ATP6V1A encodes the catalytic A subunit of the V1 peripheral domain of the vacuolar-type H+-ATPase (V-ATPase), the principal ATP-driven proton pump of eukaryotic cells. The V1 domain hydrolyzes ATP; subunit A forms three catalytic AB heterodimers that together with subunit B create the hexameric ring responsible for ATP hydrolysis, whose energy is transduced via a central rotor to drive proton translocation through the membrane-embedded V0 domain. V-ATPase is the primary source of organellar acidification in all eukaryotes, acidifying lysosomes, endosomes, the Golgi apparatus, and secretory vesicles; in specialized cells it is also found at the plasma membrane. ATP6V1A is expressed ubiquitously, with high expression in the skin and neurons. In neurons, V-ATPase plays additional roles in neurotransmitter loading into synaptic vesicles and in regulating synaptic transmission. Through its role in lysosomal acidification, V-ATPase (with subunit A as catalytic core) is required for activation of mTORC1 by amino acids at the lysosomal surface, for intracellular iron homeostasis via endosomal transferrin processing, and for autophagic flux. De novo heterozygous ATP6V1A mutations cause a developmental encephalopathy with epilepsy (IECEE3), while biallelic loss-of-function variants cause autosomal recessive cutis laxa type 2D (ARCL2D).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005774 vacuolar membrane | IBA GO_REF:0000033 | ACCEPT | Summary: The V-ATPase A subunit is active in vacuolar/lysosomal membranes where the holoenzyme acidifies these compartments. This is central to ATP6V1A function. Reason: Vacuolar membrane is the primary site of V-ATPase activity; the is_active_in qualifier correctly captures that this is where ATP6V1A performs its catalytic function as part of the V-ATPase complex. Supporting Evidence: file:human/ATP6V1A/ATP6V1A-uniprot.txt Catalytic subunit of the V1 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons |
| GO:1902600 proton transmembrane transport | IBA GO_REF:0000033 | ACCEPT | Summary: Proton transmembrane transport is the core biological process of V-ATPase; the catalytic A subunit is essential for this activity. Reason: This is the primary biological process carried out by V-ATPase, and the A subunit is the ATP-hydrolyzing catalytic subunit that powers proton translocation. 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:0046961 proton-transporting ATPase activity, rotational mechanism | IBA GO_REF:0000033 | ACCEPT | Summary: Proton-transporting ATPase activity by rotational mechanism is the precise molecular function of the V-ATPase complex; subunit A is the catalytic subunit. Reason: This is the correct molecular function annotation for the catalytic subunit of V-ATPase, supported by extensive biochemical and structural data. Supporting Evidence: file:human/ATP6V1A/ATP6V1A-uniprot.txt Catalytic subunit of the V1 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: The A subunit contains the ATP-binding/hydrolysis site of V-ATPase, directly supported by structural studies. Reason: ATP binding is directly demonstrated at the A-B subunit interface by crystallography and cryo-EM. This is a core molecular function annotation. Supporting Evidence: PMID:33065002 We build all known protein subunits with associated N-linked glycans and identify glycolipids and phospholipids in the Vo complex. |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: The V1 domain including subunit A can exist in the cytoplasm as a dissociated complex during nutrient starvation; this represents the regulated V1-V0 disassembly. Reason: Cytoplasmic localization reflects reversible V1-V0 disassembly, a real but non-primary functional state. The primary functional state is when V1 is assembled with V0 at organellar membranes. Supporting Evidence: file:human/ATP6V1A/ATP6V1A-uniprot.txt Cytoplasm {ECO:0000269|PubMed:29668857, ECO:0000269|PubMed:33208464}. Cytoplasm, cytosol {ECO:0000250|UniProtKB:P50516}. |
| GO:0005765 lysosomal membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Lysosomal membrane localization is well supported and is the primary functional compartment for V-ATPase. Reason: The lysosomal membrane is where the assembled V-ATPase complex acidifies the lysosomal lumen. This is a core localization. Supporting Evidence: file:human/ATP6V1A/ATP6V1A-uniprot.txt Lysosome {ECO:0000250|UniProtKB:P50516}. |
