{"gene":"ATP6V1A","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":1990,"finding":"The yeast VMA1 gene encodes the catalytic subunit (subunit A) of the vacuolar membrane H+-translocating ATPase; the 1,071 amino acid precursor undergoes post-translational protein splicing, excising an internal 454-residue domain and ligating the flanking regions to produce the functional 69-kDa subunit.","method":"Gene cloning, sequencing, N-terminal peptide sequencing, Northern blotting, molecular mass analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — original molecular characterization with sequence analysis and functional splicing inference, foundational paper with 391 citations","pmids":["2139027"],"is_preprint":false},{"year":1988,"finding":"The Neurospora crassa vma-1-encoded 67-kDa subunit A of the vacuolar ATPase contains the active site for ATP hydrolysis, as indicated by a putative nucleotide-binding region in its sequence and high homology to catalytic subunits of other ATPases including F0F1 beta subunits.","method":"Gene cloning, cDNA sequencing, sequence homology analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — sequence-based identification of ATP hydrolysis active site with 199 citations, foundational paper","pmids":["2971651"],"is_preprint":false},{"year":1992,"finding":"Cysteine residues at positions 284 and 738 in yeast Vma1p are essential for the protein splicing reaction: Cys-284 mutation blocks cleavage at the N-terminal junction, while Cys-738 mutation blocks processing at both junction sites, preventing generation of functional 69-kDa V-ATPase subunit A.","method":"Site-directed mutagenesis, expression in vma1 null mutant yeast, immunoblotting","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis of specific catalytic residues with defined biochemical phenotype","pmids":["1417861"],"is_preprint":false},{"year":1996,"finding":"Protein splicing of the yeast Vma1p protozyme is a folding-dependent, intramolecular, autocatalytic reaction that proceeds at optimal pH 7, is not inhibited by protease inhibitors, and can be reconstituted in vitro by refolding denatured precursor.","method":"In vitro protein splicing reconstitution, refolding assay, gel filtration, protease inhibitor panel","journal":"Biochemical and biophysical research communications / FEBS letters","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution of the splicing reaction with multiple mechanistic probes","pmids":["8651930","9276458"],"is_preprint":false},{"year":1997,"finding":"Random mutagenesis of the entire VDE (intein) region of yeast VMA1 identified three core regions essential for protein splicing: His-362 is required for first cleavage at the N-terminal junction, and His-736 assists the second cleavage via Asn cyclization at the C-terminal junction, while mutations in these regions do not destroy VDE endonuclease activity.","method":"PCR-based random mutagenesis, bacterial expression screen, yeast complementation, immunoblotting","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — systematic mutagenesis across entire intein with specific residue-to-phenotype mapping","pmids":["9188457"],"is_preprint":false},{"year":1997,"finding":"A conserved hydrophobic valine triplet preceding the C-terminal splicing junction of yeast Vma1p genetically interacts with hydrophobic residues preceding the N-terminal junction, demonstrating that the N-terminal portion of the V-ATPase subunit A participates in the protein splicing reaction through intramolecular beta-strand interactions.","method":"Random mutagenesis, intragenic suppressor analysis, yeast genetic complementation","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis/suppressor analysis in yeast, single study","pmids":["9286669"],"is_preprint":false},{"year":2002,"finding":"Crystal structure (2.1 Å) of the yeast VMA1-derived endonuclease intein precursor reveals that protein splicing proceeds via an N→S acyl shift forming a thiazolidine intermediate at the N-terminal junction (Cys-284 attacks Gly-283 carbonyl), followed by transesterification involving Ser-738 at the C-terminal junction.","method":"X-ray crystallography at 2.1 Å resolution with mutagenesis of splice site residues","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 — high-resolution crystal structure combined with mutagenesis, defining the catalytic mechanism","pmids":["11884132"],"is_preprint":false},{"year":2013,"finding":"AMPK directly phosphorylates the V-ATPase A subunit (ATP6V1A) at Ser-384, and this phosphorylation inhibits V-ATPase-dependent H+ secretion in kidney intercalated cells and causes cytoplasmic redistribution of the V-ATPase; the phosphorylation-deficient S384A mutant prevents AMPK-mediated inhibition of extracellular acidification and blocks AICAR-induced V-ATPase redistribution.","method":"In vitro kinase assay, mass spectrometry identification of phosphorylation site, site-directed mutagenesis (S384A), perfused collecting duct H+ secretion assay, extracellular acidification assay in HEK-293 cells, immunofluorescence localization","journal":"American journal of physiology. Renal physiology","confidence":"High","confidence_rationale":"Tier 1 — in vitro kinase assay + MS site identification + mutagenesis + functional assays in multiple systems","pmids":["23863464"],"is_preprint":false},{"year":2007,"finding":"Morpholino knockdown of atp6v1a in zebrafish embryos suppresses acid secretion from H+-pump-rich skin cells, causes growth retardation, trunk deformation, and loss of internal Ca2+ and Na+, demonstrating that V-ATPase subunit A is required for acid secretion and ion balance in vivo.","method":"Morpholino antisense knockdown in zebrafish, in vivo acid secretion measurement, ion concentration analysis","journal":"American journal of physiology. Regulatory, integrative and comparative physiology","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function in vertebrate model with specific physiological readouts, 126 citations","pmids":["17272665"],"is_preprint":false},{"year":2017,"finding":"Biallelic missense mutations in ATP6V1A (encoding the A subunit of the V1 domain) cause autosomal-recessive cutis laxa; complexome profiling showed these mutations disturb either assembly or stability of the V-ATPase complex, and patient fibroblasts exhibit delayed retrograde Golgi transport and abnormal Golgi fragmentation, linking ATP6V1A to vesicular trafficking.","method":"Whole-exome sequencing, complexome profiling (BN-PAGE + LC-MS/MS), structural modeling, brefeldin A retrograde transport assay, transmission electron microscopy, protein glycosylation analysis","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including complexome profiling and functional cellular assays","pmids":["28065471"],"is_preprint":false},{"year":2018,"finding":"De novo heterozygous ATP6V1A mutations cause differential effects on lysosomal function: p.Asp349Asn (gain-of-function) increases lysosomal proton pumping (increased LysoTracker fluorescence, lower organelle pH), while p.Asp100Tyr (loss-of-function) reduces ATP6V1A expression through increased degradation and decreases lysosomal markers; both mutations reduce V-ATPase recruitment to autophagosomes