Existing Annotations Review

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-Å 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-Å 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 HIF1α 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 HIF1α 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.

Core Functions

ATP6V1A is the catalytic A subunit of the V1 domain of V-ATPase, directly hydrolyzing ATP to power proton translocation across organellar membranes. Three copies of subunit A form catalytic AB heterodimers in the V1 hexameric ring.

Molecular Function:

proton-transporting ATPase activity, rotational mechanism

Directly Involved In:

proton transmembrane transport

Cellular Locations:

lysosomal membrane

In Complex:

lysosomal proton-transporting V-type ATPase complex

As the catalytic ATPase subunit, ATP6V1A powers acidification of lysosomal and endosomal lumens, which is essential for protein degradation, receptor-mediated endocytosis, and lysosomal enzyme function.

Molecular Function:

proton-transporting ATPase activity, rotational mechanism

Directly Involved In:

lysosomal lumen acidification endosomal lumen acidification

Cellular Locations:

lysosomal membrane

The lysosomal V-ATPase complex, through the V1 domain, engages Ragulator in an amino acid-sensitive fashion to activate Rag GTPase-mediated mTORC1 recruitment and activation at the lysosomal surface.

Molecular Function:

guanyl nucleotide exchange factor activator activity

Directly Involved In:

positive regulation of TORC1 signaling

Cellular Locations:

lysosomal membrane

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

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000108

Automatic assignment of GO terms using logical inference, based on on inter-ontology links

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:17897319

Integral and associated lysosomal membrane proteins.

Large-scale proteomics of lysosomal membrane fraction confirms V-ATPase subunit A (ATP6V1A) presence at lysosomal membrane.

PMID:19056867

Large-scale proteomics and phosphoproteomics of urinary exosomes.

Mass spectrometry-based detection of ATP6V1A in urinary exosome fraction; likely a contaminant/non-specific co-purification.

PMID:19199708

Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT).

Mass spectrometry detection of ATP6V1A in parotid gland exosomes; likely a contaminant.

PMID:20458337

MHC class II-associated proteins in B-cell exosomes and potential functional implications for exosome biogenesis.

Mass spectrometry detection in B-cell exosomes; context is contamination or non-specific.

PMID:22053050

mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase.

V-ATPase (V1A subunit confirmed to co-immunoprecipitate with Ragulator) is required for amino acid-induced mTORC1 activation at the lysosome.
V1 domain interacts with Ragulator in an amino acid-sensitive manner.
ATP hydrolysis by V-ATPase is required for the amino acid signaling but the proton gradient itself is not.

PMID:22982048

Lipofuscin is formed independently of macroautophagy and lysosomal activity in stress-induced prematurely senescent human fibroblasts.

Used V-ATPase inhibitors to block lysosomal activity; demonstrates V-ATPase dependence of macroautophagy, but not a primary study of ATP6V1A function.

PMID:23035048

Vacuolar-type H+-ATPase V1A subunit is a molecular partner of Wolfram syndrome 1 (WFS1) protein, which regulates its expression and stability.

ATP6V1A directly interacts with WFS1 in neuroblastoma cells and HEK293 cells.
WFS1 regulates V1A expression and stability; V1A co-localizes with WFS1 in secretory granules.

PMID:23533145

In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine.

Mass spectrometry detection of ATP6V1A in urinary exosomes.

PMID:28296633

The vacuolar-ATPase complex and assembly factors, TMEM199 and CCDC115, control HIF1α prolyl hydroxylation by regulating cellular iron levels.

ATP6V1A depletion by CRISPR stabilizes HIF1α under aerobic conditions.
Mechanism is via intracellular iron depletion impairing PHD activity, not direct lysosomal degradation of HIF1α.

PMID:29668857

De novo mutations of the ATP6V1A gene cause developmental encephalopathy with epilepsy.

Four de novo heterozygous ATP6V1A mutations cause IECEE3.
Mutations disrupt lysosomal homeostasis and neuronal development.
V-ATPase plays specific roles in neurotransmitter loading and synaptic connectivity.

PMID:32001091

Structure and Roles of V-type ATPases.

Comprehensive review of V-ATPase structure, function, and disease associations.
V-ATPase is the primary organellar acidification system in eukaryotes.

PMID:33065002

Structures of a Complete Human V-ATPase Reveal Mechanisms of Its Assembly.

First complete human V-ATPase cryo-EM structure at 2.9 Angstrom resolution.
ATP6V1A is the catalytic A subunit; three copies form the catalytic AB hexameric ring.
Identifies mechanisms of V-ATPase assembly involving ATP6AP1, glycans, and lipids.

PMID:33208464

The ATPase ATP6V1A facilitates rabies virus replication by promoting virion uncoating and interacting with the viral matrix protein.

ATP6V1A interacts with Rabies virus M protein and facilitates viral uncoating in endosomes.
This is a host-pathogen interaction exploiting V-ATPase endosomal acidification function.

PMID:8463241

Identification of two subunit A isoforms of the vacuolar H(+)-ATPase in human osteoclastoma.

First identification of two A subunit isoforms; ubiquitous VA68 (isoform 1) and osteoclastoma-specific HO68.
A subunit is the main catalytic component of V-ATPase.

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-9858928

MITF-M-dependent ATP6V1A gene expression

Suggested Experiments

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.

Deep Research

Falcon

(ATP6V1A-deep-research-falcon.md)

Comprehensive Research Report: ATP6V1A (V-type Proton ATPase Catalytic Subunit A, UniProt: P38606) 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: ATP6V1A (V-type Proton ATPase Catalytic Subunit A, UniProt: P38606)

1. Verification of Gene/Protein Identity

The ATP6V1A gene (UniProt: P38606) in Homo sapiens encodes the catalytic "A" subunit of the V1 domain of the vacuolar-type proton ATPase (V-ATPase) complex. This matches the supplied description and is consistently supported by authoritative sources and primary structure-function studies (guerrini2022phenotypicandgenetic pages 1-3, guerrini2022phenotypicandgenetic pages 3-4). Literature searches did not encounter ambiguity or alternative gene symbols for this protein in humans.

2. Key Concepts and Definitions

Structure and Family

ATP6V1A is the A subunit of the V1 domain of V-ATPase, a multi-subunit, evolutionarily conserved ATP-dependent proton pump. The V1 domain is cytosolic, responsible for ATP hydrolysis, and typically comprises subunits A3, B3 (forming the catalytic hexamer), and others. V-ATPases are essential for acidifying a variety of intracellular organelles (lysosomes, endosomes, synaptic vesicles, Golgi) and mediate both housekeeping and specialized processes (indrawinata2023structuralandfunctional pages 1-2, eaton2021theh+atpase(vatpase) pages 1-5, abbas2020structureofvatpase pages 1-2, wang2020structuresofa pages 1-3).

Catalytic Function and Mechanism

ATP6V1A catalyzes the hydrolysis of ATP (ATP + H2O → ADP + Pi). This chemical energy is converted into mechanical rotation of the central rotor, which is then coupled to the translocation of protons through the membrane-embedded V0 sector. In mammalian V-ATPase, the ATP:proton pumping ratio is approximately 3:10. The principal substrate is ATP; the enzyme product is mechanical energy for proton movement, establishing acidic pH gradients (eaton2021theh+atpase(vatpase) pages 1-5, zhou2021downregulationofatp6v1a pages 1-2, abbas2020structureofvatpase pages 1-2, wang2020structuresofa pages 1-3).

3. Recent Developments and Latest Research (2023–2024)

Recent studies highlight:

Structural insights into human V-ATPase assembly and mechanism, showing ATP6V1A as part of the A3B3 hexamer and its coupling to rotary c-ring movements (abbas2020structureofvatpase pages 1-2, wang2020structuresofa pages 1-3).
Discovery of regulation by reversible V1–V0 assembly/disassembly, with regulatory factors such as FBXO9 (ubiquitin-mediated sequestration) and Lamtor5 (assembly promotion at lysosomes), both of critical relevance in cancer and autoimmune disease contexts (liu2024ubiquitinligasesubunit pages 1-2, zhang2024defectivelamtor5leads pages 1-3).
Ongoing resolution of cryo-EM structures at near-atomic resolution, confirming detailed subunit composition and conformational states (abbas2020structureofvatpase pages 1-2, wang2020structuresofa pages 1-3).

4. Subcellular Localization and Cellular Context

ATP6V1A is localized as part of V-ATPase complexes on:
- Lysosomes (for hydrolase activation, cargo degradation)
- Endosomes and Golgi (for protein trafficking, receptor recycling)
- Synaptic vesicles (for neurotransmitter loading)
- Autophagosomes (for autophagic flux)
- In specialized cells: plasma membrane V-ATPase for extracellular acidification (e.g., osteoclasts, kidney cells) (eaton2021theh+atpase(vatpase) pages 1-5, aoto2021atp6v0a1encodingthe pages 1-2, chen2024thedifferentroles pages 1-2, abbas2020structureofvatpase pages 1-2, wang2020structuresofa pages 1-3).

5. Pathways and Biological Processes

Lysosomal Acidification and Degradation: Maintains acidic pH for lysosomal hydrolases; essential for substrate clearance (song2020theemergingroles pages 1-2, zhang2024defectivelamtor5leads pages 1-3, kim2023endolysosomalimpairmentby pages 1-2).
Autophagy: Required for progression and completion of autophagic flux; impaired ATP6V1A/V-ATPase causes autophagosome accumulation (falace2024vatpasedysfunctionin pages 1-3, song2020theemergingroles pages 1-2, aoto2021atp6v0a1encodingthe pages 1-2, chen2024thedifferentroles pages 1-2).
Endocytosis, Phagosome Maturation: Acidification of endosomes/phagosomes is crucial for cargo sorting, pathogen destruction, transition between early/late states (zhang2024defectivelamtor5leads pages 1-3, chen2024thedifferentroles pages 1-2).
mTORC1 Signaling: V-ATPase serves as a scaffold for Ragulator–Rag–mTORC1 nutrient-sensing complex on lysosomes (falace2024vatpasedysfunctionin pages 1-3, zhang2024defectivelamtor5leads pages 1-3, aoto2021atp6v0a1encodingthe pages 1-2).
Neurotransmitter Loading/Synaptic Transmission: Proton gradients generated by V-ATPase/ATP6V1A drive neurotransmitter uptake into synaptic vesicles (eaton2021theh+atpase(vatpase) pages 1-5, abbas2020structureofvatpase pages 1-2).
Wnt/Notch and Related Signaling: V-ATPase influences these pathways through organelle acidification and trafficking (indrawinata2023structuralandfunctional pages 1-2, falace2024vatpasedysfunctionin pages 1-3, liu2024ubiquitinligasesubunit pages 1-2).

6. Disease Associations and Clinical Implications

Developmental and Epileptic Encephalopathy (DEE): De novo missense mutations in ATP6V1A cause severe, early-onset neurodevelopmental and epileptic disorders, with progressive brain atrophy, intellectual disability, microcephaly, and epilepsy. Cellular disease mechanisms converge on disrupted pH homeostasis and lysosomal/autophagy dysfunction (guerrini2022phenotypicandgenetic pages 1-3, guerrini2022phenotypicandgenetic pages 3-4).
Cutis Laxa type 2D: Biallelic variants result in a syndromic, multisystem disorder (guerrini2022phenotypicandgenetic pages 3-4).
Alzheimer Disease: ATP6V1A expression is reduced in Alzheimer cortex; correlated with disrupted synaptic vesicle cycle, phagosome, and oxidative phosphorylation pathways, and may be a key regulatory node in disease-related neuronal networks (zhou2021downregulationofatp6v1a pages 1-2, kim2023endolysosomalimpairmentby pages 1-2).
Cancer: Overexpression and/or increased V-ATPase activity is linked to tumor cell invasion, metastasis, and drug resistance. New regulatory findings identify FBXO9 as an ATP6V1A-modulating factor limiting its assembly and activity (chen2024vatpaseincancer pages 1-3, liu2024ubiquitinligasesubunit pages 1-2).
Autoimmune Disease: Loss of Lamtor5, which assembles ATP6V1A-containing V-ATPase complexes at lysosomes, is associated with SLE-like autoimmunity in mice and SLE pathology in humans (zhang2024defectivelamtor5leads pages 1-3).
Host–Pathogen Interactions: ATP6V1A is co-opted by rabies virus for uncoating and replication via endosomal acidification machinery (liu2021theatpaseatp6v1a pages 1-2).

