pages 1-2, vogt2021expandingtheclinical pages 1-5, pottie2021lossofzebrafish pages 3-5)
  • Delayed Brefeldin A-induced retrograde transport (pottie2021lossofzebrafish pages 1-2, vogt2021expandingtheclinical pages 1-5)

These glycosylation defects have been documented in both human patients with ATP6V1E1 mutations and zebrafish atp6v1e1b knockout models (pottie2021lossofzebrafish pages 1-2, pottie2021lossofzebrafish pages 5-7, pottie2021lossofzebrafish pages 3-5).

Signaling Pathways

Beyond its role as a proton pump, V-ATPase serves as a signaling hub that interacts with multiple cellular pathways (falace2024vatpasedysfunctionin pages 1-3, eaton2021theh+atpase(vatpase) pages 1-5, wang2020structuresofa pages 1-3):

  1. mTORC1 signaling: V-ATPase interacts with the Ragulator-Rag GTPase complex on the lysosomal surface, playing a key role in amino acid sensing and mTORC1 activation (falace2024vatpasedysfunctionin pages 1-3, eaton2021theh+atpase(vatpase) pages 1-5, chen2022thevatpasesin pages 1-2, pottie2021lossofzebrafish pages 5-7). Loss of V-ATPase function disrupts mTORC1 signaling and affects downstream processes including cell growth, protein synthesis, and autophagy (falace2024vatpasedysfunctionin pages 1-3, pottie2021lossofzebrafish pages 5-7).

  2. Wnt signaling: V-ATPase components participate in Wnt pathway regulation, with disruption of V-ATPase function affecting Wnt-related processes (falace2024vatpasedysfunctionin pages 1-3, eaton2021theh+atpase(vatpase) pages 1-5, wang2020structuresofa pages 1-3, pottie2021lossofzebrafish pages 5-7).

  3. Notch signaling: V-ATPase has been implicated in Notch pathway regulation, contributing to cell differentiation and developmental processes (falace2024vatpasedysfunctionin pages 1-3, eaton2021theh+atpase(vatpase) pages 1-5).

  4. Neurotransmitter loading: In neurons, V-ATPase activity energizes synaptic vesicle membranes, providing the proton gradient necessary for neurotransmitter transporters to load neurotransmitters (glutamate, GABA, acetylcholine, monoamines) into vesicles (abbas2020structureofvatpase pages 1-2, eaton2021theh+atpase(vatpase) pages 1-5, indrawinata2023structuralandfunctional pages 1-2).

Experimental Evidence from Model Systems

Zebrafish Studies

Loss-of-function studies in zebrafish have provided extensive insights into ATP6V1E1 function. Knockout of atp6v1e1b (one of two zebrafish paralogs) resulted in (pottie2021lossofzebrafish pages 1-2, pottie2021lossofzebrafish pages 5-7, pottie2021lossofzebrafish pages 3-5):

  • Early lethality: Mutant larvae died at 3-5 days post-fertilization and were unable to hatch without manual chorion removal
  • Hypotonia: Impaired touch-evoked escape response, indicating muscular weakness
  • Craniofacial abnormalities: Maxillary and mandibular hypoplasia, shortened Meckel's cartilage, palatoquadrate, and ceratohyal structures
  • Cardiovascular defects: Vascular malformations, decreased stroke volume and cardiac output, pericardial edema, and dilated ventral aorta
  • Connective tissue defects: Epidermal detachment, disorganized collagen fibrils, folded basement membranes, and altered collagen and elastin expression
  • Glycosylation abnormalities: Increased oligomannose N-glycans (particularly Man9) and altered complex glycan profiles
  • Golgi dysfunction: Golgi dilation and fragmentation observed by transmission electron microscopy
  • Endolysosomal alterations: Increased early endosomal markers (EEA1, Rab5), altered late endosomal markers (Rab7), reduced lysosomal acidification (by LysoTracker staining), and perturbed LAMP1 expression
  • Pathway dysregulation: Altered mTOR and Wnt signaling pathways

These phenotypes closely recapitulate features of human autosomal recessive cutis laxa type 2C (ARCL2C), demonstrating evolutionary conservation of ATP6V1E1 function (pottie2021lossofzebrafish pages 1-2, pottie2021lossofzebrafish pages 5-7, pottie2021lossofzebrafish pages 3-5).