and impair neurite elongation and excitatory synaptic input in hippocampal neurons.","method":"LysoTracker/LysoSensor fluorescence, LAMP1/EEA1 immunoblotting, cycloheximide chase (protein stability), autophagosome recruitment assay, neurite morphology analysis, synaptic input measurement in primary rat neurons","journal":"Brain : a journal of neurology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal functional assays in HEK293T cells, patient lymphoblasts, and primary neurons; gain- and loss-of-function mutations with opposite lysosomal phenotypes","pmids":["29668857"],"is_preprint":false},{"year":2019,"finding":"αB-crystallin interacts directly with ATP6V1A (the A subunit of V-ATPase V1 domain) at lysosomes, stabilizing it against proteasomal degradation; mTORC1 phosphorylates ATP6V1A at Ser-441 to promote this interaction; HSF4 deficiency reduces αB-crystallin expression, leading to ubiquitination and degradation of ATP6V1A and elevated lysosomal pH.","method":"GST pull-down, co-immunoprecipitation, lysosome fractionation by ultracentrifugation, immunoblotting, site-directed mutagenesis (S441A), rapamycin/siRNA mTOR inhibition, zebrafish HSF4 knockdown model","journal":"Biochimica et biophysica acta. General subjects","confidence":"High","confidence_rationale":"Tier 1-2 — GST pull-down, mutagenesis of phosphorylation site, fractionation, and in vivo zebrafish model all supporting the same mechanism","pmids":["31786107"],"is_preprint":false},{"year":2020,"finding":"ATP6V1A interacts with the rabies virus matrix protein (M) via the middle domain of ATP6V1A (dependent on Lys-256 and Glu-279 of M protein) in endosomes, and facilitates viral uncoating by promoting dissociation of incoming M proteins; ATP6V1A knockdown reduces and overexpression enhances RABV replication.","method":"Proteomic interactome mapping, co-immunoprecipitation, domain deletion mapping, ATP6V1A knockdown/overexpression in HEK293T and Vero cells, viral growth assay, viral uncoating assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP with domain mapping, loss- and gain-of-function with viral phenotype, trans-complementation rescue","pmids":["33208464"],"is_preprint":false},{"year":2023,"finding":"HIF-1α transcriptionally downregulates ATP6V1A under hypoxia, which impairs lysosomal homeostasis, reduces fusion of multivesicular bodies (MVBs) with lysosomes, and thereby increases secretion of endosome-derived extracellular vesicles in head and neck squamous cell carcinoma cells.","method":"HIF-1α ChIP/direct binding to ATP6V1A promoter, ATP6V1A knockdown/overexpression, MVB-lysosome fusion assay, EV characterization, LysoTracker staining","journal":"Journal of extracellular vesicles","confidence":"Medium","confidence_rationale":"Tier 2 — direct transcriptional regulation demonstrated with functional cellular readouts, single study","pmids":["36748335"],"is_preprint":false},{"year":2022,"finding":"De novo missense ATP6V1A variants cause lysosomal impairment with phenotype severity correlating with direction of dysfunction: severe DEE patient fibroblasts show decreased LAMP1, reduced LysoTracker staining and increased organelle pH (loss of function), while milder disease fibroblasts show increased LysoTracker staining and decreased organelle pH; iPSC-derived neurons show smaller lysosomes and accumulation of electron-dense inclusions.","method":"LysoTracker staining, LAMP1 immunoblotting, organelle pH measurement, substrate accumulation assay, transmission electron microscopy of fibroblasts and iPSC-derived neurons","journal":"Brain : a journal of neurology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods in patient-derived cells and iPSC neurons across multiple patients, replicating and extending prior mechanistic findings","pmids":["35675510"],"is_preprint":false},{"year":2024,"finding":"Atp6v1a depletion in murine hippocampal neurons impairs lysosomal pH regulation and autophagy progression, leading to accumulation of aberrant lysosomes at the soma and enlarged vacuoles at synaptic boutons, and prevents synaptic rearrangement upon plasticity induction; overall V1 subunit expression is decreased upon Atp6v1a loss.","method":"shRNA knockdown in primary murine hippocampal neurons, immunofluorescence, electrophysiological recordings, electron microscopy, LysoTracker staining, autophagy flux assays","journal":"Acta physiologica (Oxford, England)","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function with multiple orthogonal readouts (morphology, electrophysiology, EM) in primary neurons","pmids":["38837572"],"is_preprint":false},{"year":2025,"finding":"GPNMB interacts with ATP6V1A (lysosomal V-ATPase catalytic subunit A) in microglia; GPNMB is internalized and presents engulfed pathogenic particles to lysosomes via this interaction; activating ATP6V1A rescues phagocytosis defects caused by GPNMB deficiency.","method":"Co-immunoprecipitation, GPNMB genetic ablation, phagocytosis assay, rescue by ATP6V1A activation, immunofluorescence","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP with functional rescue, single study","pmids":["39992792"],"is_preprint":false},{"year":2017,"finding":"Transcription factor YY1 directly binds three sites in the ATP6V1A core promoter and transcriptionally activates ATP6V1A expression; YY1 RNAi knockdown in gastric cancer cells significantly decreases ATP6V1A mRNA and protein, while YY1 overexpression increases it.","method":"Promoter analysis, RNAi knockdown, overexpression, RT-PCR, immunoblotting","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — promoter binding and bidirectional expression manipulation, single study","pmids":["28592880"],"is_preprint":false},{"year":2026,"finding":"AHR (aryl hydrocarbon receptor) transcriptionally upregulates CISH by binding its promoter; CISH then promotes ubiquitination and proteasomal degradation of ATP6V1A, disrupting lysosomal acidification in decidual macrophages under high kynurenine conditions.","method":"ChIP for AHR binding to CISH promoter, CISH siRNA, ubiquitination assay, lysosomal pH measurement, in vivo mouse pregnancy model with KYN administration and AHR inhibitor","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic pathway defined by ChIP, ubiquitination assay, and in vivo rescue, single study","pmids":["41522347"],"is_preprint":false},{"year":2003,"finding":"Nuclear import of the VMA1-derived endonuclease (VDE/intein) during meiosis requires karyopherins Srp1p and Kap142p; TOR kinase inactivation or nutrient depletion triggers relocalization of VDE from cytoplasm to nucleus, enabling homing endonuclease activity at the VMA1 locus.","method":"Functional genomics screen, genetic interaction analysis, physical interaction (Srp1p-VDE), live imaging of VDE localization, TOR kinase inhibition, artificial NLS insertion","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic and physical interaction with localization data, relevant to VMA1 intein biology","pmids":["12588991"],"is_preprint":false}],"current_model":"ATP6V1A encodes the catalytic A subunit of the V-ATPase V1 domain, which hydrolyzes ATP to drive proton translocation into intracellular compartments; it is regulated post-translationally by AMPK-mediated phosphorylation at Ser-384 (inhibiting pump activity and causing its cytoplasmic redistribution), by mTORC1-dependent phosphorylation at Ser-441 that promotes its stabilization through interaction with αB-crystallin, and by ubiquitin-proteasome degradation triggered by CISH; it is essential for lysosomal acidification, autophagy flux, vesicular trafficking, neurite elongation, and synaptic plasticity in neurons, and its dysfunction—through either gain- or loss-of-function mutations—causes lysosomal pH dysregulation underlying developmental epileptic encephalopathy and cutis laxa."