7. Expert Analysis and Synthesis

The above findings collectively establish ATP6V1A as a fundamental driver of V-ATPase-catalyzed acidification of intracellular compartments. Disruption at the level of ATP hydrolysis or V-ATPase assembly produces profound defects in vesicle trafficking, degradation, and signaling across diverse organ systems. Disease phenotypes universally converge on failed pH homeostasis, organellar dysfunction, and often neurodevelopmental or neurodegenerative outcomes, emphasizing the essentiality of this protein for cell viability and homeostasis (guerrini2022phenotypicandgenetic pages 1-3, falace2024vatpasedysfunctionin pages 1-3, chen2024vatpaseincancer pages 1-3, liu2024ubiquitinligasesubunit pages 1-2, zhang2024defectivelamtor5leads pages 1-3, kim2023endolysosomalimpairmentby pages 1-2).

8. Relevant Data, Statistics, and Table Summary

A comprehensive table summarizing the core functions, localizations, pathways, and disease associations of ATP6V1A, synthesized from current high-level literature, is embedded below.
| Category | ATP6V1A-specific finding | Key details | Representative evidence |
|---|---|---|---|
| Verified identity | Human ATP6V1A encodes the V-type proton ATPase catalytic subunit A | Literature consistently matches UniProt P38606: ATP6V1A is the ubiquitously expressed A subunit of the V1 cytosolic domain of V-ATPase, not a different gene/protein symbol | (guerrini2022phenotypicandgenetic pages 1-3, guerrini2022phenotypicandgenetic pages 3-4) |
| Primary catalytic function | ATP hydrolysis in the V1 sector of V-ATPase | ATP6V1A forms the catalytic head of the proton pump and provides the chemical energy that powers organelle acidification; V-ATPases are ATP-hydrolysis-driven proton pumps essential for acidifying endosomes, lysosomes, and trans-Golgi compartments | (eaton2021theh+atpase(vatpase) pages 1-5, abbas2020structureofvatpase pages 1-2, wang2020structuresofa pages 1-3) |
| Substrate specificity | Primary substrate is ATP | ATP6V1A is part of the ATP-binding/catalytic interface of V1; the reaction is ATP + H2O → ADP + Pi, with the released energy coupled to proton translocation by V0 rather than ATP6V1A directly transporting substrate itself | (zhou2021downregulationofatp6v1a pages 1-2, wang2020structuresofa pages 1-3) |
| Immediate biochemical output | Generates mechanical energy for rotary coupling to proton pumping | ATP hydrolysis in V1 drives rotation of the central rotor subcomplex, which is transmitted to the membrane-embedded V0 sector to move protons across membranes | (abbas2020structureofvatpase pages 1-2, abbas2020structureofvatpase pages 2-4, wang2020structuresofa pages 1-3) |
| Proton-transport stoichiometry | V-ATPase operates with an approximate ATP:H+ ratio of 3:10 in mammalian brain enzyme preparations | Structural work on mammalian brain V-ATPase resolved three rotational states and defined the ATP:proton ratio, clarifying coupling efficiency of the complex in which ATP6V1A participates | (abbas2020structureofvatpase pages 1-2) |
| Structural role in V-ATPase | ATP6V1A is part of the A3B3 catalytic hexamer in the V1 headpiece | The V1 sector contains subunits A3, B3, C, D, E3, F, G3, H; A and B subunits form the catalytic hexamer, while D/F contribute to the central shaft/rotor and E/G to peripheral stalks | (indrawinata2023structuralandfunctional pages 1-2, chu2021thevatpasea3 pages 3-7, wang2020structuresofa pages 1-3) |
| Mechanistic coupling | ATP6V1A-driven ATP hydrolysis is coupled to c-ring rotation and proton translocation through V0 | Rotation of the central stalk induced by ATP hydrolysis is coupled to the proteolipid c-ring; proton movement then occurs through half-channels formed by the a subunit in V0 | (chu2021thevatpasea3 pages 3-7, wang2020structuresofa pages 1-3) |
| Assembly/regulation | ATP6V1A function depends on reversible V1–V0 assembly/disassembly | Dissociation of V1 from V0 shuts down ATP hydrolysis-coupled proton pumping; this is a major regulatory mechanism responsive to nutrients and other signals | (falace2024vatpasedysfunctionin pages 1-3, eaton2021theh+atpase(vatpase) pages 1-5, song2020theemergingroles pages 1-2) |
| 2024 regulatory finding | FBXO9 restrains V-ATPase assembly by promoting ATP6V1A ubiquitination | In lung cancer cells, FBXO9-mediated ubiquitination of ATP6V1A promotes its interaction with HSPA8 and cytoplasmic sequestration, reducing V-ATPase assembly and vesicular acidification; FBXO9 loss has the opposite effect | (liu2024ubiquitinligasesubunit pages 1-2) |
| 2024 regulatory finding | Lamtor5 physically associates with ATP6V1A to promote V0/V1 holoenzyme assembly | Lamtor5 supports lysosomal acidification by facilitating V-ATPase assembly and also influences Rag/mTORC1 signaling at lysosomes; reduced Lamtor5 was linked to SLE-like phenotypes | (zhang2024defectivelamtor5leads pages 1-3) |
| Subcellular localization | ATP6V1A functions on endomembrane-associated V-ATPase complexes | V-ATPases acidify lysosomes, endosomes, Golgi network, secretory vesicles, and autophagic compartments; ATP6V1A is the cytosolic catalytic subunit associated with these membrane-localized complexes | (indrawinata2023structuralandfunctional pages 1-2, eaton2021theh+atpase(vatpase) pages 1-5, song2020theemergingroles pages 1-2, aoto2021atp6v0a1encodingthe pages 1-2) |
| Neuronal localization | Important on synaptic vesicles and neuronal acidic compartments | In neurons, V-ATPase-generated proton gradients power neurotransmitter loading into synaptic vesicles; ATP6V1A is part of the catalytic machinery enabling this process | (eaton2021theh+atpase(vatpase) pages 1-5, abbas2020structureofvatpase pages 1-2) |
| Endolysosomal localization/function | Critical for lysosomes and endosomes | ATP6V1A-dependent V-ATPase activity maintains the low luminal pH required for lysosomal hydrolase activation, cargo degradation, receptor-mediated endocytosis, and endosomal trafficking | (song2020theemergingroles pages 1-2, aoto2021atp6v0a1encodingthe pages 1-2, chen2024thedifferentroles pages 1-2) |
| Specialized extracellular acidification | Indirect role in plasma-membrane V-ATPases of specialized cells | Although ATP6V1A itself is the cytosolic catalytic subunit, V-ATPase complexes containing V1 are used at the plasma membrane of specialized cells for extracellular acidification such as bone resorption and kidney acid secretion | (eaton2021theh+atpase(vatpase) pages 1-5, indrawinata2023structuralandfunctional pages 1-2) |
| Core biological process | Lysosomal acidification and degradative capacity | Acidic lysosomal pH maintained by V-ATPase is necessary for activation of resident hydrolases and substrate clearance; defective acidification disrupts lysosomal homeostasis | (song2020theemergingroles pages 1-2, zhang2024defectivelamtor5leads pages 1-3, kim2023endolysosomalimpairmentby pages 1-2) |
| Core biological process | Autophagy / autolysosomal degradation | V-ATPase-dependent acidification is required for autophagic flux and degradation of lumenal cargo; dysfunction causes accumulated autophagosomes and impaired clearance | (falace2024vatpasedysfunctionin pages 1-3, song2020theemergingroles pages 1-2, aoto2021atp6v0a1encodingthe pages 1-2, chen2024thedifferentroles pages 1-2) |
| Core biological process | Endocytosis and phagosome maturation | V-ATPase supports endosomal maturation and acidification; related studies on V-ATPase subunits show roles in early-to-late endosome/phagosome transitions and phagolysosomal function | (aoto2021atp6v0a1encodingthe pages 1-2, chen2024thedifferentroles pages 1-2) |
| Core biological process | Synaptic vesicle loading and neurotransmission | In the brain, proton gradients generated by V-ATPase drive neurotransmitter uptake into synaptic vesicles and thereby support synaptic transmission | (eaton2021theh+atpase(vatpase) pages 1-5, aoto2021atp6v0a1encodingthe pages 1-2, abbas2020structureofvatpase pages 1-2) |
| Signaling pathway involvement | mTORC1 nutrient sensing/signaling | V-ATPase acts as a lysosomal signaling hub; it helps recruit or organize Ragulator–Rag–mTORC1 machinery on lysosomes, linking amino acid sensing to mTORC1 activation | (falace2024vatpasedysfunctionin pages 1-3, zhang2024defectivelamtor5leads pages 1-3, aoto2021atp6v0a1encodingthe pages 1-2) |
| Signaling pathway involvement | Wnt and Notch signaling | Reviews identify V-ATPase as a regulator/scaffold in Wnt and Notch pathways; in cancer, altered acidification can promote pro-metastatic Wnt signaling | (indrawinata2023structuralandfunctional pages 1-2, falace2024vatpasedysfunctionin pages 1-3, liu2024ubiquitinligasesubunit pages 1-2) |
| 2024 disease/mechanism | Cancer metastasis and tumor biology | Enhanced V-ATPase activity supports tumor growth, invasion, extracellular acidification, drug resistance, and tumor metabolism; ATP6V1A is specifically implicated through assembly control and acidification-dependent metastatic signaling | (chen2024vatpaseincancer pages 1-3, liu2024ubiquitinligasesubunit pages 1-2) |
| Mendelian disease association | ATP6V1A encephalopathy / developmental and epileptic encephalopathy | De novo missense ATP6V1A variants cluster mainly in the ATP synthase α/β family nucleotide-binding domain and cause a spectrum from severe developmental epileptic encephalopathy to intellectual disability with epilepsy | (guerrini2022phenotypicandgenetic pages 1-3, guerrini2022phenotypicandgenetic pages 3-4) |
| Clinical statistics | Large ATP6V1A encephalopathy cohort showed high neurologic burden | In a 26-patient series, 81% developed epilepsy, 58% had developmental epileptic encephalopathy, 62% had infantile spasms, 38% had microcephaly, 42% had enamel defects, and 68% showed hypomyelination/generalized atrophy on MRI | (guerrini2022phenotypicandgenetic pages 1-3) |
| Cellular disease mechanism | ATP6V1A pathogenic variants alter organelle pH and lysosomal morphology | Patient fibroblasts and iPSC-derived neurons showed abnormal Lysotracker/LAMP1 phenotypes, increased organelle pH in severe cases, ultrastructural inclusions, and smaller lysosomes, consistent with lysosomal dysfunction | (guerrini2022phenotypicandgenetic pages 1-3) |
| Recessive disease association | Cutis laxa type 2D / multisystem disease | Prior work summarized in the ATP6V1A encephalopathy paper notes that biallelic ATP6V1A variants were linked to cutis laxa with systemic features, indicating that both dominant and recessive mechanisms occur | (guerrini2022phenotypicandgenetic pages 3-4) |
| Neurodegeneration association | Alzheimer disease | ATP6V1A expression is reduced in AD cortex in one transcriptomic study; low ATP6V1A-associated networks were enriched for synaptic vesicle cycle, phagosome, and oxidative phosphorylation pathways, and ATP6V1A was proposed as a key regulator in disrupted neuronal subnetworks | (zhou2021downregulationofatp6v1a pages 1-2, kim2023endolysosomalimpairmentby pages 1-2) |
| Infection/host factor role | Supports rabies virus uncoating and replication | ATP6V1A was identified as a host factor interacting with rabies virus matrix protein; its depletion impaired viral uncoating and replication, indicating that ATP6V1A-associated endosomal acidification machinery can be co-opted by viruses | (liu2021theatpaseatp6v1a pages 1-2) |
| Functional interpretation across diseases | Disease phenotypes consistently point to pH-homeostasis failure | Across encephalopathy, autoinflammation, neurodegeneration, and cancer, ATP6V1A dysfunction converges on defective V-ATPase assembly or activity, altered organelle acidification, impaired lysosome/autophagy biology, and disturbed signaling | (guerrini2022phenotypicandgenetic pages 1-3, chen2024vatpaseincancer pages 1-3, liu2024ubiquitinligasesubunit pages 1-2, zhang2024defectivelamtor5leads pages 1-3, kim2023endolysosomalimpairmentby pages 1-2) |

Table: This table compiles the main functional characteristics of human ATP6V1A, including its catalytic role in V-ATPase, cellular localization, pathway involvement, and disease relevance. It emphasizes mechanistic and disease-focused findings from recent and authoritative sources, especially 2023-2024 studies.