Cell Culture Studies

Studies in human cells have further elucidated ATP6V1E1 function (ye2023tauoverloadassociated pages 1-5):

  • In tau-overloaded cells, increased levels of V-ATPase subunits including ATP6V1E1 were detected, but V-ATPase assembly on lysosomal membranes was impaired due to abnormal binding of tau protein to ATP6V1B2 subunit (ye2023tauoverloadassociated pages 1-5)
  • This resulted in lysosomal deacidification (elevated pH), accumulation of undegraded material, and reduced hydrolytic activity (ye2023tauoverloadassociated pages 1-5)
  • Loss of V-ATPase function in various cell models leads to impaired autophagy, accumulation of autophagosomes, and cellular dysfunction (falace2024vatpasedysfunctionin pages 1-3, indrawinata2023structuralandfunctional pages 1-2, chen2022thevatpasesin pages 1-2, ye2023tauoverloadassociated pages 1-5)

Human Disease: Autosomal Recessive Cutis Laxa Type 2C (ARCL2C)

Biallelic pathogenic variants in ATP6V1E1 cause ARCL2C (OMIM #219150), a metabolic cutis laxa syndrome characterized by (pottie2021lossofzebrafish pages 1-2, vogt2021expandingtheclinical pages 1-5):

Clinical Features

  • Cutis laxa: Wrinkled or loose redundant skin folds, leading to a progeroid appearance
  • Craniofacial dysmorphism: Midface hypoplasia, micrognathia, triangular facial features
  • Connective tissue abnormalities: Reduced dermal elastic fibers, abnormal collagen structure
  • Hypotonia: Muscular weakness and reduced muscle tone
  • Cardiac abnormalities: Structural heart defects and cardiovascular dysfunction
  • Vascular anomalies: Vascular malformations and dilated vessels
  • Glycosylation defects: Abnormal N-glycosylation patterns detectable in serum transferrin analysis
  • Variable neurological manifestations: Some patients exhibit developmental delays or seizures

Molecular Mechanisms

At the cellular level, ATP6V1E1 deficiency causes (pottie2021lossofzebrafish pages 1-2, vogt2021expandingtheclinical pages 1-5, pottie2021lossofzebrafish pages 5-7):

  • Golgi fragmentation: Disruption of normal Golgi apparatus structure
  • Impaired protein glycosylation: Altered glycosyltransferase activity due to perturbed Golgi pH
  • Defective protein trafficking: Delayed retrograde transport and secretory pathway dysfunction
  • Endolysosomal dysfunction: Impaired acidification leading to accumulation of undegraded substrates
  • Disrupted autophagy: Failure of autophagic flux contributes to cellular stress
  • Mitochondrial defects: Secondary effects on oxidative phosphorylation and energy metabolism have been reported in some models (pottie2021lossofzebrafish pages 1-2)

The severity and specific manifestations can vary depending on the nature of the pathogenic variants, with some patients surviving into adolescence with mild intellectual disability while others experience early infant mortality (pottie2021lossofzebrafish pages 1-2, vogt2021expandingtheclinical pages 1-5).

Broader Context: V-ATPase in Human Disease

Beyond ARCL2C, dysfunction of other V-ATPase subunits is associated with multiple human disorders (falace2024vatpasedysfunctionin pages 1-3, indrawinata2023structuralandfunctional pages 1-2, falace2024vatpasedysfunctionin pages 3-4):

  • Neurological diseases: Mutations in ATP6V0A1, ATP6V0C, ATP6V1B2, and ATP6V1A cause developmental and epileptic encephalopathies, progressive myoclonus epilepsy, and neurodegenerative conditions (falace2024vatpasedysfunctionin pages 1-3, indrawinata2023structuralandfunctional pages 1-2, falace2024vatpasedysfunctionin pages 3-4)
  • Osteopetrosis: Loss of the a3 isoform (TCIRG1/ATP6V0A3) impairs osteoclast function and bone resorption (chen2024vatpaseincancer pages 1-3, eaton2021theh+atpase(vatpase) pages 1-5)
  • Renal tubular acidosis: Mutations affecting kidney-specific V-ATPase subunits disrupt acid secretion (chen2024vatpaseincancer pages 1-3, eaton2021theh+atpase(vatpase) pages 1-5)
  • Cancer: Upregulation and altered localization of V-ATPase subunits promote tumor cell survival, invasion, metastasis, and drug resistance by modulating tumor microenvironment pH (chen2024vatpaseincancer pages 1-3, chen2022thevatpasesin pages 1-2)
  • Alzheimer's disease: V-ATPase dysfunction and lysosomal deacidification have been implicated in neurodegenerative processes (ye2023tauoverloadassociated pages 1-5)
  • IgA nephropathy: Altered urinary levels of ATP6V1A and ATP6V1E1 have been reported as potential biomarkers (hu2024correlationbetweeninitial pages 1-2)

These findings underscore the fundamental importance of V-ATPase function across multiple organ systems and highlight the diverse pathological consequences of its dysfunction (falace2024vatpasedysfunctionin pages 1-3, eaton2021theh+atpase(vatpase) pages 1-5, indrawinata2023structuralandfunctional pages 1-2, falace2024vatpasedysfunctionin pages 3-4).