},"narrative":{"teleology":[{"year":1988,"claim":"Establishing that the V-ATPase subunit A contains the catalytic ATP hydrolysis site resolved a key question about which subunit drives proton pumping, grounding all subsequent functional studies of ATP6V1A.","evidence":"Gene cloning and sequence homology analysis of Neurospora crassa vma-1 revealing a conserved nucleotide-binding region","pmids":["2971651"],"confidence":"High","gaps":["No direct biochemical demonstration of ATP hydrolysis by purified subunit A alone","Mammalian ortholog not yet characterized"]},{"year":1992,"claim":"Defining the protein splicing mechanism of the yeast VMA1 intein established that specific cysteine residues catalyze an autocatalytic excision reaction required to generate the functional 69-kDa subunit A — a unique post-translational processing event among ATPase subunits.","evidence":"Site-directed mutagenesis of Cys-284 and Cys-738 in yeast, in vitro reconstitution of splicing, and X-ray crystallography (2.1 Å) of the intein precursor revealing the N→S acyl shift mechanism","pmids":["1417861","8651930","11884132"],"confidence":"High","gaps":["Intein splicing is specific to yeast/fungal VMA1 and does not occur in metazoan ATP6V1A","Regulation of splicing efficiency in vivo not fully understood"]},{"year":2007,"claim":"Demonstrating that atp6v1a knockdown in zebrafish abolishes acid secretion and disrupts ion homeostasis in vivo established the subunit's non-redundant role in organismal physiology beyond yeast genetics.","evidence":"Morpholino antisense knockdown in zebrafish with in vivo acid secretion and ion measurements","pmids":["17272665"],"confidence":"High","gaps":["Morpholino approach cannot distinguish cell-autonomous from systemic effects","Mammalian in vivo loss-of-function not yet performed at this stage"]},{"year":2013,"claim":"Identifying AMPK as a direct kinase phosphorylating ATP6V1A at Ser-384 revealed the first post-translational regulatory switch controlling V-ATPase membrane targeting and proton secretion, linking cellular energy sensing to pump activity.","evidence":"In vitro kinase assay, mass spectrometry site identification, S384A mutagenesis, H+ secretion assay in perfused kidney collecting duct and HEK-293 cells","pmids":["23863464"],"confidence":"High","gaps":["Whether Ser-384 phosphorylation regulates V-ATPase in non-renal tissues was untested","Structural basis for how phosphorylation disrupts membrane association unknown"]},{"year":2017,"claim":"Linking biallelic ATP6V1A missense mutations to autosomal-recessive cutis laxa — with complexome profiling showing disrupted V-ATPase assembly and functional assays revealing impaired Golgi retrograde trafficking — established ATP6V1A as a disease gene and connected it to vesicular trafficking beyond lysosomes.","evidence":"Whole-exome sequencing, BN-PAGE/LC-MS/MS complexome profiling, brefeldin A transport assay, electron microscopy in patient fibroblasts","pmids":["28065471"],"confidence":"High","gaps":["How specific missense mutations differentially affect V1–V0 assembly versus catalytic activity not resolved","No animal model recapitulating cutis laxa phenotype at this time"]},{"year":2018,"claim":"Characterizing de novo heterozygous ATP6V1A mutations revealed that gain-of-function and loss-of-function variants cause opposing lysosomal pH changes yet both impair autophagosome recruitment and neuronal function, establishing the mechanistic basis of developmental epileptic encephalopathy and showing that precise V-ATPase activity is required for neuronal health.","evidence":"LysoTracker/LysoSensor fluorescence, cycloheximide chase, autophagosome recruitment assay, neurite morphology and synaptic input measurements in HEK293T cells, patient lymphoblasts, and primary rat neurons","pmids":["29668857"],"confidence":"High","gaps":["How gain-of-function mutations mechanistically increase proton pumping not defined","Patient-specific neuronal models (iPSC) not yet fully developed at this stage"]},{"year":2019,"claim":"Discovery that mTORC1 phosphorylates ATP6V1A at Ser-441 to promote αB-crystallin binding and protect it from proteasomal degradation established a second signaling axis (mTORC1–αB-crystallin) controlling V-ATPase stability at lysosomes, complementing the AMPK pathway.","evidence":"GST pull-down, co-immunoprecipitation, S441A mutagenesis, rapamycin treatment, lysosome fractionation, zebrafish HSF4 knockdown model","pmids":["31786107"],"confidence":"High","gaps":["Whether mTORC1-mediated stabilization operates in neurons or immune cells not tested","E3 ligase mediating ATP6V1A ubiquitination in this context not identified"]},{"year":2022,"claim":"Extending genotype–phenotype correlations across multiple ATP6V1A variants in patient fibroblasts and iPSC-derived neurons confirmed that phenotype severity scales with the direction and magnitude of lysosomal pH disruption, and revealed ultrastructural pathology (electron-dense inclusions, small lysosomes) in human neurons.","evidence":"LysoTracker staining, LAMP1 immunoblotting, organelle pH measurement, substrate accumulation assay, electron microscopy in patient fibroblasts and iPSC-derived neurons","pmids":["35675510"],"confidence":"High","gaps":["Molecular basis for differential assembly defects of individual variants not structurally resolved","Whether lysosomal storage material composition differs between variants unknown"]},{"year":2024,"claim":"Demonstrating that Atp6v1a depletion in primary hippocampal neurons blocks autophagy progression, causes aberrant lysosome accumulation, and prevents synaptic rearrangement upon plasticity induction directly linked V-ATPase catalytic subunit function to synaptic plasticity mechanisms.","evidence":"shRNA knockdown in murine hippocampal neurons, electrophysiology, electron microscopy, autophagy flux assays","pmids":["38837572"],"confidence":"High","gaps":["Whether synaptic phenotypes are cell-autonomous or involve non-cell-autonomous signaling not determined","In vivo conditional knockout model in brain not yet reported"]},{"year":2025,"claim":"Identifying CISH as an E3 ligase adaptor that ubiquitinates ATP6V1A for proteasomal degradation, downstream of AHR transcriptional activation, defined a third regulatory axis controlling V-ATPase protein levels and connected ATP6V1A turnover to immune microenvironment signaling.","evidence":"ChIP for AHR binding to CISH promoter, CISH siRNA, ubiquitination assay, lysosomal pH measurement, in vivo mouse pregnancy model","pmids":["41522347"],"confidence":"Medium","gaps":["Whether CISH directly ubiquitinates ATP6V1A or acts through a complex is not distinguished","Relevance outside decidual macrophages not established","Single study without independent replication"]},{"year":null,"claim":"Key unresolved questions include the structural basis for how specific disease-causing missense mutations alter V-ATPase catalytic activity or assembly, whether the multiple regulatory phosphorylation and ubiquitination pathways converge on a common mechanism of V1–V0 dissociation, and whether in vivo conditional knockout in mammalian brain recapitulates the synaptic and epileptic phenotypes seen in patients.