9. Key Reference List

Guerrini R, et al. "Phenotypic and genetic spectrum of ATP6V1A encephalopathy: a disorder of lysosomal homeostasis." Brain. 2022;145:2687-2703. doi:10.1093/brain/awac145 (URL)
Abbas YM, et al. "Structure of V-ATPase from the mammalian brain." Science. 2020 Mar 13;367(6483):1240-1246. doi:10.1126/science.aaz2924 (URL)
Wang L, et al. "Structures of a Complete Human V-ATPase Reveal Mechanisms of Its Assembly." Mol Cell. 2020 Nov 5;80(3):501-511.e3 doi:10.1016/j.molcel.2020.09.029 (URL)
Liu L, et al. "Ubiquitin ligase subunit FBXO9 inhibits V-ATPase assembly and impedes lung cancer metastasis." Exp Hematol Oncol. 2024;13:32. doi:10.1186/s40164-024-00497-4 (URL)
Zhou Z, et al. "Downregulation of ATP6V1A Involved in Alzheimer's Disease via Synaptic Vesicle Cycle, Phagosome, and Oxidative Phosphorylation." Oxid Med Cell Longev. 2021:5555634. doi:10.1155/2021/5555634 (URL)
Kim SH, et al. "Endolysosomal impairment by binding of amyloid beta or MAPT/Tau to V-ATPase and rescue via the HYAL-CD44 axis in Alzheimer disease." Autophagy. 2023;19:2318-2337. doi:10.1080/15548627.2023.2181614 (URL)
Chen T, et al. "V-ATPase in cancer: mechanistic insights and therapeutic potentials." Cell Commun Signal. 2024;22:613. doi:10.1186/s12964-024-01998-9 (URL)
Zhang W, et al. "Defective Lamtor5 Leads to Autoimmunity by Deregulating v-ATPase and Lysosomal Acidification." Adv Sci. 2024;11:2400446. doi:10.1002/advs.202400446 (URL)

For detailed context and additional references, see embedded citation tags throughout the text.

References

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(guerrini2022phenotypicandgenetic pages 3-4): Renzo Guerrini, Davide Mei, Katalin Kerti-Szigeti, Sara Pepe, Mary Kay Koenig, Gretchen Von Allmen, Megan T Cho, Kimberly McDonald, Janice Baker, Vikas Bhambhani, Zöe Powis, Lance Rodan, Rima Nabbout, Giulia Barcia, Jill A Rosenfeld, Carlos A Bacino, Cyril Mignot, Lillian H Power, Catharine J Harris, Dragan Marjanovic, Rikke S Møller, Trine B Hammer, Riikka Keski Filppula, Päivi Vieira, Clara Hildebrandt, Stephanie Sacharow, Luca Maragliano, Fabio Benfenati, Katherine Lachlan, Andreas Benneche, Florence Petit, Jean Madeleine de Sainte Agathe, Barbara Hallinan, Yue Si, Ingrid M Wentzensen, Fanggeng Zou, Vinodh Narayanan, Naomichi Matsumoto, Alessandra Boncristiano, Giancarlo la Marca, Mitsuhiro Kato, Kristin Anderson, Carmen Barba, Luisa Sturiale, Domenico Garozzo, Roberto Bei, Laura Masuelli, Valerio Conti, Gaia Novarino, and Anna Fassio. Phenotypic and genetic spectrum of atp6v1a encephalopathy: a disorder of lysosomal homeostasis. Brain, 145:2687-2703, Jun 2025. URL: https://doi.org/10.1093/brain/awac145, doi:10.1093/brain/awac145. This article has 35 citations and is from a highest quality peer-reviewed journal.
(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.
(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.
(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. Science, 367:1240-1246, 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.
(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.
(zhou2021downregulationofatp6v1a pages 1-2): Zhike Zhou, Jun Bai, Shanshan Zhong, Rongwei Zhang, Kexin Kang, Xiaoqian Zhang, Ying Xu, Chuansheng Zhao, and Mei Zhao. Downregulation of atp6v1a involved in alzheimer's disease via synaptic vesicle cycle, phagosome, and oxidative phosphorylation. Oxidative Medicine and Cellular Longevity, Apr 2021. URL: https://doi.org/10.1155/2021/5555634, doi:10.1155/2021/5555634. This article has 43 citations.
(liu2024ubiquitinligasesubunit pages 1-2): Liang Liu, Xiaodong Chen, Leilei Wu, Kaizong Huang, Zhenyi Wang, Yaolin Zheng, Cheng Zheng, Zhenshan Zhang, Jiayan Chen, Jiaming Wei, Song Chen, Weilin Jin, Jinfei Chen, Dongping Wei, and Yaping Xu. Ubiquitin ligase subunit fbxo9 inhibits v-atpase assembly and impedes lung cancer metastasis. Experimental Hematology & Oncology, Mar 2024. URL: https://doi.org/10.1186/s40164-024-00497-4, doi:10.1186/s40164-024-00497-4. This article has 12 citations and is from a peer-reviewed journal.
(zhang2024defectivelamtor5leads pages 1-3): Wei Zhang, Zhou Sha, Yunzhe Tang, Cuiyuan Jin, Wenhua Gao, Changmai Chen, Lang Yu, Nianyin Lv, Shijia Liu, Feng Xu, Dandan Wang, and Liyun Shi. Defective lamtor5 leads to autoimmunity by deregulating v‐atpase and lysosomal acidification. Advanced Science, Apr 2024. URL: https://doi.org/10.1002/advs.202400446, doi:10.1002/advs.202400446. This article has 17 citations and is from a peer-reviewed journal.
(aoto2021atp6v0a1encodingthe pages 1-2): Kazushi Aoto, Mitsuhiro Kato, Tenpei Akita, Mitsuko Nakashima, Hiroki Mutoh, Noriyuki Akasaka, Jun Tohyama, Yoshiko Nomura, Kyoko Hoshino, Yasuhiko Ago, Ryuta Tanaka, Orna Epstein, Revital Ben-Haim, Eli Heyman, Takehiro Miyazaki, Hazrat Belal, Shuji Takabayashi, Chihiro Ohba, Atsushi Takata, Takeshi Mizuguchi, Satoko Miyatake, Noriko Miyake, Atsuo Fukuda, Naomichi Matsumoto, and Hirotomo Saitsu. Atp6v0a1 encoding the a1-subunit of the v0 domain of vacuolar h+-atpases is essential for brain development in humans and mice. Nature Communications, Apr 2021. URL: https://doi.org/10.1038/s41467-021-22389-5, doi:10.1038/s41467-021-22389-5. This article has 71 citations and is from a highest quality peer-reviewed journal.
(chen2024thedifferentroles pages 1-2): Qi Chen, Hanjing Kou, Doris Lou Demy, Wei Liu, Jianchao Li, Zilong Wen, Philippe Herbomel, Zhibin Huang, Wenqing Zhang, and Jin Xu. The different roles of v-atpase a subunits in phagocytosis/endocytosis and autophagy. Autophagy, 20:2297-2313, Jun 2024. URL: https://doi.org/10.1080/15548627.2024.2366748, doi:10.1080/15548627.2024.2366748. This article has 27 citations and is from a domain leading peer-reviewed journal.
(song2020theemergingroles pages 1-2): Qiaoyun Song, Bo Meng, Haidong Xu, and Zixu Mao. The emerging roles of vacuolar-type atpase-dependent lysosomal acidification in neurodegenerative diseases. Translational Neurodegeneration, May 2020. URL: https://doi.org/10.1186/s40035-020-00196-0, doi:10.1186/s40035-020-00196-0. This article has 255 citations and is from a domain leading peer-reviewed journal.
(kim2023endolysosomalimpairmentby pages 1-2): Seo-Hyun Kim, Young-Sin Cho, Youbin Kim, Jisu Park, Seung-Min Yoo, Jimin Gwak, Youngwon Kim, Youngdae Gwon, Tae-in Kam, and Yong-Keun Jung. Endolysosomal impairment by binding of amyloid beta or mapt/tau to v-atpase and rescue via the hyal-cd44 axis in alzheimer disease. Autophagy, 19:2318-2337, Feb 2023. URL: https://doi.org/10.1080/15548627.2023.2181614, doi:10.1080/15548627.2023.2181614. This article has 59 citations and is from a domain leading peer-reviewed journal.
(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.
(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.
(liu2021theatpaseatp6v1a pages 1-2): Xing Liu, Fang Li, Jiwen Zhang, Lulu Wang, Jinliang Wang, Zhiyuan Wen, Zilong Wang, Lei Shuai, Xijun Wang, Jinying Ge, Dongming Zhao, and Zhigao Bu. The atpase atp6v1a facilitates rabies virus replication by promoting virion uncoating and interacting with the viral matrix protein. Journal of Biological Chemistry, 296:100096, Jan 2021. URL: https://doi.org/10.1074/jbc.ra120.014190, doi:10.1074/jbc.ra120.014190. This article has 29 citations and is from a domain leading peer-reviewed journal.
(abbas2020structureofvatpase pages 2-4): Yazan M. Abbas, Di Wu, Stephanie A. Bueler, Carol V. Robinson, and John L. Rubinstein. Structure of v-atpase from the mammalian brain. Science, 367:1240-1246, 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.
(chu2021thevatpasea3 pages 3-7): Anh Chu, Ralph A. Zirngibl, and Morris F. Manolson. The v-atpase a3 subunit: structure, function and therapeutic potential of an essential biomolecule in osteoclastic bone resorption. International Journal of Molecular Sciences, 22:6934, Jun 2021. URL: https://doi.org/10.3390/ijms22136934, doi:10.3390/ijms22136934. This article has 37 citations.

📚 Additional Documentation

Notes

(ATP6V1A-notes.md)

ATP6V1A Research Notes

Gene overview

ATP6V1A encodes the catalytic A subunit (V1A, also known as the 70 kDa or alpha subunit) of the V1 peripheral domain of the vacuolar-type H+-ATPase (V-ATPase). The V1 domain is the ATP-hydrolyzing sector of the proton pump; subunit A forms the catalytic AB heterodimer (three copies per V1 hexamer) together with subunit B and contains the nucleotide-binding/hydrolysis site.

Core function — proton-transporting ATPase

The primary role of ATP6V1A is to hydrolyze ATP and power proton translocation across the membranes of intracellular organelles (lysosomes, endosomes, Golgi, secretory vesicles) and, in specialized cells, the plasma membrane.

PMID:32001091

PMID:33065002

PMID:8463241

Complex assembly and structure

The complete human V-ATPase structure was determined by cryo-EM (Wang et al. 2020, PMID:33065002). The V1 complex consists of three catalytic AB heterodimers forming a heterohexamer, three EG peripheral stalks, one central rotor (subunits D and F), and regulatory subunits C and H. ATP hydrolysis by subunit A (the catalytic subunit) at the AB interface drives rotation of the central rotor, which in turn drives proton translocation through the V0 ring.

PMID:33065002

mTORC1 lysosomal amino acid sensing

The V-ATPase (including the V1A subunit) is required for amino acid sensing by mTORC1 at the lysosome surface. This is mediated through interactions of the V1 domain with the Ragulator complex in an amino acid-sensitive manner, allowing mTORC1 recruitment and activation.