Summary

Gene name Protein name UniProt ID Molecular function Structural role in V-ATPase complex Subcellular localization Biological processes / pathways Human disease associations Key phenotypes from loss-of-function studies
ATP6V1E1 V-type proton ATPase subunit E1 P36543 Encodes the E1 subunit of the cytosolic V1 sector of vacuolar-type H+-ATPase (V-ATPase), an ATP-driven rotary proton pump. The holoenzyme uses ATP hydrolysis in V1 to drive proton translocation through V0, thereby acidifying intracellular compartments and, in specialized cells, extracellular spaces. ATP6V1E1 itself is not the catalytic ATP-hydrolyzing subunit; instead it is required for assembly/coupling of the active complex (chen2024vatpaseincancer pages 1-3, falace2024vatpasedysfunctionin pages 1-3, eaton2021theh+atpase(vatpase) pages 1-5, chen2022thevatpasesin pages 1-2). E subunits form part of the three peripheral stalks of V-ATPase as E:G heterodimers. These stalks act as stators that connect V1 to V0, counteracting torque and preventing co-rotation of the catalytic A3B3 head during ATP hydrolysis, thereby enabling efficient coupling of ATP hydrolysis to proton pumping (chen2024vatpaseincancer pages 1-3, wang2020structuresofa pages 1-3, vasanthakumar2019structuralcomparisonof pages 1-2, colinatenorio2018theperipheralstalk pages 1-2, colinatenorio2018theperipheralstalk pages 2-3). As a component of V-ATPase complexes, ATP6V1E1 functions on endomembrane organelles including lysosomes, endosomes, Golgi/trans-Golgi network, secretory vesicles, and synaptic vesicles; V-ATPases can also localize to the plasma membrane of specialized cells such as osteoclasts and renal intercalated cells (pottie2021lossofzebrafish pages 1-2, abbas2020structureofvatpase pages 1-2, eaton2021theh+atpase(vatpase) pages 1-5, indrawinata2023structuralandfunctional pages 1-2). Required for organelle acidification, lysosomal degradation, autophagy, endocytic trafficking, protein maturation/degradation, Golgi pH control and glycosylation, synaptic vesicle neurotransmitter loading, and signaling functions linked to mTORC1, Wnt, and Notch pathways through V-ATPase-dependent membrane signaling hubs (falace2024vatpasedysfunctionin pages 1-3, eaton2021theh+atpase(vatpase) pages 1-5, indrawinata2023structuralandfunctional pages 1-2, wang2020structuresofa pages 1-3, chen2022thevatpasesin pages 1-2, falace2024vatpasedysfunctionin pages 3-4). Biallelic pathogenic variants in ATP6V1E1 cause autosomal recessive cutis laxa type 2C (ARCL2C), a multisystem disorder associated with wrinkled/loose skin, connective tissue abnormalities, craniofacial dysmorphism, hypotonia, cardiac and vascular involvement, and abnormal glycosylation/Golgi dysfunction. V-ATPase dysfunction more broadly is implicated in neurological and other human diseases (pottie2021lossofzebrafish pages 1-2, vogt2021expandingtheclinical pages 1-5, falace2024vatpasedysfunctionin pages 3-4, hu2024correlationbetweeninitial pages 1-2). In zebrafish atp6v1e1b deficiency, loss of function caused early mortality, impaired hatching, hypotonia, craniofacial defects, vascular malformations, reduced stroke volume/cardiac output, pericardial edema, epidermal/basement membrane defects, disorganized collagen/elastin expression, Golgi dilation/fragmentation, N-glycosylation abnormalities, altered endosomal/lysosomal markers, reduced LysoTracker acidification, and disturbed mTOR/Wnt-related pathways. These phenotypes recapitulate key features of human ARCL2C and support ATP6V1E1's essential role in endolysosomal acidification and Golgi homeostasis (pottie2021lossofzebrafish pages 1-2, pottie2021lossofzebrafish pages 5-7, pottie2021lossofzebrafish pages 3-5).

Table: This table compiles core functional annotation for human ATP6V1E1, including its identity, role in the V-ATPase complex, localization, pathways, disease relevance, and loss-of-function phenotypes. It is useful as a concise evidence-backed reference for interpreting ATP6V1E1 biology and pathogenicity.