| GO:0005829 cytosol | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Cytosolic localization reflects the dissociated V1 complex under nutrient starvation. Supported by experimental evidence (HPA IDA). Reason: The free V1 complex including subunit A can be cytosolic, but the functionally relevant location is membrane-associated. Valid but non-core. Supporting Evidence: file:human/ATP6V1A/ATP6V1A-uniprot.txt Cytoplasm, cytosol {ECO:0000250|UniProtKB:P50516}. |
| GO:0016887 ATP hydrolysis activity | IEA GO_REF:0000002 | ACCEPT | Summary: ATP hydrolysis is the direct catalytic activity of subunit A in the V1 complex. Well supported. Reason: ATP hydrolysis at the A-B interface is the primary molecular activity of the V1 domain, and the A subunit bears the catalytic residues. Supporting Evidence: file:human/ATP6V1A/ATP6V1A-uniprot.txt Reaction=ATP + H2O + 4 H(+)(in) = ADP + phosphate + 5 H(+)(out); EC=7.1.2.2; |
| GO:0030133 transport vesicle | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: V-ATPase presence on transport vesicles reflects its general role in acidifying trafficking compartments. Reason: While V-ATPase is present on various vesicular compartments, this generic term is not the most informative localization for the core function of the A subunit. Supporting Evidence: file:human/ATP6V1A/ATP6V1A-uniprot.txt Cytoplasmic vesicle, clathrin-coated vesicle membrane {ECO:0000250|UniProtKB:P31404}; Peripheral membrane protein |
| GO:0030665 clathrin-coated vesicle membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Clathrin-coated vesicle membrane localization reflects V-ATPase role in endosomal acidification during endocytic trafficking. Reason: This is a legitimate localization derived from ortholog data but is not the primary functional compartment for the core proton pump activity. |
| GO:0033180 proton-transporting V-type ATPase, V1 domain | IEA GO_REF:0000120 | ACCEPT | Summary: ATP6V1A is definitionally a subunit of the V1 domain of V-type ATPase. Reason: This is the fundamental structural annotation for the A subunit, supported by all structural and biochemical studies. Supporting Evidence: PMID:33065002 The V 1 ATPase is composed of three copies of subunits A, B, E, and G, and one copy of subunit C, D, F, and H |
| GO:0042592 homeostatic process | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: Homeostatic process is too broad to be an informative annotation. V-ATPase contributes to pH homeostasis but this is captured by more specific terms. Reason: This ARBA annotation is too general. The specific homeostatic processes (lysosomal acidification, pH regulation) are better captured by more precise GO terms already annotated. |
| GO:0046034 ATP metabolic process | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: ATP hydrolysis by the V1 catalytic domain is part of ATP metabolic process. However, this is a consequence of the ATP hydrolysis activity rather than the primary functional annotation. Reason: While technically correct (ATP is hydrolyzed), the primary annotation should focus on the proton transport function. ATP hydrolysis by V-ATPase is energetically coupled to proton transport, not an end in itself. The more specific proton transport terms are more informative. |
| GO:0046961 proton-transporting ATPase activity, rotational mechanism | IEA GO_REF:0000120 | ACCEPT | Summary: Duplicate annotation of GO:0046961 from a different automated pipeline; same conclusion as the IBA annotation. Reason: This is the core molecular function of V-ATPase and the A subunit is the catalytic component. Consistent with all evidence. |
| GO:0098793 presynapse | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: V-ATPase is expressed at high levels in neurons including presynaptic compartments, where it acidifies synaptic vesicles to enable neurotransmitter loading. Reason: Presynaptic localization is real in neurons but is a specialized cell-type-specific role, not the core ubiquitous function. Supporting Evidence: PMID:29668857 the v-ATPase complex is expressed at high levels in neurons where it plays additional and unique roles in neurotransmitter loading into synaptic vesicles and in regulating synaptic transmission |
| GO:1902600 proton transmembrane transport | IEA GO_REF:0000002 | ACCEPT | Summary: Duplicate annotation of proton transmembrane transport from a different pipeline. Core function of V-ATPase. Reason: Proton transmembrane transport is the primary biological process for V-ATPase. |
| GO:0005515 protein binding | IPI PMID:33208464 The ATPase ATP6V1A facilitates rabies virus replication by p... | MARK AS OVER ANNOTATED | Summary: This protein binding annotation comes from the interaction of ATP6V1A with the Rabies virus matrix protein. Generic protein binding is uninformative. Reason: Generic protein binding does not capture the relevant function. The interaction with viral M protein is a host-pathogen interaction, not a core cellular function. Protein binding as a GO term is uninformative. |