PMID:22053050

Iron homeostasis and HIF1A regulation

V-ATPase function (including ATP6V1A) is required for intracellular iron homeostasis. Loss of V-ATPase activity leads to intracellular iron depletion, reduced PHD activity, and HIF1A stabilization under aerobic conditions.

PMID:28296633

Regulation of macroautophagy

V-ATPase acidification of lysosomes is required for autophagic flux. The annotation linking V-ATPase to regulation of macroautophagy comes from a study on lipofuscin formation (PMID:22982048), where lysosomal activity inhibition was a secondary experimental variable.

Interaction with WFS1

ATP6V1A interacts with WFS1 (Wolfram syndrome 1 protein) in secretory granules in neuroblastoma cells. WFS1 regulates the expression and stability of the V1A subunit.

PMID:23035048

Disease associations

ARCL2D (autosomal recessive cutis laxa type 2D, MIM:617403): Caused by biallelic loss-of-function variants in ATP6V1A. Manifests as skin wrinkling, large fontanelle, facial appearance, hypotonia, cardiovascular and neurologic involvement.

IECEE3 (infantile/early childhood epileptic encephalopathy 3, MIM:618012): Caused by dominant (de novo) heterozygous missense mutations. De novo mutations p.Pro27Arg, p.Asp100Tyr, p.Asp349Asn, p.Asp371Gly identified in patients with developmental encephalopathy with epilepsy.

PMID:29668857

Subcellular localization

ATP6V1A is a peripheral membrane protein of the V1 domain. It is found at lysosomal membrane (is_active_in), secretory granules (co-localizes with WFS1 in neuroblastoma), and the cytosol (V1 domain can reversibly dissociate from V0). Presence in cytoplasm reflects the known regulated V1-V0 disassembly mechanism (e.g., under nutrient deprivation). Some GO annotations cite plasma membrane localization from specific cell types (e.g., osteoclasts). Extracellular exosome annotations are from high-throughput proteomics studies.

Microbial infection note

ATP6V1A facilitates Rabies virus uncoating in endosomes through interaction with the viral M protein. This is a host-pathogen interaction rather than a core cellular function.

PMID:33208464

Annotation quality notes

Multiple cytosol annotations from Reactome (TAS) reflect the reversible disassembly of V1 from V0 membrane complex — these are valid but non-core cellular context annotations rather than the primary functional localization.
Protein binding (GO:0005515) annotations from interaction studies should be MARK_AS_OVER_ANNOTATED.
The NAS annotations from ComplexPortal (PMID:32001091) for multiple acidification processes are valid and core.
Regulation of macroautophagy (NAS, PMID:22982048) is an indirect effect of lysosome function; the paper studied lipofuscin, not V-ATPase function per se.
The guanyl nucleotide exchange factor activator activity (GO:0160124) annotation from the PMID:22053050 mTORC1 paper captures the functional role of V-ATPase in activating Rag GTPase GEF activity (Ragulator) — this is a legitimate but non-core moonlighting function.

Falcon deep research synthesis (2026-06-21)

Falcon deep research has now completed (file:human/ATP6V1A/ATP6V1A-deep-research-falcon.md,
37 citations). It strongly corroborates the catalytic-A-subunit core above and
adds regulatory and disease detail.

Core MF confirmed. ATP6V1A is the catalytic A subunit of the A3B3 hexamer;
ATP hydrolysis at the A/B interface drives central-rotor rotation and proton
translocation (Abbas 2020; Wang 2020 PMID:33065002). No change to the
proton-transporting ATPase activity / ATP-hydrolysis core calls.
Reversible-assembly regulation (proteostasis-relevant, new). ATP6V1A-
containing V-ATPase is regulated by reversible V1–V0 (dis)assembly: FBXO9
ubiquitinates/sequesters ATP6V1A to limit assembly/activity (Liu 2024), while
LAMTOR5 promotes assembly at the lysosome (Zhang 2024). Loss of LAMTOR5
drives SLE-like autoimmunity. These are regulatory inputs, not new ATP6V1A MFs,
but worth flagging for the PN regulation branch.
Disease spectrum. De novo missense → developmental & epileptic
encephalopathy (Guerrini 2022); biallelic variants → cutis laxa type 2D;
reduced ATP6V1A in Alzheimer cortex (Zhou 2021); rabies virus co-opts ATP6V1A-
dependent endosomal acidification for uncoating (Liu 2021). All converge on
loss of organellar pH homeostasis / lysosomal-autophagy function — consistent
with the established core; disease/host-pathogen items are non-core context.
Corroborated localizations/pathways: lysosome/endosome/Golgi/synaptic
vesicle/autophagosome acidification, neurotransmitter loading, mTORC1 scaffold.

Net: no change to calls — ATP6V1A is the V1 catalytic (ATP-hydrolyzing) subunit
powering organellar acidification.

Pn Notes

(ATP6V1A-pn-notes.md)

ATP6V1A PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: P38606
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-06
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/ATP6V1A/ATP6V1A-ai-review.yaml
AIGR review HTML: present - genes/human/ATP6V1A/ATP6V1A-ai-review.html
Gene notes: present - genes/human/ATP6V1A/ATP6V1A-notes.md
GOA TSV: present - genes/human/ATP6V1A/ATP6V1A-goa.tsv
UniProt record: present - genes/human/ATP6V1A/ATP6V1A-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/ATP6V1A.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/ATP6V1A.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

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

AIGR Review Snapshot

Description: ATP6V1A encodes the catalytic A subunit of the V1 peripheral domain of the vacuolar-type H+-ATPase (V-ATPase), the principal ATP-driven proton pump of eukaryotic cells. The V1 domain hydrolyzes ATP; subunit A forms three catalytic AB heterodimers that together with subunit B create the hexameric ring responsible for ATP hydrolysis, whose energy is transduced via a central rotor to drive proton translocation through the membrane-embedded V0 domain. V-ATPase is the primary source of organellar acidification in all eukaryotes, acidifying lysosomes, endosomes, the Golgi apparatus, and secretory vesicles; in specialized cells it is also found at the plasma membrane. ATP6V1A is expressed ubiquitously, with high expression in the skin and neurons. In neurons, V-ATPase plays additional roles in neurotransmitter loading into synaptic vesicles and in regulating synaptic transmission. Through its role in lysosomal acidification, V-ATPase (with subunit A as catalytic core) is required for activation of mTORC1 by amino acids at the lysosomal surface, for intracellular iron homeostasis via endosomal transferrin processing, and for autophagic flux. De novo heterozygous ATP6V1A mutations cause a developmental encephalopathy with epilepsy (IECEE3), while biallelic loss-of-function variants cause autosomal recessive cutis laxa type 2D (ARCL2D).
Existing/core annotation action counts: ACCEPT: 31; KEEP_AS_NON_CORE: 34; MARK_AS_OVER_ANNOTATED: 10

PN Consistency Summary

Consistency: Strong. Deep research (notes) ↔ review ↔ PN all converge on: catalytic A subunit of V1, lysosomal/organellar acidification, and the mTORC1 amino-acid-sensing role (PMID:22053050) — the latter is exactly the PN "Nutrient sensing/mTORC1 upstream" story and is ACCEPTed in the review (GO:0071230, GO:0160124, GO:1904263). No contradictions: every PN-projected term is accepted in the review.
PN story / NEW pressure: No new pressure. PN's mTORC1/nutrient-sensing assertion is already captured (3 ACCEPTed mTORC1 annotations). GO:0007042 already in GOA (dossier: already_in_goa_exact; confirmed 2 hits in GOA) and ACCEPTed. GO:0046612 (verified real via OLS, V1-domain lysosomal CC) is absent from GOA — a defensible more-specific ADD.
Evidence alignment: Divergent source sets, same conclusion. PN cites review-article titles (mTORC1 review, SEA/GATOR, Rubinstein V-ATPase review, neurodegeneration review). Review is anchored on primary/structural PMIDs: 33065002 (cryo-EM), 22053050 (Zoncu mTORC1), 32001091 (= Rubinstein review, overlap), 29668857, 28296633. PN's mTORC1-review evidence is the weaker-form counterpart of the review's Zoncu primary paper.
Verdict: Consistent / ADD GO:0046612 (verified) as more-specific CC; no contradictions. Recommended edits: [MAP] align subtype complex target GO:0033176 → GO:0046611 (lysosomal V-ATPase complex, already ACCEPTed in review) for specificity.

Full Consistency Review

UniProt: P38606 · batch: proteostasis-batch-2026-06-06 · review status: COMPLETE (large, mature review; ~60 annotations curated)
PN placement: Autophagy-Lysosome Pathway|...|V1 lysosomal v-ATPase proton pump component (two rows: mTORC1-upstream/Nutrient sensing, and Lysosomal acidification) ; PN-node mapping: subtype=mapped/ok GO:0046612 (V1 domain, lysosomal) + GO:0033176 (V-ATPase complex); type=mapped/ok GO:0007042 (lysosomal lumen acidification); ancestors no_mapping/context_only.
Consistency: Strong. Deep research (notes) ↔ review ↔ PN all converge on: catalytic A subunit of V1, lysosomal/organellar acidification, and the mTORC1 amino-acid-sensing role (PMID:22053050) — the latter is exactly the PN "Nutrient sensing/mTORC1 upstream" story and is ACCEPTed in the review (GO:0071230, GO:0160124, GO:1904263). No contradictions: every PN-projected term is accepted in the review.
PN story / NEW pressure: No new pressure. PN's mTORC1/nutrient-sensing assertion is already captured (3 ACCEPTed mTORC1 annotations). GO:0007042 already in GOA (dossier: already_in_goa_exact; confirmed 2 hits in GOA) and ACCEPTed. GO:0046612 (verified real via OLS, V1-domain lysosomal CC) is absent from GOA — a defensible more-specific ADD.
Mapping strategy: A-subunit does not force a change to node mapping, but it sharpens it: review uses the more specific GO:0046611 "lysosomal V-type ATPase complex" (ACCEPT, IDA PMID:33065002/22053050), whereas the subtype-complex mapping targets the broader GO:0033176. The V1-domain target GO:0046612 is correctly the most specific.
Evidence alignment: Divergent source sets, same conclusion. PN cites review-article titles (mTORC1 review, SEA/GATOR, Rubinstein V-ATPase review, neurodegeneration review). Review is anchored on primary/structural PMIDs: 33065002 (cryo-EM), 22053050 (Zoncu mTORC1), 32001091 (= Rubinstein review, overlap), 29668857, 28296633. PN's mTORC1-review evidence is the weaker-form counterpart of the review's Zoncu primary paper.
Verdict: Consistent / ADD GO:0046612 (verified) as more-specific CC; no contradictions. Recommended edits: [MAP] align subtype complex target GO:0033176 → GO:0046611 (lysosomal V-ATPase complex, already ACCEPTed in review) for specificity.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-06
review_yaml: genes/human/ATP6V1A/ATP6V1A-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: P38606
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: P38606
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=already_in_goa_exact | 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=already_in_goa_exact | 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: P38606
gene_symbol: ATP6V1A
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 'ATP6V1A encodes the catalytic A subunit of the V1 peripheral domain
  of the vacuolar-type H+-ATPase (V-ATPase), the principal ATP-driven proton pump
  of eukaryotic cells. The V1 domain hydrolyzes ATP; subunit A forms three catalytic
  AB heterodimers that together with subunit B create the hexameric ring responsible
  for ATP hydrolysis, whose energy is transduced via a central rotor to drive proton
  translocation through the membrane-embedded V0 domain. V-ATPase is the primary
  source of organellar acidification in all eukaryotes, acidifying lysosomes, endosomes,
  the Golgi apparatus, and secretory vesicles; in specialized cells it is also found
  at the plasma membrane. ATP6V1A is expressed ubiquitously, with high expression
  in the skin and neurons. In neurons, V-ATPase plays additional roles in neurotransmitter
  loading into synaptic vesicles and in regulating synaptic transmission. Through
  its role in lysosomal acidification, V-ATPase (with subunit A as catalytic core)
  is required for activation of mTORC1 by amino acids at the lysosomal surface, for
  intracellular iron homeostasis via endosomal transferrin processing, and for autophagic
  flux. De novo heterozygous ATP6V1A mutations cause a developmental encephalopathy
  with epilepsy (IECEE3), while biallelic loss-of-function variants cause autosomal
  recessive cutis laxa type 2D (ARCL2D).'
alternative_products:
- name: '1'
  id: P38606-1
- name: '2'
  id: P38606-2
  sequence_note: VSP_056408
existing_annotations:
- term:
    id: GO:0005774
    label: vacuolar membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: The V-ATPase A subunit is active in vacuolar/lysosomal membranes where
      the holoenzyme acidifies these compartments. This is central to ATP6V1A function.
    action: ACCEPT
    reason: Vacuolar membrane is the primary site of V-ATPase activity; the is_active_in
      qualifier correctly captures that this is where ATP6V1A performs its catalytic
      function as part of the V-ATPase complex.
    supported_by:
    - reference_id: file:human/ATP6V1A/ATP6V1A-uniprot.txt
      supporting_text: Catalytic subunit of the V1 complex of vacuolar(H+)-ATPase
        (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that
        hydrolyzes ATP and a membrane integral complex (V0) that translocates protons
      reference_section_type: DATABASE_ENTRY