ATP6V1E1 encodes an essential structural component of the V-ATPase proton pump. As part of the peripheral stalk structures, the E subunit plays a critical role in coupling ATP hydrolysis to proton translocation, enabling the V-ATPase to acidify intracellular organelles and maintain cellular pH homeostasis. This function is fundamental to lysosomal degradation, autophagy, endocytic trafficking, Golgi-mediated protein processing and glycosylation, and various signaling pathways including mTORC1, Wnt, and Notch. Loss of ATP6V1E1 function causes autosomal recessive cutis laxa type 2C, a multisystem disorder characterized by connective tissue abnormalities, glycosylation defects, and variable systemic manifestations. The phenotypic consequences of ATP6V1E1 deficiency, as demonstrated in zebrafish models and human patients, underscore the indispensable role of V-ATPase-mediated acidification in embryonic development, tissue homeostasis, and cellular function (chen2024vatpaseincancer pages 1-3, falace2024vatpasedysfunctionin pages 1-3, pottie2021lossofzebrafish pages 1-2, eaton2021theh+atpase(vatpase) pages 1-5, indrawinata2023structuralandfunctional pages 1-2, vogt2021expandingtheclinical pages 1-5, pottie2021lossofzebrafish pages 5-7, pottie2021lossofzebrafish pages 3-5).

References

  1. (pottie2021lossofzebrafish pages 1-2): Lore Pottie, Wouter Van Gool, Michiel Vanhooydonck, Franz-Georg Hanisch, Geert Goeminne, Andreja Rajkovic, Paul Coucke, Patrick Sips, and Bert Callewaert. Loss of zebrafish atp6v1e1b, encoding a subunit of vacuolar atpase, recapitulates human arcl type 2c syndrome and identifies multiple pathobiological signatures. Jun 2021. URL: https://doi.org/10.1371/journal.pgen.1009603, doi:10.1371/journal.pgen.1009603. This article has 10 citations and is from a domain leading peer-reviewed journal.

  2. (chen2024vatpaseincancer pages 1-3): Tingting Chen, Xiaotan Lin, Shuo Lu, and Bo Li. V-atpase in cancer: mechanistic insights and therapeutic potentials. Cell Communication and Signaling : CCS, Dec 2024. URL: https://doi.org/10.1186/s12964-024-01998-9, doi:10.1186/s12964-024-01998-9. This article has 25 citations.

  3. (falace2024vatpasedysfunctionin pages 1-3): Antonio Falace, Greta Volpedo, Marcello Scala, Federico Zara, Pasquale Striano, and Anna Fassio. V-atpase dysfunction in the brain: genetic insights and therapeutic opportunities. Cells, 13:1441, Aug 2024. URL: https://doi.org/10.3390/cells13171441, doi:10.3390/cells13171441. This article has 22 citations.

  4. (eaton2021theh+atpase(vatpase) pages 1-5): Amity F. Eaton, Maria Merkulova, and Dennis Brown. The h+-atpase (v-atpase): from proton pump to signaling complex in health and disease. Mar 2021. URL: https://doi.org/10.1152/ajpcell.00442.2020, doi:10.1152/ajpcell.00442.2020. This article has 188 citations.

  5. (chen2022thevatpasesin pages 1-2): Fangquan Chen, Rui Kang, Jiao Liu, and Daolin Tang. The v-atpases in cancer and cell death. Cancer Gene Therapy, 29:1529-1541, May 2022. URL: https://doi.org/10.1038/s41417-022-00477-y, doi:10.1038/s41417-022-00477-y. This article has 129 citations and is from a peer-reviewed journal.

  6. (abbas2020structureofvatpase pages 1-2): Yazan M. Abbas, Di Wu, Stephanie A. Bueler, Carol V. Robinson, and John L. Rubinstein. Structure of v-atpase from the mammalian brain. Mar 2020. URL: https://doi.org/10.1126/science.aaz2924, doi:10.1126/science.aaz2924. This article has 278 citations and is from a highest quality peer-reviewed journal.

  7. (vasanthakumar2019structuralcomparisonof pages 1-2): Thamiya Vasanthakumar, Stephanie A. Bueler, Di Wu, Victoria Beilsten-Edmands, Carol V. Robinson, and John L. Rubinstein. Structural comparison of the vacuolar and golgi v-atpases from saccharomyces cerevisiae. Proceedings of the National Academy of Sciences, 116:7272-7277, Mar 2019. URL: https://doi.org/10.1073/pnas.1814818116, doi:10.1073/pnas.1814818116. This article has 97 citations and is from a highest quality peer-reviewed journal.

  8. (colinatenorio2018theperipheralstalk pages 1-2): Lilia Colina-Tenorio, Alain Dautant, Héctor Miranda-Astudillo, Marie-France Giraud, and Diego González-Halphen. The peripheral stalk of rotary atpases. Frontiers in Physiology, Sep 2018. URL: https://doi.org/10.3389/fphys.2018.01243, doi:10.3389/fphys.2018.01243. This article has 27 citations.

  9. (wang2020structuresofa pages 1-3): Longfei Wang, Di Wu, Carol V. Robinson, Hao Wu, and Tian-Min Fu. Structures of a complete human v-atpase reveal mechanisms of its assembly. Molecular Cell, 80:501-511.e3, Nov 2020. URL: https://doi.org/10.1016/j.molcel.2020.09.029, doi:10.1016/j.molcel.2020.09.029. This article has 184 citations and is from a highest quality peer-reviewed journal.