| GO:0005886 plasma membrane | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Plasma membrane V-ATPase is present in specialized cells such as osteoclasts and renal intercalated cells. First identified in osteoclastoma (PMID:8463241). Reason: Plasma membrane localization is real but cell-type-specific (osteoclasts, renal intercalated cells). Not the primary ubiquitous functional localization. Supporting Evidence: PMID:8463241 HO68 could correspond to an isoform of subunit A specific for a vacuolar-type H(+)-ATPase located in the osteoclast plasma membrane. |
| GO:0005902 microvillus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Microvillus localization from ortholog transfer; apical plasma membrane V-ATPase in specialized epithelial cells can be associated with microvilli. Reason: Microvillus is a specialized apical structure; V-ATPase presence there is a context-specific localization in polarized epithelial cells. |
| GO:0015078 proton transmembrane transporter activity | IEA GO_REF:0000107 | ACCEPT | Summary: The contributes_to qualifier correctly notes that the A subunit alone does not transport protons; it is part of the holoenzyme complex. This annotation is appropriate. Reason: The contributes_to qualifier is correct for a subunit of a multi-subunit proton pump. The annotation captures the molecular transporter function appropriately. |
| GO:0016324 apical plasma membrane | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Apical plasma membrane V-ATPase is found in specialized epithelial cells (intercalated cells, proximal tubule). This is a specialized non-core localization. Reason: Apical plasma membrane is a real but cell-type-specific localization for V-ATPase in polarized epithelial cells. |
| GO:0033176 proton-transporting V-type ATPase complex | IEA GO_REF:0000107 | ACCEPT | Summary: ATP6V1A is a core component of the proton-transporting V-type ATPase complex. This is a fundamental structural annotation. Reason: Being part of the V-type ATPase complex is the defining structural annotation for ATP6V1A. |
| GO:0097401 synaptic vesicle lumen acidification | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: V-ATPase acidifies synaptic vesicles to enable neurotransmitter loading in neurons. This is a specialized but well-supported neuronal function. Reason: Synaptic vesicle acidification is a specialized neuronal role for V-ATPase. Real and important in the nervous system but not the core ubiquitous function. Supporting Evidence: PMID:29668857 the v-ATPase complex is expressed at high levels in neurons where it plays additional and unique roles in neurotransmitter loading into synaptic vesicles and in regulating synaptic transmission |
| GO:0071230 cellular response to amino acid stimulus | IDA PMID:22053050 mTORC1 senses lysosomal amino acids through an inside-out me... | ACCEPT | Summary: V-ATPase (V1A subunit directly involved as part of the holoenzyme) mediates the cellular response to amino acid levels through mTORC1 activation at the lysosome. Supported by PMID:22053050. Reason: The role of V-ATPase in amino acid sensing and mTORC1 activation is well-established. The V1 domain interacts with Ragulator in an amino acid-sensitive fashion. This is a core function of the lysosomal V-ATPase. Supporting Evidence: PMID:22053050 We found that the vacuolar H(+)-adenosine triphosphatase ATPase (v-ATPase) is necessary for amino acids to activate mTORC1. PMID:22053050 These results identify the v-ATPase as a component of the mTOR pathway and delineate a lysosome-associated machinery for amino acid sensing. |
| GO:0160124 guanyl nucleotide exchange factor activator activity | IDA PMID:22053050 mTORC1 senses lysosomal amino acids through an inside-out me... | ACCEPT | Summary: V-ATPase interacts with Ragulator (the GEF complex for RagA/B) and activates Rag GTPase nucleotide exchange in an amino acid-sensitive manner. The contributes_to qualifier is appropriate as this is a complex-level function. Reason: The functional interaction of V-ATPase with Ragulator to activate Rag GTPases for mTORC1 translocation is well-supported. This is a distinct molecular function of the lysosomal V-ATPase. 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. PMID:22053050 amino acids regulated the interaction between the V1 domain of v-ATPase and Ragulator and Rag GTPases. |