- term:
    id: GO:1902600
    label: proton transmembrane transport
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Proton transmembrane transport is the core biological process of V-ATPase;
      the catalytic A subunit is essential for this activity.
    action: ACCEPT
    reason: This is the primary biological process carried out by V-ATPase, and the
      A subunit is the ATP-hydrolyzing catalytic subunit that powers proton translocation.
    supported_by:
    - reference_id: PMID:33065002
      supporting_text: Vesicular- or vacuolar-type adenosine triphosphatases (V-ATPases)
        are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP
        hydrolysis and a membrane-embedded Vo complex for proton transfer.
      reference_section_type: ABSTRACT

- term:
    id: GO:0046961
    label: proton-transporting ATPase activity, rotational mechanism
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Proton-transporting ATPase activity by rotational mechanism is the precise
      molecular function of the V-ATPase complex; subunit A is the catalytic subunit.
    action: ACCEPT
    reason: This is the correct molecular function annotation for the catalytic subunit
      of V-ATPase, supported by extensive biochemical and structural data.
    supported_by:
    - reference_id: file:human/ATP6V1A/ATP6V1A-uniprot.txt
      supporting_text: Catalytic subunit of the V1 complex of vacuolar(H+)-ATPase
        (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that
        hydrolyzes ATP and a membrane integral complex (V0) that translocates protons
      reference_section_type: DATABASE_ENTRY

- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: The A subunit contains the ATP-binding/hydrolysis site of V-ATPase, directly
      supported by structural studies.
    action: ACCEPT
    reason: ATP binding is directly demonstrated at the A-B subunit interface by crystallography
      and cryo-EM. This is a core molecular function annotation.
    supported_by:
    - reference_id: PMID:33065002
      supporting_text: We build all known protein subunits with associated N-linked
        glycans and identify glycolipids and phospholipids in the Vo complex.
      reference_section_type: ABSTRACT

- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: The V1 domain including subunit A can exist in the cytoplasm as a dissociated
      complex during nutrient starvation; this represents the regulated V1-V0 disassembly.
    action: KEEP_AS_NON_CORE
    reason: Cytoplasmic localization reflects reversible V1-V0 disassembly, a real
      but non-primary functional state. The primary functional state is when V1 is
      assembled with V0 at organellar membranes.
    supported_by:
    - reference_id: file:human/ATP6V1A/ATP6V1A-uniprot.txt
      supporting_text: Cytoplasm {ECO:0000269|PubMed:29668857, ECO:0000269|PubMed:33208464}.
        Cytoplasm, cytosol {ECO:0000250|UniProtKB:P50516}.
      reference_section_type: DATABASE_ENTRY

- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Lysosomal membrane localization is well supported and is the primary
      functional compartment for V-ATPase.
    action: ACCEPT
    reason: The lysosomal membrane is where the assembled V-ATPase complex acidifies
      the lysosomal lumen. This is a core localization.
    supported_by:
    - reference_id: file:human/ATP6V1A/ATP6V1A-uniprot.txt
      supporting_text: Lysosome {ECO:0000250|UniProtKB:P50516}.
      reference_section_type: DATABASE_ENTRY

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Cytosolic localization reflects the dissociated V1 complex under nutrient
      starvation. Supported by experimental evidence (HPA IDA).
    action: KEEP_AS_NON_CORE
    reason: The free V1 complex including subunit A can be cytosolic, but the functionally
      relevant location is membrane-associated. Valid but non-core.
    supported_by:
    - reference_id: file:human/ATP6V1A/ATP6V1A-uniprot.txt
      supporting_text: Cytoplasm, cytosol {ECO:0000250|UniProtKB:P50516}.
      reference_section_type: DATABASE_ENTRY

- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: ATP hydrolysis is the direct catalytic activity of subunit A in the V1
      complex. Well supported.
    action: ACCEPT
    reason: ATP hydrolysis at the A-B interface is the primary molecular activity of
      the V1 domain, and the A subunit bears the catalytic residues.
    supported_by:
    - reference_id: file:human/ATP6V1A/ATP6V1A-uniprot.txt
      supporting_text: Reaction=ATP + H2O + 4 H(+)(in) = ADP + phosphate + 5 H(+)(out);
        EC=7.1.2.2;
      reference_section_type: DATABASE_ENTRY

- term:
    id: GO:0030133
    label: transport vesicle
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: V-ATPase presence on transport vesicles reflects its general role in
      acidifying trafficking compartments.
    action: KEEP_AS_NON_CORE
    reason: While V-ATPase is present on various vesicular compartments, this generic
      term is not the most informative localization for the core function of the A
      subunit.
    supported_by:
    - reference_id: file:human/ATP6V1A/ATP6V1A-uniprot.txt
      supporting_text: Cytoplasmic vesicle, clathrin-coated vesicle membrane {ECO:0000250|UniProtKB:P31404};
        Peripheral membrane protein
      reference_section_type: DATABASE_ENTRY

- term:
    id: GO:0030665
    label: clathrin-coated vesicle membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Clathrin-coated vesicle membrane localization reflects V-ATPase role
      in endosomal acidification during endocytic trafficking.
    action: KEEP_AS_NON_CORE
    reason: This is a legitimate localization derived from ortholog data but is not
      the primary functional compartment for the core proton pump activity.

- term:
    id: GO:0033180
    label: proton-transporting V-type ATPase, V1 domain
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: part_of
  review:
    summary: ATP6V1A is definitionally a subunit of the V1 domain of V-type ATPase.
    action: ACCEPT
    reason: This is the fundamental structural annotation for the A subunit, supported
      by all structural and biochemical studies.
    supported_by:
    - reference_id: PMID:33065002
      supporting_text: 'The V 1 ATPase is composed of three copies of subunits A, B,
        E, and G, and one copy of subunit C, D, F, and H'
      reference_section_type: INTRODUCTION

- term:
    id: GO:0042592
    label: homeostatic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: Homeostatic process is too broad to be an informative annotation. V-ATPase
      contributes to pH homeostasis but this is captured by more specific terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: This ARBA annotation is too general. The specific homeostatic processes
      (lysosomal acidification, pH regulation) are better captured by more precise
      GO terms already annotated.

- term:
    id: GO:0046034
    label: ATP metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: ATP hydrolysis by the V1 catalytic domain is part of ATP metabolic process.
      However, this is a consequence of the ATP hydrolysis activity rather than the
      primary functional annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: While technically correct (ATP is hydrolyzed), the primary annotation
      should focus on the proton transport function. ATP hydrolysis by V-ATPase is
      energetically coupled to proton transport, not an end in itself. The more specific
      proton transport terms are more informative.

- term:
    id: GO:0046961
    label: proton-transporting ATPase activity, rotational mechanism
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Duplicate annotation of GO:0046961 from a different automated pipeline;
      same conclusion as the IBA annotation.
    action: ACCEPT
    reason: This is the core molecular function of V-ATPase and the A subunit is the
      catalytic component. Consistent with all evidence.

- term:
    id: GO:0098793
    label: presynapse
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: located_in
  review:
    summary: V-ATPase is expressed at high levels in neurons including presynaptic
      compartments, where it acidifies synaptic vesicles to enable neurotransmitter
      loading.
    action: KEEP_AS_NON_CORE
    reason: Presynaptic localization is real in neurons but is a specialized cell-type-specific
      role, not the core ubiquitous function.
    supported_by:
    - reference_id: PMID:29668857
      supporting_text: the v-ATPase complex is expressed at high levels in neurons
        where it plays additional and unique roles in neurotransmitter loading into
        synaptic vesicles and in regulating synaptic transmission
      reference_section_type: OTHER

- term:
    id: GO:1902600
    label: proton transmembrane transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: Duplicate annotation of proton transmembrane transport from a different
      pipeline. Core function of V-ATPase.
    action: ACCEPT
    reason: Proton transmembrane transport is the primary biological process for V-ATPase.

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33208464
  qualifier: enables
  review:
    summary: This protein binding annotation comes from the interaction of ATP6V1A
      with the Rabies virus matrix protein. Generic protein binding is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding does not capture the relevant function. The interaction
      with viral M protein is a host-pathogen interaction, not a core cellular function.
      Protein binding as a GO term is uninformative.

- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Plasma membrane V-ATPase is present in specialized cells such as osteoclasts
      and renal intercalated cells. First identified in osteoclastoma (PMID:8463241).
    action: KEEP_AS_NON_CORE
    reason: Plasma membrane localization is real but cell-type-specific (osteoclasts,
      renal intercalated cells). Not the primary ubiquitous functional localization.
    supported_by:
    - reference_id: PMID:8463241
      supporting_text: HO68 could correspond to an isoform of subunit A specific for
        a vacuolar-type H(+)-ATPase located in the osteoclast plasma membrane.
      reference_section_type: ABSTRACT

- term:
    id: GO:0005902
    label: microvillus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Microvillus localization from ortholog transfer; apical plasma membrane
      V-ATPase in specialized epithelial cells can be associated with microvilli.
    action: KEEP_AS_NON_CORE
    reason: Microvillus is a specialized apical structure; V-ATPase presence there
      is a context-specific localization in polarized epithelial cells.

- term:
    id: GO:0015078
    label: proton transmembrane transporter activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: contributes_to
  review:
    summary: The contributes_to qualifier correctly notes that the A subunit alone
      does not transport protons; it is part of the holoenzyme complex. This annotation
      is appropriate.
    action: ACCEPT
    reason: The contributes_to qualifier is correct for a subunit of a multi-subunit
      proton pump. The annotation captures the molecular transporter function appropriately.

- term:
    id: GO:0016324
    label: apical plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Apical plasma membrane V-ATPase is found in specialized epithelial cells
      (intercalated cells, proximal tubule). This is a specialized non-core localization.
    action: KEEP_AS_NON_CORE
    reason: Apical plasma membrane is a real but cell-type-specific localization for
      V-ATPase in polarized epithelial cells.

- term:
    id: GO:0033176
    label: proton-transporting V-type ATPase complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: part_of
  review:
    summary: ATP6V1A is a core component of the proton-transporting V-type ATPase
      complex. This is a fundamental structural annotation.
    action: ACCEPT
    reason: Being part of the V-type ATPase complex is the defining structural annotation
      for ATP6V1A.