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of mammalian V-ATPase with disease mutations","No conditional brain-specific Atp6v1a knockout mouse model reported","Crosstalk between AMPK, mTORC1, and CISH regulatory axes on the same subunit unexplored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[10,11,14,15]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[12]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[7,10]},{"term_id":"GO:0005773","term_label":"vacuole","supporting_discovery_ids":[0,8]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[7,8,10,15]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[10,15]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[9,13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[9,10,14]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[7,11,18]}],"complexes":["V-ATPase V1 domain"],"partners":["CRYAB","PRKAA1","MTOR","CISH","GPNMB","YY1"],"other_free_text":[]},"mechanistic_narrative":"ATP6V1A encodes the catalytic A subunit of the V1 domain of the vacuolar H+-ATPase (V-ATPase), which hydrolyzes ATP to drive proton translocation across intracellular membranes and is essential for lysosomal acidification, autophagy flux, vesicular trafficking, and synaptic plasticity. The subunit is regulated post-translationally by AMPK phosphorylation at Ser-384, which inhibits proton secretion and causes cytoplasmic redistribution [PMID:23863464], and by mTORC1 phosphorylation at Ser-441, which promotes stabilization through interaction with αB-crystallin at lysosomes; loss of this stabilization leads to ubiquitin–proteasome-mediated degradation and elevated lysosomal pH [PMID:31786107], a pathway also engaged by CISH-mediated ubiquitination [PMID:41522347]. De novo heterozygous missense mutations in ATP6V1A cause developmental epileptic encephalopathy through either gain-of-function (hyperacidification) or loss-of-function (impaired acidification) effects on lysosomes, while biallelic mutations cause autosomal-recessive cutis laxa linked to disrupted V-ATPase complex assembly and Golgi trafficking defects [PMID:29668857, PMID:28065471, PMID:35675510]. In neurons, ATP6V1A depletion impairs lysosomal pH regulation, blocks autophagy progression, reduces neurite elongation and excitatory synaptic input, and prevents synaptic rearrangement upon plasticity induction [PMID:38837572, PMID:29668857]."},"prefetch_data":{"uniprot":{"accession":"P38606","full_name":"V-type proton ATPase catalytic subunit A","aliases":["V-ATPase 69 kDa subunit","Vacuolar ATPase isoform VA68","Vacuolar proton pump subunit alpha"],"length_aa":617,"mass_kda":68.3,"function":"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 (PubMed:8463241). V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments and in some cell types, is targeted to the plasma membrane, where it is responsible for acidifying the extracellular environment (PubMed:32001091). In aerobic conditions, involved in intracellular iron homeostasis, thus triggering the activity of Fe(2+) prolyl hydroxylase (PHD) enzymes, and leading to HIF1A hydroxylation and subsequent proteasomal degradation (PubMed:28296633). May play a role in neurite development and synaptic connectivity (PubMed:29668857) (Microbial infection) Plays an important role in virion uncoating during Rabies virus replication after membrane fusion. Specifically, participates in the dissociation of incoming viral matrix M proteins uncoating through direct interaction","subcellular_location":"Cytoplasm; Cytoplasm, cytosol; Cytoplasmic vesicle, secretory vesicle; Cytoplasmic vesicle, clathrin-coated vesicle membrane; Lysosome","url":"https://www.uniprot.org/uniprotkb/P38606/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/ATP6V1A","classification":"Common Essential","n_dependent_lines":1195,"n_total_lines":1208,"dependency_fraction":0.9892384105960265},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000114573","cell_line_id":"CID001646","localizations":[{"compartment":"vesicles","grade":3}],"interactors":[{"gene":"ATP6AP2","stoichiometry":10.0},{"gene":"ATP6V1G1","stoichiometry":10.0},{"gene":"ATP6V1E1","stoichiometry":10.0},{"gene":"ATP6V1B2","stoichiometry":10.0},{"gene":"ATP6V1D","stoichiometry":10.0},{"gene":"ATP6V1H","stoichiometry":10.0},{"gene":"ATP6V0A1","stoichiometry":4.0},{"gene":"ATP6V0D1","stoichiometry":4.0},{"gene":"ATP6V1C1","stoichiometry":4.0},{"gene":"ATP6V1F","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001646","total_profiled":1310},"omim":[{"mim_id":"618012","title":"DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 93; DEE93","url":"https://www.omim.org/entry/618012"},{"mim_id":"617403","title":"CUTIS LAXA, AUTOSOMAL RECESSIVE, TYPE IID; ARCL2D","url":"https://www.omim.org/entry/617403"},{"mim_id":"617402","title":"CUTIS LAXA, AUTOSOMAL RECESSIVE, TYPE IIC; ARCL2C","url":"https://www.omim.org/entry/617402"},{"mim_id":"609007","title":"LEUCINE-RICH REPEAT KINASE 2; LRRK2","url":"https://www.omim.org/entry/609007"},{"mim_id":"607027","title":"ATPase, H+ TRANSPORTING, LYSOSOMAL, 70-KD, VI SUBUNIT A; ATP6V1A","url":"https://www.omim.org/entry/607027"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ATP6V1A"},"hgnc":{"alias_symbol":["Vma1","VA68"],"prev_symbol":["VPP2","ATP6A1","ATP6V1A1"]},"alphafold":{"accession":"P38606","domains":[{"cath_id":"2.40.30.20","chopping":"1-85","consensus_level":"medium","plddt":84.6893,"start":1,"end":85},{"cath_id":"2.40.50.100","chopping":"132-205","consensus_level":"high","plddt":93.7461,"start":132,"end":205},{"cath_id":"3.40.50.300","chopping":"216-456","consensus_level":"high","plddt":92.2109,"start":216,"end":456},{"cath_id":"1.10.1140.10","chopping":"470-615","consensus_level":"high","plddt":92.0588,"start":470,"end":615}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P38606","model_url":"https://alphafold.ebi.ac.uk/files/AF-P38606-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P38606-F1-predicted_aligned_error_v6.png","plddt_mean":90.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ATP6V1A","jax_strain_url":"https://www.jax.org/strain/search?query=ATP6V1A"},"sequence":{"accession":"P38606","fasta_url":"https://rest.uniprot.org/uniprotkb/P38606.