| GO:0005765 lysosomal membrane | IDA PMID:22053050 mTORC1 senses lysosomal amino acids through an inside-out me... | ACCEPT | Summary: V-ATPase is active at the lysosomal membrane where it acidifies the lysosomal lumen. The is_active_in qualifier from this mTOR signaling study is correct. Reason: The lysosomal membrane is the primary functional location of the assembled V-ATPase complex. Supporting Evidence: PMID:22053050 The mTOR complex 1 (mTORC1) protein kinase is a master growth regulator that is stimulated by amino acids. Amino acids activate the Rag guanosine triphosphatases (GTPases), which promote the translocation of mTORC1 to the lysosomal surface, the site of mTORC1 activation. |
| GO:0046611 lysosomal proton-transporting V-type ATPase complex | IDA PMID:22053050 mTORC1 senses lysosomal amino acids through an inside-out me... | ACCEPT | Summary: ATP6V1A is part of the lysosomal V-type ATPase complex as shown in the mTOR study. Reason: Part of lysosomal V-ATPase complex is the most specific and accurate structural annotation for this subunit in its primary functional context. 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:1904263 positive regulation of TORC1 signaling | IDA PMID:22053050 mTORC1 senses lysosomal amino acids through an inside-out me... | ACCEPT | Summary: V-ATPase is required for mTORC1 activation by amino acids. Inhibition of V-ATPase blocks mTORC1 activation. This is a well-supported function. Reason: Positive regulation of TORC1 signaling by V-ATPase is directly demonstrated. This is an important regulatory function of the lysosomal V-ATPase. Supporting Evidence: PMID:22053050 We found that the vacuolar H(+)-adenosine triphosphatase ATPase (v-ATPase) is necessary for amino acids to activate mTORC1. PMID:22053050 these results place the v-ATPase downstream of amino acids but upstream of the regulation of nucleotide loading of the Rag GTPases |
| GO:0046611 lysosomal proton-transporting V-type ATPase complex | IDA PMID:33065002 Structures of a Complete Human V-ATPase Reveal Mechanisms of... | ACCEPT | Summary: Cryo-EM structure of complete human V-ATPase directly confirms ATP6V1A as part of the lysosomal proton-transporting V-type ATPase complex. Reason: Direct structural evidence from the complete human V-ATPase cryo-EM structure. Supporting Evidence: PMID:33065002 Here, we report cryoelectron microscopy structures of human V-ATPase in three rotational states at up to 2.9-Γ
resolution. |
| GO:0046961 proton-transporting ATPase activity, rotational mechanism | ISS GO_REF:0000024 | ACCEPT | Summary: Ortholog-transfer of the core molecular function. Consistent with all direct evidence. Reason: Core molecular function annotation. Consistent with direct experimental evidence. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: HPA immunofluorescence data supports cytosolic localization. This reflects the free V1 domain found in cytosol during regulated disassembly. Reason: Cytosolic V1 complex is a regulated state during nutrient deprivation. Real but non-core relative to membrane-assembled V-ATPase function. |
| GO:0005737 cytoplasm | EXP PMID:29668857 De novo mutations of the ATP6V1A gene cause developmental en... | KEEP AS NON CORE | Summary: Cytoplasmic localization confirmed in the disease-variant study. Reflects the known cytoplasmic pool of V1 subunits. Reason: Cytoplasmic localization is real but non-primary functional state. Supporting Evidence: PMID:29668857 both mutations caused a similar defect in neurite elongation accompanied by loss of excitatory inputs, revealing that altered lysosomal homeostasis markedly affects neurite development and synaptic connectivity |
| GO:0005737 cytoplasm | EXP PMID:33208464 The ATPase ATP6V1A facilitates rabies virus replication by p... | KEEP AS NON CORE | Summary: Cytoplasmic localization confirmed in the rabies virus study. Reason: Cytoplasmic localization reflects a real but non-primary functional state of the V1 domain. |
| GO:0005764 lysosome | ISS GO_REF:0000024 | ACCEPT | Summary: Lysosomal localization by ortholog transfer. Consistent with the primary functional compartment. Reason: Lysosomal localization is a core annotation for V-ATPase. The assembled holoenzyme is associated with lysosomal membranes. |
| GO:0000139 Golgi membrane | NAS PMID:32001091 Structure and Roles of V-type ATPases. | KEEP AS NON CORE | Summary: V-ATPase is found on Golgi membranes where it acidifies the Golgi lumen, supporting glycosylation and vesicular trafficking. Reason: Golgi membrane localization is real and important for Golgi function, but it is not the primary functional localization for the core proton pump activity in the context of lysosomal degradation and mTOR signaling. Supporting Evidence: PMID:32001091 V-ATPases are the primary source of organellar acidification in all eukaryotes, making them essential for many fundamental cellular processes. |