  10. (colinatenorio2018theperipheralstalk pages 2-3): Lilia Colina-Tenorio, Alain Dautant, Héctor Miranda-Astudillo, Marie-France Giraud, and Diego González-Halphen. The peripheral stalk of rotary atpases. Frontiers in Physiology, Sep 2018. URL: https://doi.org/10.3389/fphys.2018.01243, doi:10.3389/fphys.2018.01243. This article has 27 citations.

  11. (indrawinata2023structuralandfunctional pages 1-2): Karen Indrawinata, Peter Argiropoulos, and Shuzo Sugita. Structural and functional understanding of disease-associated mutations in v-atpase subunit a1 and other isoforms. Frontiers in Molecular Neuroscience, Jul 2023. URL: https://doi.org/10.3389/fnmol.2023.1135015, doi:10.3389/fnmol.2023.1135015. This article has 16 citations.

  12. (ye2023tauoverloadassociated pages 1-5): Chao-Yuan Ye, Peng Zeng, Yuan-Cheng Liu, Yan Shi, Gong-Ping Liu, Jian-Zhi Wang, Xin-Wen Zhou, and Qing Tian. Tau overload associated insufficient lysosomal hydrolysis activity through deacidification of lysosomes. Unknown journal, Aug 2023. URL: https://doi.org/10.21203/rs.3.rs-3294833/v1, doi:10.21203/rs.3.rs-3294833/v1.

  13. (pottie2021lossofzebrafish pages 5-7): Lore Pottie, Wouter Van Gool, Michiel Vanhooydonck, Franz-Georg Hanisch, Geert Goeminne, Andreja Rajkovic, Paul Coucke, Patrick Sips, and Bert Callewaert. Loss of zebrafish atp6v1e1b, encoding a subunit of vacuolar atpase, recapitulates human arcl type 2c syndrome and identifies multiple pathobiological signatures. Jun 2021. URL: https://doi.org/10.1371/journal.pgen.1009603, doi:10.1371/journal.pgen.1009603. This article has 10 citations and is from a domain leading peer-reviewed journal.

  14. (vogt2021expandingtheclinical pages 1-5): Guido Vogt, Naji El Choubassi, Ágnes Herczegfalvi, Heike Kölbel, Anja Lekaj, Ulrike Schara, Manuel Holtgrewe, Sabine Krause, Rita Horvath, Markus Schuelke, Christoph Hübner, Stefan Mundlos, Andreas Roos, Hanns Lochmüller, Veronika Karcagi, Uwe Kornak, and Björn Fischer‐Zirnsak. Expanding the clinical and molecular spectrum of atp6v1a related metabolic cutis laxa. Journal of Inherited Metabolic Disease, 44:972-986, Feb 2021. URL: https://doi.org/10.1002/jimd.12341, doi:10.1002/jimd.12341. This article has 12 citations and is from a peer-reviewed journal.

  15. (pottie2021lossofzebrafish pages 3-5): Lore Pottie, Wouter Van Gool, Michiel Vanhooydonck, Franz-Georg Hanisch, Geert Goeminne, Andreja Rajkovic, Paul Coucke, Patrick Sips, and Bert Callewaert. Loss of zebrafish atp6v1e1b, encoding a subunit of vacuolar atpase, recapitulates human arcl type 2c syndrome and identifies multiple pathobiological signatures. Jun 2021. URL: https://doi.org/10.1371/journal.pgen.1009603, doi:10.1371/journal.pgen.1009603. This article has 10 citations and is from a domain leading peer-reviewed journal.

  16. (hu2024correlationbetweeninitial pages 1-2): Lin Hu and Liang Peng. Correlation between initial urine v-atpase and pathological changes in iga nephropathy: implications for short-term outcomes. Journal of Medicine and Health Science, 2:126-131, Sep 2024. URL: https://doi.org/10.62517/jmhs.202405315, doi:10.62517/jmhs.202405315. This article has 0 citations.

  17. (falace2024vatpasedysfunctionin pages 3-4): Antonio Falace, Greta Volpedo, Marcello Scala, Federico Zara, Pasquale Striano, and Anna Fassio. V-atpase dysfunction in the brain: genetic insights and therapeutic opportunities. Cells, 13:1441, Aug 2024. URL: https://doi.org/10.3390/cells13171441, doi:10.3390/cells13171441. This article has 22 citations.