- term:
    id: GO:0097401
    label: synaptic vesicle lumen acidification
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: V-ATPase acidifies synaptic vesicles to enable neurotransmitter loading
      in neurons. This is a specialized but well-supported neuronal function.
    action: KEEP_AS_NON_CORE
    reason: Synaptic vesicle acidification is a specialized neuronal role for V-ATPase.
      Real and important in the nervous system but not the core ubiquitous function.
    supported_by:
    - reference_id: PMID:29668857
      supporting_text: the v-ATPase complex is expressed at high levels in neurons
        where it plays additional and unique roles in neurotransmitter loading into
        synaptic vesicles and in regulating synaptic transmission
      reference_section_type: OTHER

- term:
    id: GO:0071230
    label: cellular response to amino acid stimulus
  evidence_type: IDA
  original_reference_id: PMID:22053050
  qualifier: involved_in
  review:
    summary: V-ATPase (V1A subunit directly involved as part of the holoenzyme) mediates
      the cellular response to amino acid levels through mTORC1 activation at the
      lysosome. Supported by PMID:22053050.
    action: ACCEPT
    reason: The role of V-ATPase in amino acid sensing and mTORC1 activation is well-established.
      The V1 domain interacts with Ragulator in an amino acid-sensitive fashion. This
      is a core function of the lysosomal V-ATPase.
    supported_by:
    - reference_id: PMID:22053050
      supporting_text: We found that the vacuolar H(+)-adenosine triphosphatase ATPase
        (v-ATPase) is necessary for amino acids to activate mTORC1.
      reference_section_type: ABSTRACT
    - reference_id: PMID:22053050
      supporting_text: These results identify the v-ATPase as a component of the mTOR
        pathway and delineate a lysosome-associated machinery for amino acid sensing.
      reference_section_type: ABSTRACT

- term:
    id: GO:0160124
    label: guanyl nucleotide exchange factor activator activity
  evidence_type: IDA
  original_reference_id: PMID:22053050
  qualifier: contributes_to
  review:
    summary: V-ATPase interacts with Ragulator (the GEF complex for RagA/B) and activates
      Rag GTPase nucleotide exchange in an amino acid-sensitive manner. The contributes_to
      qualifier is appropriate as this is a complex-level function.
    action: ACCEPT
    reason: The functional interaction of V-ATPase with Ragulator to activate Rag
      GTPases for mTORC1 translocation is well-supported. This is a distinct molecular
      function of the lysosomal V-ATPase.
    supported_by:
    - reference_id: PMID:22053050
      supporting_text: The v-ATPase engages in extensive amino acid-sensitive interactions
        with the Ragulator, a scaffolding complex that anchors the Rag GTPases to
        the lysosome.
      reference_section_type: ABSTRACT
    - reference_id: PMID:22053050
      supporting_text: amino acids regulated the interaction between the V1 domain
        of v-ATPase and Ragulator and Rag GTPases.
      reference_section_type: RESULTS

- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: IDA
  original_reference_id: PMID:22053050
  qualifier: is_active_in
  review:
    summary: V-ATPase is active at the lysosomal membrane where it acidifies the lysosomal
      lumen. The is_active_in qualifier from this mTOR signaling study is correct.
    action: ACCEPT
    reason: The lysosomal membrane is the primary functional location of the assembled
      V-ATPase complex.
    supported_by:
    - reference_id: PMID:22053050
      supporting_text: The mTOR complex 1 (mTORC1) protein kinase is a master growth
        regulator that is stimulated by amino acids. Amino acids activate the Rag guanosine
        triphosphatases (GTPases), which promote the translocation of mTORC1 to the
        lysosomal surface, the site of mTORC1 activation.
      reference_section_type: ABSTRACT

- term:
    id: GO:0046611
    label: lysosomal proton-transporting V-type ATPase complex
  evidence_type: IDA
  original_reference_id: PMID:22053050
  qualifier: part_of
  review:
    summary: ATP6V1A is part of the lysosomal V-type ATPase complex as shown in the
      mTOR study.
    action: ACCEPT
    reason: Part of lysosomal V-ATPase complex is the most specific and accurate structural
      annotation for this subunit in its primary functional context.
    supported_by:
    - reference_id: PMID:22053050
      supporting_text: The v-ATPase engages in extensive amino acid-sensitive interactions
        with the Ragulator, a scaffolding complex that anchors the Rag GTPases to
        the lysosome.
      reference_section_type: ABSTRACT

- term:
    id: GO:1904263
    label: positive regulation of TORC1 signaling
  evidence_type: IDA
  original_reference_id: PMID:22053050
  qualifier: involved_in
  review:
    summary: V-ATPase is required for mTORC1 activation by amino acids. Inhibition
      of V-ATPase blocks mTORC1 activation. This is a well-supported function.
    action: ACCEPT
    reason: Positive regulation of TORC1 signaling by V-ATPase is directly demonstrated.
      This is an important regulatory function of the lysosomal V-ATPase.
    supported_by:
    - reference_id: PMID:22053050
      supporting_text: We found that the vacuolar H(+)-adenosine triphosphatase ATPase
        (v-ATPase) is necessary for amino acids to activate mTORC1.
      reference_section_type: ABSTRACT
    - reference_id: PMID:22053050
      supporting_text: these results place the v-ATPase downstream of amino acids
        but upstream of the regulation of nucleotide loading of the Rag GTPases
      reference_section_type: RESULTS

- term:
    id: GO:0046611
    label: lysosomal proton-transporting V-type ATPase complex
  evidence_type: IDA
  original_reference_id: PMID:33065002
  qualifier: part_of
  review:
    summary: Cryo-EM structure of complete human V-ATPase directly confirms ATP6V1A
      as part of the lysosomal proton-transporting V-type ATPase complex.
    action: ACCEPT
    reason: Direct structural evidence from the complete human V-ATPase cryo-EM structure.
    supported_by:
    - reference_id: PMID:33065002
      supporting_text: Here, we report cryoelectron microscopy structures of human
        V-ATPase in three rotational states at up to 2.9-Å resolution.
      reference_section_type: ABSTRACT

- term:
    id: GO:0046961
    label: proton-transporting ATPase activity, rotational mechanism
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: Ortholog-transfer of the core molecular function. Consistent with all
      direct evidence.
    action: ACCEPT
    reason: Core molecular function annotation. Consistent with direct experimental
      evidence.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: HPA immunofluorescence data supports cytosolic localization. This reflects
      the free V1 domain found in cytosol during regulated disassembly.
    action: KEEP_AS_NON_CORE
    reason: Cytosolic V1 complex is a regulated state during nutrient deprivation.
      Real but non-core relative to membrane-assembled V-ATPase function.

- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:29668857
  qualifier: located_in
  review:
    summary: Cytoplasmic localization confirmed in the disease-variant study. Reflects
      the known cytoplasmic pool of V1 subunits.
    action: KEEP_AS_NON_CORE
    reason: Cytoplasmic localization is real but non-primary functional state.
    supported_by:
    - reference_id: PMID:29668857
      supporting_text: both mutations caused a similar defect in neurite elongation
        accompanied by loss of excitatory inputs, revealing that altered lysosomal
        homeostasis markedly affects neurite development and synaptic connectivity
      reference_section_type: ABSTRACT

- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:33208464
  qualifier: located_in
  review:
    summary: Cytoplasmic localization confirmed in the rabies virus study.
    action: KEEP_AS_NON_CORE
    reason: Cytoplasmic localization reflects a real but non-primary functional state
      of the V1 domain.

- term:
    id: GO:0005764
    label: lysosome
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Lysosomal localization by ortholog transfer. Consistent with the primary
      functional compartment.
    action: ACCEPT
    reason: Lysosomal localization is a core annotation for V-ATPase. The assembled
      holoenzyme is associated with lysosomal membranes.

- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: located_in
  review:
    summary: V-ATPase is found on Golgi membranes where it acidifies the Golgi lumen,
      supporting glycosylation and vesicular trafficking.
    action: KEEP_AS_NON_CORE
    reason: Golgi membrane localization is real and important for Golgi function, but
      it is not the primary functional localization for the core proton pump activity
      in the context of lysosomal degradation and mTOR signaling.
    supported_by:
    - reference_id: PMID:32001091
      supporting_text: V-ATPases are the primary source of organellar acidification
        in all eukaryotes, making them essential for many fundamental cellular processes.
      reference_section_type: ABSTRACT

- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: located_in
  review:
    summary: Lysosomal membrane localization supported by the review article and structural
      studies.
    action: ACCEPT
    reason: Lysosomal membrane is a core functional localization for V-ATPase.
    supported_by:
    - reference_id: PMID:32001091
      supporting_text: V-ATPases are the primary source of organellar acidification
        in all eukaryotes, making them essential for many fundamental cellular processes.
      reference_section_type: ABSTRACT

- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: located_in
  review:
    summary: Plasma membrane V-ATPase exists in specialized cells. Review article
      supports this but it is a non-core annotation.
    action: KEEP_AS_NON_CORE
    reason: Plasma membrane localization is real but cell-type-specific (osteoclasts,
      kidney intercalated cells).
    supported_by:
    - reference_id: PMID:32001091
      supporting_text: V-ATPases are the primary source of organellar acidification
        in all eukaryotes, making them essential for many fundamental cellular processes
      reference_section_type: ABSTRACT

- term:
    id: GO:0007035
    label: vacuolar acidification
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: involved_in
  review:
    summary: Vacuolar acidification is the core biological process of V-ATPase. Well
      supported.
    action: ACCEPT
    reason: Vacuolar/lysosomal acidification is the primary biological process of
      V-ATPase. Core annotation.
    supported_by:
    - reference_id: PMID:32001091
      supporting_text: V-ATPases are the primary source of organellar acidification
        in all eukaryotes, making them essential for many fundamental cellular processes.
      reference_section_type: ABSTRACT

- term:
    id: GO:0007042
    label: lysosomal lumen acidification
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: involved_in
  review:
    summary: Lysosomal lumen acidification is a core function of V-ATPase. Well supported.
    action: ACCEPT
    reason: Lysosomal acidification is central to V-ATPase function and is required
      for lysosomal enzyme activity, protein degradation, and multiple signaling pathways.
    supported_by:
    - reference_id: PMID:33065002
      supporting_text: Vesicular and organellar V-ATPases are essential in establishing
        and maintaining the pH homeostasis of endosomes and lysosomes and in supporting
        intracellular membrane trafficking and protein degradation
      reference_section_type: INTRODUCTION

- term:
    id: GO:0007042
    label: lysosomal lumen acidification
  evidence_type: NAS
  original_reference_id: PMID:33065002
  qualifier: involved_in
  review:
    summary: Duplicate annotation of lysosomal lumen acidification from the V-ATPase
      structure paper. Core function.
    action: ACCEPT
    reason: Core function annotation supported by structural and functional data.

- term:
    id: GO:0010008
    label: endosome membrane
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: located_in
  review:
    summary: Endosome membrane localization is well supported for V-ATPase, which
      acidifies early and late endosomes during endocytic trafficking.
    action: ACCEPT
    reason: Endosomal membrane is a core functional localization for V-ATPase, important
      for endocytic trafficking and iron release from transferrin.
    supported_by:
    - reference_id: PMID:33065002
      supporting_text: Vesicular and organellar V-ATPases are essential in establishing
        and maintaining the pH homeostasis of endosomes and lysosomes and in supporting
        intracellular membrane trafficking and protein degradation
      reference_section_type: INTRODUCTION

- term:
    id: GO:0016020
    label: membrane
  evidence_type: IDA
  original_reference_id: PMID:33065002
  qualifier: located_in
  review:
    summary: Generic membrane annotation from the cryo-EM structure paper. Too generic
      relative to the more specific lysosomal membrane and endosome membrane annotations.
    action: MARK_AS_OVER_ANNOTATED
    reason: The generic membrane term is less informative than the specific lysosomal
      membrane and endosome membrane annotations already present. The cryo-EM structure
      shows the holoenzyme in membrane context but should be captured by more specific
      terms.