| GO:0005765 lysosomal membrane | NAS PMID:32001091 Structure and Roles of V-type ATPases. | ACCEPT | Summary: Lysosomal membrane localization supported by the review article and structural studies. Reason: Lysosomal membrane is a core functional localization for V-ATPase. Supporting Evidence: PMID:32001091 V-ATPases are the primary source of organellar acidification in all eukaryotes, making them essential for many fundamental cellular processes. |
| GO:0005886 plasma membrane | NAS PMID:32001091 Structure and Roles of V-type ATPases. | KEEP AS NON CORE | Summary: Plasma membrane V-ATPase exists in specialized cells. Review article supports this but it is a non-core annotation. Reason: Plasma membrane localization is real but cell-type-specific (osteoclasts, kidney intercalated cells). Supporting Evidence: PMID:32001091 V-ATPases are the primary source of organellar acidification in all eukaryotes, making them essential for many fundamental cellular processes |
| GO:0007035 vacuolar acidification | NAS PMID:32001091 Structure and Roles of V-type ATPases. | ACCEPT | Summary: Vacuolar acidification is the core biological process of V-ATPase. Well supported. Reason: Vacuolar/lysosomal acidification is the primary biological process of V-ATPase. Core annotation. Supporting Evidence: PMID:32001091 V-ATPases are the primary source of organellar acidification in all eukaryotes, making them essential for many fundamental cellular processes. |
| GO:0007042 lysosomal lumen acidification | NAS PMID:32001091 Structure and Roles of V-type ATPases. | ACCEPT | Summary: Lysosomal lumen acidification is a core function of V-ATPase. Well supported. Reason: Lysosomal acidification is central to V-ATPase function and is required for lysosomal enzyme activity, protein degradation, and multiple signaling pathways. Supporting Evidence: PMID:33065002 Vesicular and organellar V-ATPases are essential in establishing and maintaining the pH homeostasis of endosomes and lysosomes and in supporting intracellular membrane trafficking and protein degradation |
| GO:0007042 lysosomal lumen acidification | NAS PMID:33065002 Structures of a Complete Human V-ATPase Reveal Mechanisms of... | ACCEPT | Summary: Duplicate annotation of lysosomal lumen acidification from the V-ATPase structure paper. Core function. Reason: Core function annotation supported by structural and functional data. |
| GO:0010008 endosome membrane | NAS PMID:32001091 Structure and Roles of V-type ATPases. | ACCEPT | Summary: Endosome membrane localization is well supported for V-ATPase, which acidifies early and late endosomes during endocytic trafficking. Reason: Endosomal membrane is a core functional localization for V-ATPase, important for endocytic trafficking and iron release from transferrin. Supporting Evidence: PMID:33065002 Vesicular and organellar V-ATPases are essential in establishing and maintaining the pH homeostasis of endosomes and lysosomes and in supporting intracellular membrane trafficking and protein degradation |
| GO:0016020 membrane | IDA PMID:33065002 Structures of a Complete Human V-ATPase Reveal Mechanisms of... | MARK AS OVER ANNOTATED | Summary: Generic membrane annotation from the cryo-EM structure paper. Too generic relative to the more specific lysosomal membrane and endosome membrane annotations. Reason: The generic membrane term is less informative than the specific lysosomal membrane and endosome membrane annotations already present. The cryo-EM structure shows the holoenzyme in membrane context but should be captured by more specific terms. |
| GO:0033176 proton-transporting V-type ATPase complex | NAS PMID:33065002 Structures of a Complete Human V-ATPase Reveal Mechanisms of... | ACCEPT | Summary: Structural annotation of ATP6V1A as part of the V-type ATPase complex, directly confirmed by cryo-EM. Reason: Core structural annotation directly confirmed by the complete human V-ATPase structure. Supporting Evidence: PMID:33065002 Here, we report cryoelectron microscopy structures of human V-ATPase in three rotational states at up to 2.9-Γ
resolution. |
| GO:0048388 endosomal lumen acidification | NAS PMID:32001091 Structure and Roles of V-type ATPases. | ACCEPT | Summary: Endosomal lumen acidification is a core function of V-ATPase, required for endocytic trafficking, iron release from transferrin, and lysosomal enzyme activation. Reason: Core function of V-ATPase; well supported. Supporting Evidence: PMID:33065002 Vesicular and organellar V-ATPases are essential in establishing and maintaining the pH homeostasis of endosomes and lysosomes and in supporting intracellular membrane trafficking and protein degradation |