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P38606/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P38606"}},"corpus_meta":[{"pmid":"2139027","id":"PMC_2139027","title":"Molecular structure of a gene, VMA1, encoding the catalytic subunit of H(+)-translocating adenosine triphosphatase from vacuolar membranes of Saccharomyces cerevisiae.","date":"1990","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/2139027","citation_count":391,"is_preprint":false},{"pmid":"2971651","id":"PMC_2971651","title":"Isolation of genes encoding the Neurospora vacuolar ATPase. Analysis of vma-1 encoding the 67-kDa subunit reveals homology to other ATPases.","date":"1988","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/2971651","citation_count":199,"is_preprint":false},{"pmid":"2844751","id":"PMC_2844751","title":"Isolation of genes encoding the Neurospora vacuolar ATPase. Analysis of vma-2 encoding the 57-kDa polypeptide and comparison to vma-1.","date":"1988","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/2844751","citation_count":150,"is_preprint":false},{"pmid":"17272665","id":"PMC_17272665","title":"Knockdown of V-ATPase subunit A (atp6v1a) impairs acid secretion and ion balance in zebrafish (Danio rerio).","date":"2007","source":"American journal of physiology. Regulatory, integrative and comparative physiology","url":"https://pubmed.ncbi.nlm.nih.gov/17272665","citation_count":126,"is_preprint":false},{"pmid":"28065471","id":"PMC_28065471","title":"Mutations in ATP6V1E1 or ATP6V1A Cause Autosomal-Recessive Cutis Laxa.","date":"2017","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28065471","citation_count":86,"is_preprint":false},{"pmid":"29668857","id":"PMC_29668857","title":"De novo mutations of the ATP6V1A gene cause developmental encephalopathy with epilepsy.","date":"2018","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/29668857","citation_count":69,"is_preprint":false},{"pmid":"36748335","id":"PMC_36748335","title":"Hypoxia promotes EV secretion by impairing lysosomal homeostasis in HNSCC through negative regulation of ATP6V1A by HIF-1α.","date":"2023","source":"Journal of extracellular vesicles","url":"https://pubmed.ncbi.nlm.nih.gov/36748335","citation_count":65,"is_preprint":false},{"pmid":"9188457","id":"PMC_9188457","title":"Identification of three core regions essential for protein splicing of the yeast Vma1 protozyme. A random mutagenesis study of the entire Vma1-derived endonuclease sequence.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9188457","citation_count":65,"is_preprint":false},{"pmid":"11884132","id":"PMC_11884132","title":"Protein-splicing reaction via a thiazolidine intermediate: crystal structure of the VMA1-derived endonuclease bearing the N and C-terminal propeptides.","date":"2002","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/11884132","citation_count":61,"is_preprint":false},{"pmid":"1417861","id":"PMC_1417861","title":"Mutations at the putative junction sites of the yeast VMA1 protein, the catalytic subunit of the vacuolar membrane H(+)-ATPase, inhibit its processing by protein splicing.","date":"1992","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/1417861","citation_count":59,"is_preprint":false},{"pmid":"10092625","id":"PMC_10092625","title":"Physiological consequence of disruption of the VMA1 gene in the riboflavin overproducer Ashbya gossypii.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10092625","citation_count":49,"is_preprint":false},{"pmid":"23863464","id":"PMC_23863464","title":"AMP-activated protein kinase regulates the vacuolar H+-ATPase via direct phosphorylation of the A subunit (ATP6V1A) in the kidney.","date":"2013","source":"American journal of physiology. Renal physiology","url":"https://pubmed.ncbi.nlm.nih.gov/23863464","citation_count":49,"is_preprint":false},{"pmid":"10617601","id":"PMC_10617601","title":"Disruption of vma-1, the gene encoding the catalytic subunit of the vacuolar H(+)-ATPase, causes severe morphological changes in Neurospora crassa.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10617601","citation_count":46,"is_preprint":false},{"pmid":"1437572","id":"PMC_1437572","title":"VDE endonuclease cleaves Saccharomyces cerevisiae genomic DNA at a single site: physical mapping of the VMA1 gene.","date":"1992","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/1437572","citation_count":34,"is_preprint":false},{"pmid":"35675510","id":"PMC_35675510","title":"Phenotypic and genetic spectrum of ATP6V1A encephalopathy: a disorder of lysosomal homeostasis.","date":"2022","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/35675510","citation_count":31,"is_preprint":false},{"pmid":"9286669","id":"PMC_9286669","title":"Probing novel elements for protein splicing in the yeast Vma1 protozyme: a study of replacement mutagenesis and intragenic suppression.","date":"1997","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9286669","citation_count":31,"is_preprint":false},{"pmid":"33981384","id":"PMC_33981384","title":"Downregulation of ATP6V1A Involved in Alzheimer's Disease via Synaptic Vesicle Cycle, Phagosome, and Oxidative Phosphorylation.","date":"2021","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/33981384","citation_count":26,"is_preprint":false},{"pmid":"8651930","id":"PMC_8651930","title":"Folding-dependent in vitro protein splicing of the Saccharomyces cerevisiae VMA1 protozyme.","date":"1996","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/8651930","citation_count":22,"is_preprint":false},{"pmid":"33208464","id":"PMC_33208464","title":"The ATPase ATP6V1A facilitates rabies virus replication by promoting virion uncoating and interacting with the viral matrix protein.","date":"2020","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/33208464","citation_count":20,"is_preprint":false},{"pmid":"31786107","id":"PMC_31786107","title":"Heat shock factor 4 regulates lysosome activity by modulating the αB-crystallin-ATP6V1A-mTOR complex in ocular lens.","date":"2019","source":"Biochimica et biophysica acta. 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communications","url":"https://pubmed.ncbi.nlm.nih.gov/7575517","citation_count":14,"is_preprint":false},{"pmid":"9276458","id":"PMC_9276458","title":"Protein splicing in the yeast Vma1 protozyme: evidence for an intramolecular reaction.","date":"1997","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/9276458","citation_count":14,"is_preprint":false},{"pmid":"12588991","id":"PMC_12588991","title":"Karyopherin-mediated nuclear import of the homing endonuclease VMA1-derived endonuclease is required for self-propagation of the coding region.","date":"2003","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/12588991","citation_count":14,"is_preprint":false},{"pmid":"28592880","id":"PMC_28592880","title":"Expression and Transcriptional Regulation of Human ATP6V1A Gene in Gastric Cancers.","date":"2017","source":"Scientific 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disease","url":"https://pubmed.ncbi.nlm.nih.gov/33320377","citation_count":11,"is_preprint":false},{"pmid":"29274513","id":"PMC_29274513","title":"miR-143 inhibits intracellular salmonella growth by targeting ATP6V1A in macrophage cells in pig.","date":"2017","source":"Research in veterinary science","url":"https://pubmed.ncbi.nlm.nih.gov/29274513","citation_count":11,"is_preprint":false},{"pmid":"21472218","id":"PMC_21472218","title":"Fluid shear stress changes cell morphology and regulates the expression of ATP6V1A and TCIRG1 mRNA in rat