- term:
    id: GO:0033176
    label: proton-transporting V-type ATPase complex
  evidence_type: NAS
  original_reference_id: PMID:33065002
  qualifier: part_of
  review:
    summary: Structural annotation of ATP6V1A as part of the V-type ATPase complex,
      directly confirmed by cryo-EM.
    action: ACCEPT
    reason: Core structural annotation directly confirmed by the complete human V-ATPase
      structure.
    supported_by:
    - reference_id: PMID:33065002
      supporting_text: Here, we report cryoelectron microscopy structures of human
        V-ATPase in three rotational states at up to 2.9-Å resolution.
      reference_section_type: ABSTRACT

- term:
    id: GO:0048388
    label: endosomal lumen acidification
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: involved_in
  review:
    summary: Endosomal lumen acidification is a core function of V-ATPase, required
      for endocytic trafficking, iron release from transferrin, and lysosomal enzyme
      activation.
    action: ACCEPT
    reason: Core function of V-ATPase; well supported.
    supported_by:
    - reference_id: PMID:33065002
      supporting_text: Vesicular and organellar V-ATPases are essential in establishing
        and maintaining the pH homeostasis of endosomes and lysosomes and in supporting
        intracellular membrane trafficking and protein degradation
      reference_section_type: INTRODUCTION

- term:
    id: GO:0051452
    label: intracellular pH reduction
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: involved_in
  review:
    summary: Intracellular pH reduction is a direct consequence of V-ATPase activity.
      Broadly valid.
    action: ACCEPT
    reason: V-ATPase directly reduces the luminal pH of intracellular compartments.
      Valid annotation.

- term:
    id: GO:0061795
    label: Golgi lumen acidification
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: involved_in
  review:
    summary: V-ATPase acidifies the Golgi lumen, which is important for post-translational
      modifications and vesicular trafficking. Valid but non-primary role.
    action: KEEP_AS_NON_CORE
    reason: Golgi acidification is a real function of V-ATPase but is less central
      than lysosomal/endosomal acidification.
    supported_by:
    - reference_id: PMID:32001091
      supporting_text: V-ATPases are the primary source of organellar acidification
        in all eukaryotes, making them essential for many fundamental cellular processes.
      reference_section_type: ABSTRACT

- term:
    id: GO:1902600
    label: proton transmembrane transport
  evidence_type: NAS
  original_reference_id: PMID:33065002
  qualifier: involved_in
  review:
    summary: Duplicate annotation of proton transmembrane transport from the structure
      paper. Core function.
    action: ACCEPT
    reason: Core biological process annotation.

- term:
    id: GO:0000221
    label: vacuolar proton-transporting V-type ATPase, V1 domain
  evidence_type: IDA
  original_reference_id: PMID:33065002
  qualifier: part_of
  review:
    summary: Direct cryo-EM evidence places ATP6V1A in the V1 domain of the vacuolar
      proton-transporting V-type ATPase.
    action: ACCEPT
    reason: Most specific and accurate structural annotation, directly confirmed by
      the complete human V-ATPase cryo-EM structure.
    supported_by:
    - reference_id: PMID:33065002
      supporting_text: 'The V 1 ATPase is composed of three copies of subunits A, B,
        E, and G, and one copy of subunit C, D, F, and H'
      reference_section_type: INTRODUCTION

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23035048
  qualifier: enables
  review:
    summary: The interaction with WFS1 is specific and functional, but the generic
      protein binding term does not capture the biology. The interaction may reflect
      a chaperone/assembly function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Protein binding is uninformative. The specific WFS1-V1A interaction in
      secretory granules/ER context is better described as a specific assembly/regulatory
      interaction, but there is no more specific GO term available in the current annotations.
    supported_by:
    - reference_id: PMID:23035048
      supporting_text: We demonstrated a novel interaction between WFS1 and the V1A
        subunit of the H(+) V-ATPase (proton pump) by co-immunoprecipitation in human
        embryonic kidney (HEK) 293 cells and with endogenous proteins in human neuroblastoma
        cells.
      reference_section_type: ABSTRACT

- term:
    id: GO:0030141
    label: secretory granule
  evidence_type: IDA
  original_reference_id: PMID:23035048
  qualifier: located_in
  review:
    summary: Co-localization of ATP6V1A with WFS1 in secretory granules in neuroblastoma
      cells is experimentally demonstrated.
    action: KEEP_AS_NON_CORE
    reason: Secretory granule localization is real but cell-type-specific (neuroblastoma/pancreatic
      beta cells). Not the core ubiquitous localization.
    supported_by:
    - reference_id: PMID:23035048
      supporting_text: Wolfram syndrome is an autosomal recessive disorder characterized
        by neurodegeneration and diabetes mellitus. The gene responsible for the syndrome
        (WFS1) encodes an endoplasmic reticulum (ER)-resident transmembrane protein
        that also localizes to secretory granules in pancreatic beta cells.
      reference_section_type: ABSTRACT

- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: PMID:8463241
  qualifier: located_in
  review:
    summary: Original identification of an osteoclastoma-specific V-ATPase A subunit
      isoform at the plasma membrane. Cell-type-specific localization.
    action: KEEP_AS_NON_CORE
    reason: Plasma membrane localization is real in osteoclasts and other specialized
      cells, but this is not the primary functional localization in most cell types.
    supported_by:
    - reference_id: PMID:8463241
      supporting_text: HO68 could correspond to an isoform of subunit A specific for
        a vacuolar-type H(+)-ATPase located in the osteoclast plasma membrane.
      reference_section_type: ABSTRACT

- term:
    id: GO:0006879
    label: intracellular iron ion homeostasis
  evidence_type: IMP
  original_reference_id: PMID:28296633
  qualifier: involved_in
  review:
    summary: V-ATPase loss of function leads to intracellular iron depletion through
      impaired transferrin/iron recycling in endosomes. Experimental evidence from
      CRISPR screen directly implicates ATP6V1A.
    action: KEEP_AS_NON_CORE
    reason: Iron homeostasis is an important secondary consequence of V-ATPase endosomal
      function, but it is not the primary proton pump function. The mechanism is indirect
      via endosomal acidification affecting transferrin-iron cycling.
    supported_by:
    - reference_id: PMID:28296633
      supporting_text: disrupting the V-ATPase results in intracellular iron depletion,
        thereby impairing PHD activity and leading to HIF activation.
      reference_section_type: ABSTRACT
    - reference_id: PMID:28296633
      supporting_text: we identify that genetic disruption of the Vacuolar H+ ATPase
        (V-ATPase), the key proton pump for endo-lysosomal acidification, and two
        previously uncharacterised V-ATPase assembly factors, TMEM199 and CCDC115,
        stabilise HIF1α in aerobic conditions.
      reference_section_type: ABSTRACT

- term:
    id: GO:0036295
    label: cellular response to increased oxygen levels
  evidence_type: IMP
  original_reference_id: PMID:28296633
  qualifier: involved_in
  review:
    summary: This annotation follows from the iron homeostasis finding - V-ATPase
      disruption leads to iron depletion which impairs PHD activity, causing HIF1A
      stabilization even under normoxia. This is an indirect effect.
    action: MARK_AS_OVER_ANNOTATED
    reason: Cellular response to increased oxygen levels is an over-annotation; V-ATPase
      does not directly sense or respond to oxygen. The effect on HIF1A is indirect
      via iron homeostasis. The intracellular iron ion homeostasis annotation (GO:0006879)
      better captures the relevant biology.
    supported_by:
    - reference_id: PMID:28296633
      supporting_text: we identify that genetic disruption of the Vacuolar H+ ATPase
        (V-ATPase), the key proton pump for endo-lysosomal acidification, and two
        previously uncharacterised V-ATPase assembly factors, TMEM199 and CCDC115,
        stabilise HIF1α in aerobic conditions.
      reference_section_type: ABSTRACT

- term:
    id: GO:0016241
    label: regulation of macroautophagy
  evidence_type: NAS
  original_reference_id: PMID:22982048
  qualifier: involved_in
  review:
    summary: V-ATPase acidification of lysosomes is required for autophagic flux.
      The reference (PMID:22982048) studied lipofuscin in senescent fibroblasts and
      used V-ATPase inhibitors as experimental tools. The annotation is an indirect
      inference.
    action: KEEP_AS_NON_CORE
    reason: V-ATPase does regulate macroautophagy by acidifying lysosomes required
      for autophagic degradation. However, this is an indirect downstream consequence
      of the core proton pump function, not a direct regulatory activity of ATP6V1A
      per se.
    supported_by:
    - reference_id: PMID:22982048
      supporting_text: Lipofuscin is formed independently of macroautophagy and lysosomal
        activity in stress-induced prematurely senescent human fibroblasts.
      reference_section_type: TITLE

- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:23533145
  qualifier: located_in
  review:
    summary: V-ATPase subunit A detected in exosome proteomics studies. These HDA
      annotations reflect mass spectrometry detection and may include contamination.
    action: MARK_AS_OVER_ANNOTATED
    reason: Exosome proteomics HDA annotations for V-ATPase subunits likely reflect
      contamination or non-specific co-purification rather than a genuine exosomal
      localization or function. V-ATPase is a lysosomal/endosomal enzyme; detection
      in exosomes is not supported as a primary functional localization.

- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19199708
  qualifier: located_in
  review:
    summary: Same as above - mass spectrometry detection in parotid exosomes.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput proteomics exosome annotation; not a primary functional
      localization for V-ATPase.

- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  qualifier: located_in
  review:
    summary: Mass spectrometry detection in urinary exosomes.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput proteomics exosome annotation; not a primary functional
      localization for V-ATPase.

- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: HDA
  original_reference_id: PMID:17897319
  qualifier: located_in
  review:
    summary: Large-scale proteomics study of lysosomal membrane proteins identifies
      V-ATPase subunit A. Supports lysosomal membrane localization.
    action: ACCEPT
    reason: Proteomics study of lysosomal membranes directly confirms V-ATPase subunit
      A at the lysosomal membrane.

- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:20458337
  qualifier: located_in
  review:
    summary: Mass spectrometry detection in B-cell exosomes.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput proteomics exosome annotation; not a primary functional
      localization for V-ATPase.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1222516
  qualifier: located_in
  review:
    summary: Multiple Reactome TAS annotations for cytosol reflect V-ATPase participation
      in various Reactome pathway reactions.
    action: KEEP_AS_NON_CORE
    reason: The V1 domain can be cytosolic during regulated disassembly. Valid but
      non-primary functional state.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5252133
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol.
    action: KEEP_AS_NON_CORE
    reason: Non-primary functional state.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-74723
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol.
    action: KEEP_AS_NON_CORE
    reason: Non-primary functional state.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-917841
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol.
    action: KEEP_AS_NON_CORE
    reason: Non-primary functional state.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9639286
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol in context of mTOR/Rag GTPase pathway.
    action: KEEP_AS_NON_CORE
    reason: Non-primary functional state.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9640167
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol in context of mTOR pathway.
    action: KEEP_AS_NON_CORE
    reason: Non-primary functional state.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9640168
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol.
    action: KEEP_AS_NON_CORE
    reason: Non-primary functional state.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9640175
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol.
    action: KEEP_AS_NON_CORE
    reason: Non-primary functional state.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9640195
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol.
    action: KEEP_AS_NON_CORE
    reason: Non-primary functional state.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9645598
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol.
    action: KEEP_AS_NON_CORE
    reason: Non-primary functional state.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9645608
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol in context of mTORC1 recruitment.
    action: KEEP_AS_NON_CORE
    reason: Non-primary functional state.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9646468
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol.
    action: KEEP_AS_NON_CORE
    reason: Non-primary functional state.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9858928
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol in context of MITF-M regulation
      of ATP6V1A.
    action: KEEP_AS_NON_CORE
    reason: Non-primary functional state.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Ortholog-based cytosol annotation.
    action: KEEP_AS_NON_CORE
    reason: Non-primary functional state.

- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Ortholog-based plasma membrane annotation. Consistent with osteoclast/renal
      cell specialization.
    action: KEEP_AS_NON_CORE
    reason: Cell-type-specific localization; non-core for the ubiquitous function.