| GO:0051452 intracellular pH reduction | NAS PMID:32001091 Structure and Roles of V-type ATPases. | ACCEPT | Summary: Intracellular pH reduction is a direct consequence of V-ATPase activity. Broadly valid. Reason: V-ATPase directly reduces the luminal pH of intracellular compartments. Valid annotation. |
| GO:0061795 Golgi lumen acidification | NAS PMID:32001091 Structure and Roles of V-type ATPases. | KEEP AS NON CORE | Summary: V-ATPase acidifies the Golgi lumen, which is important for post-translational modifications and vesicular trafficking. Valid but non-primary role. Reason: Golgi acidification is a real function of V-ATPase but is less central than lysosomal/endosomal acidification. Supporting Evidence: PMID:32001091 V-ATPases are the primary source of organellar acidification in all eukaryotes, making them essential for many fundamental cellular processes. |
| GO:1902600 proton transmembrane transport | NAS PMID:33065002 Structures of a Complete Human V-ATPase Reveal Mechanisms of... | ACCEPT | Summary: Duplicate annotation of proton transmembrane transport from the structure paper. Core function. Reason: Core biological process annotation. |
| 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 cryo-EM evidence places ATP6V1A in the V1 domain of the vacuolar proton-transporting V-type ATPase. Reason: Most specific and accurate structural annotation, directly confirmed by the complete human V-ATPase cryo-EM structure. Supporting Evidence: PMID:33065002 The V 1 ATPase is composed of three copies of subunits A, B, E, and G, and one copy of subunit C, D, F, and H |
| GO:0005515 protein binding | IPI PMID:23035048 Vacuolar-type H+-ATPase V1A subunit is a molecular partner o... | MARK AS OVER ANNOTATED | Summary: The interaction with WFS1 is specific and functional, but the generic protein binding term does not capture the biology. The interaction may reflect a chaperone/assembly function. Reason: Protein binding is uninformative. The specific WFS1-V1A interaction in secretory granules/ER context is better described as a specific assembly/regulatory interaction, but there is no more specific GO term available in the current annotations. Supporting Evidence: PMID:23035048 We demonstrated a novel interaction between WFS1 and the V1A subunit of the H(+) V-ATPase (proton pump) by co-immunoprecipitation in human embryonic kidney (HEK) 293 cells and with endogenous proteins in human neuroblastoma cells. |
| GO:0030141 secretory granule | IDA PMID:23035048 Vacuolar-type H+-ATPase V1A subunit is a molecular partner o... | KEEP AS NON CORE | Summary: Co-localization of ATP6V1A with WFS1 in secretory granules in neuroblastoma cells is experimentally demonstrated. Reason: Secretory granule localization is real but cell-type-specific (neuroblastoma/pancreatic beta cells). Not the core ubiquitous localization. Supporting Evidence: PMID:23035048 Wolfram syndrome is an autosomal recessive disorder characterized by neurodegeneration and diabetes mellitus. The gene responsible for the syndrome (WFS1) encodes an endoplasmic reticulum (ER)-resident transmembrane protein that also localizes to secretory granules in pancreatic beta cells. |
| GO:0005886 plasma membrane | TAS PMID:8463241 Identification of two subunit A isoforms of the vacuolar H(+... | KEEP AS NON CORE | Summary: Original identification of an osteoclastoma-specific V-ATPase A subunit isoform at the plasma membrane. Cell-type-specific localization. Reason: Plasma membrane localization is real in osteoclasts and other specialized cells, but this is not the primary functional localization in most cell types. Supporting Evidence: PMID:8463241 HO68 could correspond to an isoform of subunit A specific for a vacuolar-type H(+)-ATPase located in the osteoclast plasma membrane. |
| GO:0006879 intracellular iron ion homeostasis | IMP PMID:28296633 The vacuolar-ATPase complex and assembly factors, TMEM199 an... | KEEP AS NON CORE | Summary: V-ATPase loss of function leads to intracellular iron depletion through impaired transferrin/iron recycling in endosomes. Experimental evidence from CRISPR screen directly implicates ATP6V1A. Reason: Iron homeostasis is an important secondary consequence of V-ATPase endosomal function, but it is not the primary proton pump function. The mechanism is indirect via endosomal acidification affecting transferrin-iron cycling. Supporting Evidence: PMID:28296633 disrupting the V-ATPase results in intracellular iron depletion, thereby impairing PHD activity and leading to HIF activation. PMID:28296633 we identify that genetic disruption of the Vacuolar H+ ATPase (V-ATPase), the key proton pump for endo-lysosomal acidification, and two previously uncharacterised V-ATPase assembly factors, TMEM199 and CCDC115, stabilise HIF1Ξ± in aerobic conditions. |