osteoclasts.","date":"2010","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/21472218","citation_count":10,"is_preprint":false},{"pmid":"10205905","id":"PMC_10205905","title":"Functional complementation of yeast vma1 delta cells by a plant subunit A homolog rescues the mutant phenotype and partially restores vacuolar H(+)-ATPase activity.","date":"1999","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/10205905","citation_count":9,"is_preprint":false},{"pmid":"7654757","id":"PMC_7654757","title":"The V-ATPase A subunit gene (vma-1) from Giardia lamblia.","date":"1995","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/7654757","citation_count":9,"is_preprint":false},{"pmid":"35452875","id":"PMC_35452875","title":"A dual action small molecule enhances azoles and overcomes resistance through co-targeting Pdr5 and Vma1.","date":"2022","source":"Translational research : the journal of laboratory and clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35452875","citation_count":5,"is_preprint":false},{"pmid":"38837572","id":"PMC_38837572","title":"ATP6V1A is required for synaptic rearrangements and plasticity in murine hippocampal neurons.","date":"2024","source":"Acta physiologica (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/38837572","citation_count":5,"is_preprint":false},{"pmid":"32045939","id":"PMC_32045939","title":"Novel Mutation in ATP6V1A Gene with Infantile Spasms in an Indian Boy.","date":"2020","source":"Neuropediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/32045939","citation_count":4,"is_preprint":false},{"pmid":"33476559","id":"PMC_33476559","title":"An Integrated Multi-omics Approach Identifies Therapeutic Potential for ATP6V1A in Late Onset Alzheimer's Disease.","date":"2021","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/33476559","citation_count":4,"is_preprint":false},{"pmid":"37729800","id":"PMC_37729800","title":"A heterozygous pathogenic variant in the ATP6V1A gene triggering epilepsy in a large Chinese pedigree.","date":"2023","source":"Clinical neurology and neurosurgery","url":"https://pubmed.ncbi.nlm.nih.gov/37729800","citation_count":3,"is_preprint":false},{"pmid":"16757746","id":"PMC_16757746","title":"Investigation of the mechanism of meiotic DNA cleavage by VMA1-derived endonuclease uncovers a meiotic alteration in chromatin structure around the target site.","date":"2006","source":"Eukaryotic cell","url":"https://pubmed.ncbi.nlm.nih.gov/16757746","citation_count":3,"is_preprint":false},{"pmid":"40225911","id":"PMC_40225911","title":"Clinical and Genetic Characteristics of Two Cases With Developmental and Epileptic Encephalopathy 93 Caused by Novel ATP6V1A Mutations and Literature Review.","date":"2024","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/40225911","citation_count":2,"is_preprint":false},{"pmid":"39336810","id":"PMC_39336810","title":"Expanding the Spectrum of Autosomal Dominant ATP6V1A-Related Disease: Case Report and Literature Review.","date":"2024","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/39336810","citation_count":1,"is_preprint":false},{"pmid":"10780447","id":"PMC_10780447","title":"Recognition and cleavage of double-stranded DNA by yeast VMA1-derived endonuclease.","date":"1999","source":"Nucleic acids symposium series","url":"https://pubmed.ncbi.nlm.nih.gov/10780447","citation_count":1,"is_preprint":false},{"pmid":"41233134","id":"PMC_41233134","title":"[Genetic and clinical characteristics in epilepsy patients with ATP6V1A gene variants].","date":"2025","source":"Zhonghua er ke za zhi = Chinese journal of pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/41233134","citation_count":0,"is_preprint":false},{"pmid":"41522347","id":"PMC_41522347","title":"Excessive Kynurenine Metabolism Impairs Lysosomal acidification and Triggers mtDNA Release via the AHR/CISH/ATP6V1A Axis in Decidual Macrophages Associated with Unexplained Recurrent Pregnancy Loss.","date":"2026","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41522347","citation_count":0,"is_preprint":false},{"pmid":"17896502","id":"PMC_17896502","title":"[Effects of fluid shear stress strength on mRNA expression of ATP6V1a1 in polarized osteoclasts].","date":"2007","source":"Hua xi kou qiang yi xue za zhi = Huaxi kouqiang yixue zazhi = West China journal of stomatology","url":"https://pubmed.ncbi.nlm.nih.gov/17896502","citation_count":0,"is_preprint":false},{"pmid":"41463574","id":"PMC_41463574","title":"Mechanistic Study of Hypoxia-Mediated Regulation of Osteoblast Senescence via ATP6V1A-Dependent Modulation of Metabolic Remodeling.","date":"2025","source":"Biology","url":"https://pubmed.ncbi.nlm.nih.gov/41463574","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":22235,"output_tokens":4947,"usd":0.070455},"stage2":{"model":"claude-opus-4-6","input_tokens":8474,"output_tokens":3119,"usd":0.180517},"total_usd":0.250972,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1990,\n      \"finding\": \"The yeast VMA1 gene encodes the catalytic subunit (subunit A) of the vacuolar membrane H+-translocating ATPase; the 1,071 amino acid precursor undergoes post-translational protein splicing, excising an internal 454-residue domain and ligating the flanking regions to produce the functional 69-kDa subunit.\",\n      \"method\": \"Gene cloning, sequencing, N-terminal peptide sequencing, Northern blotting, molecular mass analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — original molecular characterization with sequence analysis and functional splicing inference, foundational paper with 391 citations\",\n      \"pmids\": [\"2139027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"The Neurospora crassa vma-1-encoded 67-kDa subunit A of the vacuolar ATPase contains the active site for ATP hydrolysis, as indicated by a putative nucleotide-binding region in its sequence and high homology to catalytic subunits of other ATPases including F0F1 beta subunits.\",\n      \"method\": \"Gene cloning, cDNA sequencing, sequence homology analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — sequence-based identification of ATP hydrolysis active site with 199 citations, foundational paper\",\n      \"pmids\": [\"2971651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"Cysteine residues at positions 284 and 738 in yeast Vma1p are essential for the protein splicing reaction: Cys-284 mutation blocks cleavage at the N-terminal junction, while Cys-738 mutation blocks processing at both junction sites, preventing generation of functional 69-kDa V-ATPase subunit A.\",\n      \"method\": \"Site-directed mutagenesis, expression in vma1 null mutant yeast, immunoblotting\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis of specific catalytic residues with defined biochemical phenotype\",\n      \"pmids\": [\"1417861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Protein splicing of the yeast Vma1p protozyme is a folding-dependent, intramolecular, autocatalytic reaction that proceeds at optimal pH 7, is not inhibited by protease inhibitors, and can be reconstituted in vitro by refolding denatured precursor.