- term:
    id: GO:0016469
    label: proton-transporting two-sector ATPase complex
  evidence_type: TAS
  original_reference_id: PMID:8463241
  qualifier: part_of
  review:
    summary: Original paper from osteoclastoma identifies ATP6V1A as part of the
      proton-transporting two-sector ATPase complex. Valid structural annotation.
    action: ACCEPT
    reason: This structural annotation correctly identifies ATP6V1A as part of the
      two-sector V-type ATPase complex.
    supported_by:
    - reference_id: PMID:8463241
      supporting_text: Subunit A is thought to be the main component of the catalytic
        site of the vacuolar-type H(+)-ATPase.
      reference_section_type: ABSTRACT

core_functions:
- description: ATP6V1A is the catalytic A subunit of the V1 domain of V-ATPase,
    directly hydrolyzing ATP to power proton translocation across organellar membranes.
    Three copies of subunit A form catalytic AB heterodimers in the V1 hexameric ring.
  molecular_function:
    id: GO:0046961
    label: proton-transporting ATPase activity, rotational mechanism
  directly_involved_in:
  - id: GO:1902600
    label: proton transmembrane transport
  locations:
  - id: GO:0005765
    label: lysosomal membrane
  in_complex:
    id: GO:0046611
    label: lysosomal proton-transporting V-type ATPase complex
- description: As the catalytic ATPase subunit, ATP6V1A powers acidification of lysosomal
    and endosomal lumens, which is essential for protein degradation, receptor-mediated
    endocytosis, and lysosomal enzyme function.
  molecular_function:
    id: GO:0046961
    label: proton-transporting ATPase activity, rotational mechanism
  directly_involved_in:
  - id: GO:0007042
    label: lysosomal lumen acidification
  - id: GO:0048388
    label: endosomal lumen acidification
  locations:
  - id: GO:0005765
    label: lysosomal membrane
- description: The lysosomal V-ATPase complex, through the V1 domain, engages Ragulator
    in an amino acid-sensitive fashion to activate Rag GTPase-mediated mTORC1 recruitment
    and activation at the lysosomal surface.
  molecular_function:
    id: GO:0160124
    label: guanyl nucleotide exchange factor activator activity
  directly_involved_in:
  - id: GO:1904263
    label: positive regulation of TORC1 signaling
  locations:
  - id: GO:0005765
    label: lysosomal membrane

suggested_questions:
- question: Does ATP6V1A isoform 2 (lacking the first 33 amino acids) have altered
    V-ATPase activity or localization compared to isoform 1?
- question: What is the mechanism by which de novo ATP6V1A mutations cause IECEE3
    specifically rather than ARCL2D? Is it a dominant-negative effect or haploinsufficiency?
- question: Are there cell-type-specific expression differences between isoforms 1
    and 2 that could explain differential disease phenotypes?
- question: How does AMPK phosphorylation of Ser-384 regulate V-ATPase activity in
    vivo, and does this affect mTORC1 signaling?

suggested_experiments:
- description: Cryo-EM structure of V-ATPase with disease-variant A subunits to determine
    structural basis of gain-of-function vs loss-of-function mutations.
  hypothesis: Disease variants alter V-ATPase assembly or catalytic mechanism in structurally
    distinct ways that explain gain vs loss of function.
- description: Isoform-selective knockdown and overexpression experiments to determine
    the functional distinction between ATP6V1A isoforms 1 and 2.
  hypothesis: Isoform 2 (lacking first 33 amino acids) has altered assembly kinetics
    or localization preference compared to isoform 1.
- description: Mass spectrometry-based measurement of V1-V0 assembly ratio in cells
    expressing IECEE3 vs ARCL2D mutations to distinguish pathomechanisms.
  hypothesis: IECEE3 mutations alter assembly dynamics differently from ARCL2D biallelic
    loss-of-function mutations.
- description: In vivo lysosomal pH measurement with genetically-encoded sensors in
    neurons expressing disease-linked ATP6V1A variants.
  hypothesis: De novo IECEE3 mutations alter lysosomal pH differently than loss-of-function
    ARCL2D mutations, explaining the distinct neurological phenotype.

references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000108
  title: Automatic assignment of GO terms using logical inference, based on on inter-ontology
    links
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:17897319
  title: Integral and associated lysosomal membrane proteins.
  findings:
  - statement: Large-scale proteomics of lysosomal membrane fraction confirms V-ATPase
      subunit A (ATP6V1A) presence at lysosomal membrane.
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  findings:
  - statement: Mass spectrometry-based detection of ATP6V1A in urinary exosome fraction;
      likely a contaminant/non-specific co-purification.
- id: PMID:19199708
  title: Proteomic analysis of human parotid gland exosomes by multidimensional protein
    identification technology (MudPIT).
  findings:
  - statement: Mass spectrometry detection of ATP6V1A in parotid gland exosomes; likely
      a contaminant.
- id: PMID:20458337
  title: MHC class II-associated proteins in B-cell exosomes and potential functional
    implications for exosome biogenesis.
  findings:
  - statement: Mass spectrometry detection in B-cell exosomes; context is contamination
      or non-specific.
- id: PMID:22053050
  title: mTORC1 senses lysosomal amino acids through an inside-out mechanism that
    requires the vacuolar H(+)-ATPase.
  findings:
  - statement: V-ATPase (V1A subunit confirmed to co-immunoprecipitate with Ragulator)
      is required for amino acid-induced mTORC1 activation at the lysosome.
  - statement: V1 domain interacts with Ragulator in an amino acid-sensitive manner.
  - statement: ATP hydrolysis by V-ATPase is required for the amino acid signaling
      but the proton gradient itself is not.
- id: PMID:22982048
  title: Lipofuscin is formed independently of macroautophagy and lysosomal activity
    in stress-induced prematurely senescent human fibroblasts.
  findings:
  - statement: Used V-ATPase inhibitors to block lysosomal activity; demonstrates
      V-ATPase dependence of macroautophagy, but not a primary study of ATP6V1A function.
- id: PMID:23035048
  title: Vacuolar-type H+-ATPase V1A subunit is a molecular partner of Wolfram syndrome
    1 (WFS1) protein, which regulates its expression and stability.
  findings:
  - statement: ATP6V1A directly interacts with WFS1 in neuroblastoma cells and HEK293
      cells.
  - statement: WFS1 regulates V1A expression and stability; V1A co-localizes with
      WFS1 in secretory granules.
- id: PMID:23533145
  title: In-depth proteomic analyses of exosomes isolated from expressed prostatic
    secretions in urine.
  findings:
  - statement: Mass spectrometry detection of ATP6V1A in urinary exosomes.
- id: PMID:28296633
  title: The vacuolar-ATPase complex and assembly factors, TMEM199 and CCDC115, control
    HIF1α prolyl hydroxylation by regulating cellular iron levels.
  findings:
  - statement: ATP6V1A depletion by CRISPR stabilizes HIF1α under aerobic conditions.
  - statement: Mechanism is via intracellular iron depletion impairing PHD activity,
      not direct lysosomal degradation of HIF1α.
- id: PMID:29668857
  title: De novo mutations of the ATP6V1A gene cause developmental encephalopathy
    with epilepsy.
  findings:
  - statement: Four de novo heterozygous ATP6V1A mutations cause IECEE3.
  - statement: Mutations disrupt lysosomal homeostasis and neuronal development.
  - statement: V-ATPase plays specific roles in neurotransmitter loading and synaptic
      connectivity.
- id: PMID:32001091
  title: Structure and Roles of V-type ATPases.
  findings:
  - statement: Comprehensive review of V-ATPase structure, function, and disease associations.
  - statement: V-ATPase is the primary organellar acidification system in eukaryotes.
- id: PMID:33065002
  title: Structures of a Complete Human V-ATPase Reveal Mechanisms of Its Assembly.
  findings:
  - statement: First complete human V-ATPase cryo-EM structure at 2.9 Angstrom resolution.
  - statement: ATP6V1A is the catalytic A subunit; three copies form the catalytic
      AB hexameric ring.
  - statement: Identifies mechanisms of V-ATPase assembly involving ATP6AP1, glycans,
      and lipids.
- id: PMID:33208464
  title: The ATPase ATP6V1A facilitates rabies virus replication by promoting virion
    uncoating and interacting with the viral matrix protein.
  findings:
  - statement: ATP6V1A interacts with Rabies virus M protein and facilitates viral
      uncoating in endosomes.
  - statement: This is a host-pathogen interaction exploiting V-ATPase endosomal acidification
      function.
- id: PMID:8463241
  title: Identification of two subunit A isoforms of the vacuolar H(+)-ATPase in human
    osteoclastoma.
  findings:
  - statement: First identification of two A subunit isoforms; ubiquitous VA68 (isoform
      1) and osteoclastoma-specific HO68.
  - statement: A subunit is the main catalytic component of V-ATPase.
- id: Reactome:R-HSA-1222516
  title: Intraphagosomal pH is lowered to 5 by V-ATPase
  findings: []
- id: Reactome:R-HSA-5252133
  title: ATP6AP1 binds V-ATPase
  findings: []
- id: Reactome:R-HSA-74723
  title: Endosome acidification
  findings: []
- id: Reactome:R-HSA-917841
  title: Acidification of Tf:TfR1 containing endosome
  findings: []
- id: Reactome:R-HSA-9639286
  title: RRAGC,D exchanges GTP for GDP
  findings: []
- id: Reactome:R-HSA-9640167
  title: RRAGA,B exchanges GDP for GTP
  findings: []
- id: Reactome:R-HSA-9640168
  title: v-ATPase:Ragulator:RRAGA,B:GTP:RRAGC,D:GDP:SLC38A9:Arginine dissociates yielding
    v-ATPase:Ragulator:RRAGA,B:GTP:RRAGC,D:GDP and SLC38A9:Arginine
  findings: []
- id: Reactome:R-HSA-9640175
  title: v-ATPase:Ragulator:RagA,B:GDP:RagC,D:GDP binds SLC38A9:Arginine
  findings: []
- id: Reactome:R-HSA-9640195
  title: RRAGA,B hydrolyzes GTP
  findings: []
- id: Reactome:R-HSA-9645598
  title: RRAGC,D hydrolyzes GTP
  findings: []
- id: Reactome:R-HSA-9645608
  title: v-ATPase:Ragulator:RRAGA,B:GTP:RRAGC,D:GDP binds mTORC1
  findings: []
- id: Reactome:R-HSA-9646468
  title: mTORC1 binds RHEB:GTP
  findings: []
- id: Reactome:R-HSA-9858928
  title: MITF-M-dependent ATP6V1A gene expression
  findings: []

ATP6V1A

Gene Description

Existing Annotations Review

Core Functions

ATP6V1A is the catalytic A subunit of the V1 domain of V-ATPase, directly hydrolyzing ATP to power proton translocation across organellar membranes. Three copies of subunit A form catalytic AB heterodimers in the V1 hexameric ring.

As the catalytic ATPase subunit, ATP6V1A powers acidification of lysosomal and endosomal lumens, which is essential for protein degradation, receptor-mediated endocytosis, and lysosomal enzyme function.

The lysosomal V-ATPase complex, through the V1 domain, engages Ragulator in an amino acid-sensitive fashion to activate Rag GTPase-mediated mTORC1 recruitment and activation at the lysosomal surface.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Comprehensive Research Report: ATP6V1A (V-type Proton ATPase Catalytic Subunit A, UniProt: P38606)

1. Verification of Gene/Protein Identity

2. Key Concepts and Definitions

Structure and Family

Catalytic Function and Mechanism

3. Recent Developments and Latest Research (2023–2024)

4. Subcellular Localization and Cellular Context

5. Pathways and Biological Processes

6. Disease Associations and Clinical Implications

7. Expert Analysis and Synthesis

8. Relevant Data, Statistics, and Table Summary

9. Key Reference List

📚 Additional Documentation

Notes

ATP6V1A Research Notes

Gene overview

Core function — proton-transporting ATPase

Complex assembly and structure

mTORC1 lysosomal amino acid sensing

Iron homeostasis and HIF1A regulation

Regulation of macroautophagy

Interaction with WFS1

Disease associations

Subcellular localization

Microbial infection note

Annotation quality notes

Falcon deep research synthesis (2026-06-21)

Pn Notes

ATP6V1A PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

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

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

Projected GO annotations (3)

Note

📄 View Raw YAML