| GO:0036295 cellular response to increased oxygen levels | IMP PMID:28296633 The vacuolar-ATPase complex and assembly factors, TMEM199 an... | MARK AS OVER ANNOTATED | Summary: This annotation follows from the iron homeostasis finding - V-ATPase disruption leads to iron depletion which impairs PHD activity, causing HIF1A stabilization even under normoxia. This is an indirect effect. Reason: Cellular response to increased oxygen levels is an over-annotation; V-ATPase does not directly sense or respond to oxygen. The effect on HIF1A is indirect via iron homeostasis. The intracellular iron ion homeostasis annotation (GO:0006879) better captures the relevant biology. Supporting Evidence: PMID:28296633 we identify that genetic disruption of the Vacuolar H+ ATPase (V-ATPase), the key proton pump for endo-lysosomal acidification, and two previously uncharacterised V-ATPase assembly factors, TMEM199 and CCDC115, stabilise HIF1Ξ± in aerobic conditions. |
| GO:0016241 regulation of macroautophagy | NAS PMID:22982048 Lipofuscin is formed independently of macroautophagy and lys... | KEEP AS NON CORE | Summary: V-ATPase acidification of lysosomes is required for autophagic flux. The reference (PMID:22982048) studied lipofuscin in senescent fibroblasts and used V-ATPase inhibitors as experimental tools. The annotation is an indirect inference. Reason: V-ATPase does regulate macroautophagy by acidifying lysosomes required for autophagic degradation. However, this is an indirect downstream consequence of the core proton pump function, not a direct regulatory activity of ATP6V1A per se. Supporting Evidence: PMID:22982048 Lipofuscin is formed independently of macroautophagy and lysosomal activity in stress-induced prematurely senescent human fibroblasts. |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | MARK AS OVER ANNOTATED | Summary: V-ATPase subunit A detected in exosome proteomics studies. These HDA annotations reflect mass spectrometry detection and may include contamination. Reason: Exosome proteomics HDA annotations for V-ATPase subunits likely reflect contamination or non-specific co-purification rather than a genuine exosomal localization or function. V-ATPase is a lysosomal/endosomal enzyme; detection in exosomes is not supported as a primary functional localization. |
| GO:0070062 extracellular exosome | HDA PMID:19199708 Proteomic analysis of human parotid gland exosomes by multid... | MARK AS OVER ANNOTATED | Summary: Same as above - mass spectrometry detection in parotid exosomes. Reason: High-throughput proteomics exosome annotation; not a primary functional localization for V-ATPase. |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | MARK AS OVER ANNOTATED | Summary: Mass spectrometry detection in urinary exosomes. Reason: High-throughput proteomics exosome annotation; not a primary functional localization for V-ATPase. |
| GO:0005765 lysosomal membrane | HDA PMID:17897319 Integral and associated lysosomal membrane proteins. | ACCEPT | Summary: Large-scale proteomics study of lysosomal membrane proteins identifies V-ATPase subunit A. Supports lysosomal membrane localization. Reason: Proteomics study of lysosomal membranes directly confirms V-ATPase subunit A at the lysosomal membrane. |
| GO:0070062 extracellular exosome | HDA PMID:20458337 MHC class II-associated proteins in B-cell exosomes and pote... | MARK AS OVER ANNOTATED | Summary: Mass spectrometry detection in B-cell exosomes. Reason: High-throughput proteomics exosome annotation; not a primary functional localization for V-ATPase. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1222516 | KEEP AS NON CORE | Summary: Multiple Reactome TAS annotations for cytosol reflect V-ATPase participation in various Reactome pathway reactions. Reason: The V1 domain can be cytosolic during regulated disassembly. Valid but non-primary functional state. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5252133 | KEEP AS NON CORE | Summary: Reactome TAS annotation for cytosol. Reason: Non-primary functional state. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-74723 | KEEP AS NON CORE | Summary: Reactome TAS annotation for cytosol. Reason: Non-primary functional state. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-917841 | KEEP AS NON CORE | Summary: Reactome TAS annotation for cytosol. Reason: Non-primary functional state. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9639286 | KEEP AS NON CORE | Summary: Reactome TAS annotation for cytosol in context of mTOR/Rag GTPase pathway. Reason: Non-primary functional state. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9640167 | KEEP AS NON CORE | Summary: Reactome TAS annotation for cytosol in context of mTOR pathway. Reason: Non-primary functional state. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9640168 | KEEP AS NON CORE | Summary: Reactome TAS annotation for cytosol. Reason: Non-primary functional state. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9640175 | KEEP AS NON CORE | Summary: Reactome TAS annotation for cytosol. Reason: Non-primary functional state. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9640195 | KEEP AS NON CORE | Summary: Reactome TAS annotation for cytosol. Reason: Non-primary functional state. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9645598 | KEEP AS NON CORE | Summary: Reactome TAS annotation for cytosol. Reason: Non-primary functional state. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9645608 | KEEP AS NON CORE | Summary: Reactome TAS annotation for cytosol in context of mTORC1 recruitment. Reason: Non-primary functional state. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9646468 | KEEP AS NON CORE | Summary: Reactome TAS annotation for cytosol. Reason: Non-primary functional state. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9858928 | KEEP AS NON CORE | Summary: Reactome TAS annotation for cytosol in context of MITF-M regulation of ATP6V1A. Reason: Non-primary functional state. |
| GO:0005829 cytosol | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Ortholog-based cytosol annotation. Reason: Non-primary functional state. |
| GO:0005886 plasma membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Ortholog-based plasma membrane annotation. Consistent with osteoclast/renal cell specialization. Reason: Cell-type-specific localization; non-core for the ubiquitous function. |
| GO:0016469 proton-transporting two-sector ATPase complex | TAS PMID:8463241 Identification of two subunit A isoforms of the vacuolar H(+... | ACCEPT | Summary: Original paper from osteoclastoma identifies ATP6V1A as part of the proton-transporting two-sector ATPase complex. Valid structural annotation. Reason: This structural annotation correctly identifies ATP6V1A as part of the two-sector V-type ATPase complex. Supporting Evidence: PMID:8463241 Subunit A is thought to be the main component of the catalytic site of the vacuolar-type H(+)-ATPase. |
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Download this section (compressed HTML)Q: Does ATP6V1A isoform 2 (lacking the first 33 amino acids) have altered V-ATPase activity or localization compared to isoform 1?
Q: What is the mechanism by which de novo ATP6V1A mutations cause IECEE3 specifically rather than ARCL2D? Is it a dominant-negative effect or haploinsufficiency?
Q: Are there cell-type-specific expression differences between isoforms 1 and 2 that could explain differential disease phenotypes?
Q: How does AMPK phosphorylation of Ser-384 regulate V-ATPase activity in vivo, and does this affect mTORC1 signaling?
Experiment: Cryo-EM structure of V-ATPase with disease-variant A subunits to determine structural basis of gain-of-function vs loss-of-function mutations.
Hypothesis: Disease variants alter V-ATPase assembly or catalytic mechanism in structurally distinct ways that explain gain vs loss of function.
Experiment: Isoform-selective knockdown and overexpression experiments to determine the functional distinction between ATP6V1A isoforms 1 and 2.
Hypothesis: Isoform 2 (lacking first 33 amino acids) has altered assembly kinetics or localization preference compared to isoform 1.
Experiment: Mass spectrometry-based measurement of V1-V0 assembly ratio in cells expressing IECEE3 vs ARCL2D mutations to distinguish pathomechanisms.
Hypothesis: IECEE3 mutations alter assembly dynamics differently from ARCL2D biallelic loss-of-function mutations.
Experiment: In vivo lysosomal pH measurement with genetically-encoded sensors in neurons expressing disease-linked ATP6V1A variants.
Hypothesis: De novo IECEE3 mutations alter lysosomal pH differently than loss-of-function ARCL2D mutations, explaining the distinct neurological phenotype.
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