\",\n      \"method\": \"In vitro protein splicing reconstitution, refolding assay, gel filtration, protease inhibitor panel\",\n      \"journal\": \"Biochemical and biophysical research communications / FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution of the splicing reaction with multiple mechanistic probes\",\n      \"pmids\": [\"8651930\", \"9276458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Random mutagenesis of the entire VDE (intein) region of yeast VMA1 identified three core regions essential for protein splicing: His-362 is required for first cleavage at the N-terminal junction, and His-736 assists the second cleavage via Asn cyclization at the C-terminal junction, while mutations in these regions do not destroy VDE endonuclease activity.\",\n      \"method\": \"PCR-based random mutagenesis, bacterial expression screen, yeast complementation, immunoblotting\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — systematic mutagenesis across entire intein with specific residue-to-phenotype mapping\",\n      \"pmids\": [\"9188457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"A conserved hydrophobic valine triplet preceding the C-terminal splicing junction of yeast Vma1p genetically interacts with hydrophobic residues preceding the N-terminal junction, demonstrating that the N-terminal portion of the V-ATPase subunit A participates in the protein splicing reaction through intramolecular beta-strand interactions.\",\n      \"method\": \"Random mutagenesis, intragenic suppressor analysis, yeast genetic complementation\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis/suppressor analysis in yeast, single study\",\n      \"pmids\": [\"9286669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Crystal structure (2.1 Å) of the yeast VMA1-derived endonuclease intein precursor reveals that protein splicing proceeds via an N→S acyl shift forming a thiazolidine intermediate at the N-terminal junction (Cys-284 attacks Gly-283 carbonyl), followed by transesterification involving Ser-738 at the C-terminal junction.\",\n      \"method\": \"X-ray crystallography at 2.1 Å resolution with mutagenesis of splice site residues\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution crystal structure combined with mutagenesis, defining the catalytic mechanism\",\n      \"pmids\": [\"11884132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"AMPK directly phosphorylates the V-ATPase A subunit (ATP6V1A) at Ser-384, and this phosphorylation inhibits V-ATPase-dependent H+ secretion in kidney intercalated cells and causes cytoplasmic redistribution of the V-ATPase; the phosphorylation-deficient S384A mutant prevents AMPK-mediated inhibition of extracellular acidification and blocks AICAR-induced V-ATPase redistribution.\",\n      \"method\": \"In vitro kinase assay, mass spectrometry identification of phosphorylation site, site-directed mutagenesis (S384A), perfused collecting duct H+ secretion assay, extracellular acidification assay in HEK-293 cells, immunofluorescence localization\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay + MS site identification + mutagenesis + functional assays in multiple systems\",\n      \"pmids\": [\"23863464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Morpholino knockdown of atp6v1a in zebrafish embryos suppresses acid secretion from H+-pump-rich skin cells, causes growth retardation, trunk deformation, and loss of internal Ca2+ and Na+, demonstrating that V-ATPase subunit A is required for acid secretion and ion balance in vivo.\",\n      \"method\": \"Morpholino antisense knockdown in zebrafish, in vivo acid secretion measurement, ion concentration analysis\",\n      \"journal\": \"American journal of physiology. Regulatory, integrative and comparative physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function in vertebrate model with specific physiological readouts, 126 citations\",\n      \"pmids\": [\"17272665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Biallelic missense mutations in ATP6V1A (encoding the A subunit of the V1 domain) cause autosomal-recessive cutis laxa; complexome profiling showed these mutations disturb either assembly or stability of the V-ATPase complex, and patient fibroblasts exhibit delayed retrograde Golgi transport and abnormal Golgi fragmentation, linking ATP6V1A to vesicular trafficking.\",\n      \"method\": \"Whole-exome sequencing, complexome profiling (BN-PAGE + LC-MS/MS), structural modeling, brefeldin A retrograde transport assay, transmission electron microscopy, protein glycosylation analysis\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including complexome profiling and functional cellular assays\",\n      \"pmids\": [\"28065471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"De novo heterozygous ATP6V1A mutations cause differential effects on lysosomal function: p.Asp349Asn (gain-of-function) increases lysosomal proton pumping (increased LysoTracker fluorescence, lower organelle pH), while p.Asp100Tyr (loss-of-function) reduces ATP6V1A expression through increased degradation and decreases lysosomal markers; both mutations reduce V-ATPase recruitment to autophagosomes and impair neurite elongation and excitatory synaptic input in hippocampal neurons.\",\n      \"method\": \"LysoTracker/LysoSensor fluorescence, LAMP1/EEA1 immunoblotting, cycloheximide chase (protein stability), autophagosome recruitment assay, neurite morphology analysis, synaptic input measurement in primary rat neurons\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal functional assays in HEK293T cells, patient lymphoblasts, and primary neurons; gain- and loss-of-function mutations with opposite lysosomal phenotypes\",\n      \"pmids\": [\"29668857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"αB-crystallin interacts directly with ATP6V1A (the A subunit of V-ATPase V1 domain) at lysosomes, stabilizing it against proteasomal degradation; mTORC1 phosphorylates ATP6V1A at Ser-441 to promote this interaction; HSF4 deficiency reduces αB-crystallin expression, leading to ubiquitination and degradation of ATP6V1A and elevated lysosomal pH.\",\n      \"method\": \"GST pull-down, co-immunoprecipitation, lysosome fractionation by ultracentrifugation, immunoblotting, site-directed mutagenesis (S441A), rapamycin/siRNA mTOR inhibition, zebrafish HSF4 knockdown model\",\n      \"journal\": \"Biochimica et biophysica acta. General subjects\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — GST pull-down, mutagenesis of phosphorylation site, fractionation, and in vivo zebrafish model all supporting the same mechanism\",\n      \"pmids\": [\"31786107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ATP6V1A interacts with the rabies virus matrix protein (M) via the middle domain of ATP6V1A (dependent on Lys-256 and Glu-279 of M protein) in endosomes, and facilitates viral uncoating by promoting dissociation of incoming M proteins; ATP6V1A knockdown reduces and overexpression enhances RABV replication.\",\n      \"method\": \"Proteomic interactome mapping, co-immunoprecipitation, domain deletion mapping, ATP6V1A knockdown/overexpression in HEK293T and Vero cells, viral growth assay, viral uncoating assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with domain mapping, loss- and gain-of-function with viral phenotype, trans-complementation rescue\",\n      \"pmids\": [\"33208464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HIF-1α transcriptionally downregulates ATP6V1A under hypoxia, which impairs lysosomal homeostasis, reduces fusion of multivesicular bodies (MVBs) with lysosomes, and thereby increases secretion of endosome-derived extracellular vesicles in head and neck squamous cell carcinoma cells.