📚 Additional Documentation

Notes

(ATP6V1E1-notes.md)

ATP6V1E1 Research Notes

Gene Identity

  • UniProt: P36543 (VATE1_HUMAN)
  • Gene symbol: ATP6V1E1 (also known as ATP6E, ATP6E2)
  • Protein: V-type proton ATPase subunit E 1; 226 amino acids, ~26 kDa
  • Three isoforms from alternative splicing (P36543-1, P36543-2, P36543-3)

Core V-ATPase Biology

ATP6V1E1 encodes the E subunit of the V1 peripheral sector of the vacuolar-type H+-ATPase (V-ATPase). Subunit E, together with subunit G, forms the three peripheral stalks that hold the catalytic head fixed relative to the membrane-embedded V0 domain during rotation.

PMID:33065002

PMID:32001091

The E subunit structure has been resolved in the complete human V-ATPase cryo-EM structures (PDB: 6WLZ, 6WM2, 6WM3, 6WM4), confirming its position in three peripheral stalk EG heterodimers.

Interaction with Aldolase

Lu et al. (2001) identified aldolase (ALDOC) as a direct binding partner of the V-ATPase E subunit using yeast two-hybrid and confirmed it biochemically. This may couple glycolytic ATP supply to V-ATPase activity.

PMID:11399750

PMID:11399750

Interaction with RAB11B and Acidosis-Induced Trafficking

Oehlke et al. (2011) showed the E subunit interacts with RAB11B (Rab11b) and its effector Rip11, which regulate V-ATPase trafficking to the apical membrane of salivary duct cells under acidosis conditions.

[PMID:20717956 - abstract: "Rab11b and its effector Rip11 regulate the acidosis-induced traffic of V-ATPase in salivary ducts."]

Subcellular Localization

  • Primary: lysosomal membrane, as part of V-ATPase complex
  • Also: apical plasma membrane in kidney and salivary duct epithelial cells (important for urinary acidification / acid-base homeostasis)
  • Also: endosomes, clathrin-coated vesicle membrane, synaptic vesicle membrane

[PMID:29993276 - localization to apical membrane of thick ascending limb and distal convoluted tubule in kidney]

Role in mTORC1 Amino Acid Sensing

Like subunit D, subunit E is part of the V1 sector that interacts with the Ragulator complex on lysosomes to facilitate mTORC1 activation by amino acids.

PMID:22053050

Disease Association: Cutis Laxa (ARCL2C)

Loss-of-function variants in ATP6V1E1 cause autosomal recessive cutis laxa type 2C (ARCL2C; MIM:617402). Patients show congenital skin laxity, delayed fontanelle closure, facial dysmorphism, hypotonia, and cardiovascular involvement.

[PMID:28065471 - "Mutations in ATP6V1E1 or ATP6V1A cause autosomal-recessive cutis laxa."]

The variants Pro-128 and Trp-212 (substitution of normal residues) are causative. Disease phenotype reflects widespread V-ATPase dysfunction in connective tissue remodeling pathways.

Tissue Distribution

Ubiquitous expression (housekeeping); highest expression in skin; also present in kidney distal nephron (thick ascending limb and distal convoluted tubule). A testis-specific isoform exists (from separate gene ATP6V1E2).

[PMID:12036578 - "A human gene, ATP6E1, encoding a testis-specific isoform of H(+)-ATPase subunit E."]

Curation Notes

  • The "protein binding" annotations from interactome studies (IPI from PMID:16169070, PMID:35271311) are generic high-throughput entries; the most informative specific interaction is ATPase binding (GO:0051117) via interaction with RAB11B documented in PMID:20717956.
  • The PMID:21784977 "protein binding" annotation is suspicious for ATP6V1E1 — that paper concerns tristetraprolin (ZFP36) and CCL3 mRNA regulation, not V-ATPase; likely a curation error.
  • The apical plasma membrane annotation (EXP from PMID:29993276) is well-supported for kidney epithelium where V-ATPase functions in acid excretion.
  • Regulation of macroautophagy (NAS from PMID:22982048) is an indirect V-ATPase class effect; no specific evidence for subunit E in macroautophagy regulation beyond lysosomal acidification.

Falcon deep research synthesis (2026-06-21)

Falcon deep research has now completed (file:human/ATP6V1E1/ATP6V1E1-deep-research-falcon.md,
29 citations). It corroborates the E1 peripheral-stalk core and the ARCL2C
association documented above, and sharpens the disease mechanism; no change to calls.

  • Core confirmed. E1 forms the EG peripheral stalks (3 per V1) with subunit
    G, acting as a stator that holds the catalytic A3B3 head fixed against rotor
    torque — structural/regulatory, not catalytic. No change to calls.
  • ARCL2C mechanism sharpened (Pottie 2021; Vogt 2021). Biallelic ATP6V1E1
    variants cause autosomal-recessive cutis laxa type 2C through a
    Golgi-pH/glycosylation route: Golgi fragmentation, impaired N-glycosylation
    (abnormal serum transferrin / CDG-like), defective retrograde trafficking, and
    endolysosomal/autophagy dysfunction → connective-tissue (elastin/collagen),
    craniofacial, cardiac and neurological features. This links E1 loss to the same
    secretory-pathway-acidification → glycosylation theme seen for ATP6AP1/ATP6V1A,
    reinforcing the Golgi-acidification contribution of V-ATPase. Disease context;
    the normal-function calls are unchanged.

Net: no change to calls — E1 is the peripheral-stalk (EG) stator subunit supporting
V-ATPase assembly/coupling and organellar (incl. Golgi) acidification.

Pn Notes

(ATP6V1E1-pn-notes.md)

ATP6V1E1 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: P36543
  • AIGR review status: COMPLETE
  • Review batch: proteostasis-batch-2026-06-06
  • Batch change status: added

Source Files Checked

Deep Research Files

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

AIGR Review Snapshot

  • 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.
  • Existing/core annotation action counts: ACCEPT: 16; KEEP_AS_NON_CORE: 20; MARK_AS_OVER_ANNOTATED: 6; REMOVE: 1

PN Consistency Summary

  • Consistency: Consistent. Notes ↔ review agree: E (with G) = peripheral-stalk stator; ALDOC/aldolase coupling (PMID:11399750); renal apical membrane (PMID:29993276, EXP/ACCEPT); ARCL2C disease (PMID:28065471); mTORC1 role as part of V1 (PMID:22053050, KEEP_AS_NON_CORE). PN's nutrient-sensing row is supported but appropriately non-core here. No PN/review contradiction.
  • PN story / NEW pressure: No unmet PN pressure; review exceeds PN (aldolase/glycolysis coupling, renal acid-base) without conflict. GO:0007042 absent from E1 GOA (dossier: new_to_goa; confirmed 0 hits) — defensible ADD. GO:0046612 (verified real, OLS) absent — defensible more-specific ADD. Notable internal QC: review flags PMID:21784977 protein-binding annotation as a curation error → REMOVE (tristetraprolin/CCL3 paper, no ATP6V1E1 content) — a real data-quality catch, independent of PN.
  • Evidence alignment: Minimal overlap. PN cites generic review titles; review anchors on E1-specific primaries: PMID:11399750 (aldolase), 20717956 (RAB11B trafficking), 28065471 (ARCL2C), 29993276 (renal), 8250920 (cloning), 33065002. PN evidence non-E1-specific.
  • Verdict: Consistent / ADD GO:0007042 + GO:0046612 (verified, new to E1 GOA); review also makes an unrelated REMOVE for a mis-attributed citation. Recommended edits: [MAP] consider subtype complex GO:0033176 → GO:0046611 (already ACCEPTed for E1) for specificity.

Full Consistency Review

  • UniProt: P36543 · batch: proteostasis-batch-2026-06-06 · review status: COMPLETE (large, mature; ~45 annotations, full core_functions; one REMOVE flagged)
  • PN placement: Autophagy-Lysosome Pathway|...|V1 lysosomal v-ATPase proton pump component (two rows, identical pattern) ; PN-node mapping: subtype=mapped/ok GO:0046612 + GO:0033176; type=mapped/ok GO:0007042; ancestors no_mapping/context_only.
  • Consistency: Consistent. Notes ↔ review agree: E (with G) = peripheral-stalk stator; ALDOC/aldolase coupling (PMID:11399750); renal apical membrane (PMID:29993276, EXP/ACCEPT); ARCL2C disease (PMID:28065471); mTORC1 role as part of V1 (PMID:22053050, KEEP_AS_NON_CORE). PN's nutrient-sensing row is supported but appropriately non-core here. No PN/review contradiction.
  • PN story / NEW pressure: No unmet PN pressure; review exceeds PN (aldolase/glycolysis coupling, renal acid-base) without conflict. GO:0007042 absent from E1 GOA (dossier: new_to_goa; confirmed 0 hits) — defensible ADD. GO:0046612 (verified real, OLS) absent — defensible more-specific ADD. Notable internal QC: review flags PMID:21784977 protein-binding annotation as a curation error → REMOVE (tristetraprolin/CCL3 paper, no ATP6V1E1 content) — a real data-quality catch, independent of PN.
  • Mapping strategy: E1 does not change node mapping. E1 GOA carries GO:0046611 (1 hit, lysosomal complex, ACCEPTed) but not GO:0033176, so the subtype-complex projection of GO:0033176 is broader than the lysosomal-specific term the review already supports.
  • Evidence alignment: Minimal overlap. PN cites generic review titles; review anchors on E1-specific primaries: PMID:11399750 (aldolase), 20717956 (RAB11B trafficking), 28065471 (ARCL2C), 29993276 (renal), 8250920 (cloning), 33065002. PN evidence non-E1-specific.
  • Verdict: Consistent / ADD GO:0007042 + GO:0046612 (verified, new to E1 GOA); review also makes an unrelated REMOVE for a mis-attributed citation. Recommended edits: [MAP] consider subtype complex GO:0033176 → GO:0046611 (already ACCEPTed for E1) for specificity.

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-06
  • review_yaml: genes/human/ATP6V1E1/ATP6V1E1-ai-review.yaml
  • PN workbook rows: 2

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

  • UniProt: P36543
  • In branches: ALP
  • Notes: Subunit of the V1 (cytosolic) component of the lysosomal v-ATPase. The V0 and V1 components of the v-ATPase assemble during amino acid starvation creating the active v-ATPase that pumps protons into the lysosome for acidification. The v-ATPase also engages in amino acid-dependent interactions with the Ragulator complex. In the presence of amino acids, the v-ATPase-Ragulator complex undergoes a conformational change that results in Ragulator exerting its GEF activity on RAGA/B.
  • PN references (titles):
    • Regulation of mTORC1 by amino acids - ScienceDirect
    • Cells | Free Full-Text | SEA and GATOR 10 Years Later | HTML (mdpi.com)
    • Eukaryotic V-ATPase: Novel structural findings and functional insights - ScienceDirect
    • The emerging roles of vacuolar-type ATPase-dependent Lysosomal acidification in neurodegenerative diseases | Translational Neurodegeneration | Full Text (biomedcentral.com)
  • PN-node mapping records (path + ancestors):
    • [subtype] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling|mTORC1 pathway, upstream|Nutrient sensing|V1 lysosomal v-ATPase proton pump component
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0046612 lysosomal proton-transporting V-type ATPase, V1 domain]
      rationale: This PN leaf is restricted to V1-sector lysosomal V-ATPase components. The GO lysosomal V1-domain component term is the direct target.
    • [type] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling|mTORC1 pathway, upstream|Nutrient sensing
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a contextual PN role. The label is useful for curator triage, but by itself does not support a universal GO assertion for all member genes beyond curated ancestor or child mappings.
    • [group] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling|mTORC1 pathway, upstream
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad PN taxonomy container. The descendants mix components, regulators, context labels, and mechanistic leaves, so propagation should come only from narrower curated nodes.
    • [class] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling
      status=context_only scope=too_broad_to_propagate GO=[GO:0010506 regulation of autophagy]
      rationale: This class organizes upstream signaling inputs to autophagy initiation. Because the subtree contains generic insulin, AMPK, mTORC1, nutrient-sensing, and miscellaneous signaling components, class-level propagation to regulation of autophagy would over-annotate many genes.
    • [branch] Autophagy-Lysosome Pathway
      status=no_mapping scope= GO=[]
      rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

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

  • UniProt: P36543
  • In branches: ALP
  • Notes: Subunit of the V1 (cytosolic) component of the lysosomal v-ATPase. The V0 and V1 components of the v-ATPase assemble during amino acid starvation creating the active v-ATPase that pumps protons into the lysosome for acidification. The v-ATPase also engages in amino acid-dependent interactions with the Ragulator complex. In the presence of amino acids, the v-ATPase-Ragulator complex undergoes a conformational change that results in Ragulator exerting its GEF activity on RAGA/B.
  • PN references (titles):
    • Regulation of mTORC1 by amino acids - ScienceDirect
    • Cells | Free Full-Text | SEA and GATOR 10 Years Later | HTML (mdpi.com)
    • Eukaryotic V-ATPase: Novel structural findings and functional insights - ScienceDirect
    • The emerging roles of vacuolar-type ATPase-dependent Lysosomal acidification in neurodegenerative diseases | Translational Neurodegeneration | Full Text (biomedcentral.com)
  • PN-node mapping records (path + ancestors):
    • [subtype] Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification|V1 lysosomal v-ATPase proton pump component
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0033176 proton-transporting V-type ATPase complex]
      rationale: This PN subtype denotes the V1-sector component of the lysosomal V-ATPase. In the current GO cache, the broader V-type ATPase complex is the safest validated target for this component role.
    • [type] Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0007042 lysosomal lumen acidification]
      rationale: This PN group directly names the lysosomal acidification mechanism. Propagation to the GO lysosomal lumen acidification term is an exact mechanistic match.
    • [group] Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad PN taxonomy container. The descendants mix components, regulators, context labels, and mechanistic leaves, so propagation should come only from narrower curated nodes.
    • [class] Autophagy-Lysosome Pathway|Lysosomal catabolism
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad lysosomal-degradation container. The subtree includes carbohydrate, lipid, protein, nuclease, phosphatase, sulfatase, and environment-regulation roles, so mapping should occur at the enzyme or process subtype level.
    • [branch] Autophagy-Lysosome Pathway
      status=no_mapping scope= GO=[]
      rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

Projected GO annotations (3)

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

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

 
id: 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