\",\n      \"method\": \"HIF-1α ChIP/direct binding to ATP6V1A promoter, ATP6V1A knockdown/overexpression, MVB-lysosome fusion assay, EV characterization, LysoTracker staining\",\n      \"journal\": \"Journal of extracellular vesicles\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct transcriptional regulation demonstrated with functional cellular readouts, single study\",\n      \"pmids\": [\"36748335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"De novo missense ATP6V1A variants cause lysosomal impairment with phenotype severity correlating with direction of dysfunction: severe DEE patient fibroblasts show decreased LAMP1, reduced LysoTracker staining and increased organelle pH (loss of function), while milder disease fibroblasts show increased LysoTracker staining and decreased organelle pH; iPSC-derived neurons show smaller lysosomes and accumulation of electron-dense inclusions.\",\n      \"method\": \"LysoTracker staining, LAMP1 immunoblotting, organelle pH measurement, substrate accumulation assay, transmission electron microscopy of fibroblasts and iPSC-derived neurons\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in patient-derived cells and iPSC neurons across multiple patients, replicating and extending prior mechanistic findings\",\n      \"pmids\": [\"35675510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Atp6v1a depletion in murine hippocampal neurons impairs lysosomal pH regulation and autophagy progression, leading to accumulation of aberrant lysosomes at the soma and enlarged vacuoles at synaptic boutons, and prevents synaptic rearrangement upon plasticity induction; overall V1 subunit expression is decreased upon Atp6v1a loss.\",\n      \"method\": \"shRNA knockdown in primary murine hippocampal neurons, immunofluorescence, electrophysiological recordings, electron microscopy, LysoTracker staining, autophagy flux assays\",\n      \"journal\": \"Acta physiologica (Oxford, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with multiple orthogonal readouts (morphology, electrophysiology, EM) in primary neurons\",\n      \"pmids\": [\"38837572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GPNMB interacts with ATP6V1A (lysosomal V-ATPase catalytic subunit A) in microglia; GPNMB is internalized and presents engulfed pathogenic particles to lysosomes via this interaction; activating ATP6V1A rescues phagocytosis defects caused by GPNMB deficiency.\",\n      \"method\": \"Co-immunoprecipitation, GPNMB genetic ablation, phagocytosis assay, rescue by ATP6V1A activation, immunofluorescence\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP with functional rescue, single study\",\n      \"pmids\": [\"39992792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Transcription factor YY1 directly binds three sites in the ATP6V1A core promoter and transcriptionally activates ATP6V1A expression; YY1 RNAi knockdown in gastric cancer cells significantly decreases ATP6V1A mRNA and protein, while YY1 overexpression increases it.\",\n      \"method\": \"Promoter analysis, RNAi knockdown, overexpression, RT-PCR, immunoblotting\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — promoter binding and bidirectional expression manipulation, single study\",\n      \"pmids\": [\"28592880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"AHR (aryl hydrocarbon receptor) transcriptionally upregulates CISH by binding its promoter; CISH then promotes ubiquitination and proteasomal degradation of ATP6V1A, disrupting lysosomal acidification in decidual macrophages under high kynurenine conditions.\",\n      \"method\": \"ChIP for AHR binding to CISH promoter, CISH siRNA, ubiquitination assay, lysosomal pH measurement, in vivo mouse pregnancy model with KYN administration and AHR inhibitor\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway defined by ChIP, ubiquitination assay, and in vivo rescue, single study\",\n      \"pmids\": [\"41522347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Nuclear import of the VMA1-derived endonuclease (VDE/intein) during meiosis requires karyopherins Srp1p and Kap142p; TOR kinase inactivation or nutrient depletion triggers relocalization of VDE from cytoplasm to nucleus, enabling homing endonuclease activity at the VMA1 locus.\",\n      \"method\": \"Functional genomics screen, genetic interaction analysis, physical interaction (Srp1p-VDE), live imaging of VDE localization, TOR kinase inhibition, artificial NLS insertion\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic and physical interaction with localization data, relevant to VMA1 intein biology\",\n      \"pmids\": [\"12588991\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATP6V1A encodes the catalytic A subunit of the V-ATPase V1 domain, which hydrolyzes ATP to drive proton translocation into intracellular compartments; it is regulated post-translationally by AMPK-mediated phosphorylation at Ser-384 (inhibiting pump activity and causing its cytoplasmic redistribution), by mTORC1-dependent phosphorylation at Ser-441 that promotes its stabilization through interaction with αB-crystallin, and by ubiquitin-proteasome degradation triggered by CISH; it is essential for lysosomal acidification, autophagy flux, vesicular trafficking, neurite elongation, and synaptic plasticity in neurons, and its dysfunction—through either gain- or loss-of-function mutations—causes lysosomal pH dysregulation underlying developmental epileptic encephalopathy and cutis laxa.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ATP6V1A encodes the catalytic A subunit of the V1 domain of the vacuolar H+-ATPase (V-ATPase), which hydrolyzes ATP to drive proton translocation across intracellular membranes and is essential for lysosomal acidification, autophagy flux, vesicular trafficking, and synaptic plasticity. The subunit is regulated post-translationally by AMPK phosphorylation at Ser-384, which inhibits proton secretion and causes cytoplasmic redistribution [PMID:23863464], and by mTORC1 phosphorylation at Ser-441, which promotes stabilization through interaction with αB-crystallin at lysosomes; loss of this stabilization leads to ubiquitin–proteasome-mediated degradation and elevated lysosomal pH [PMID:31786107], a pathway also engaged by CISH-mediated ubiquitination [PMID:41522347]. De novo heterozygous missense mutations in ATP6V1A cause developmental epileptic encephalopathy through either gain-of-function (hyperacidification) or loss-of-function (impaired acidification) effects on lysosomes, while biallelic mutations cause autosomal-recessive cutis laxa linked to disrupted V-ATPase complex assembly and Golgi trafficking defects [PMID:29668857, PMID:28065471, PMID:35675510]. In neurons, ATP6V1A depletion impairs lysosomal pH regulation, blocks autophagy progression, reduces neurite elongation and excitatory synaptic input, and prevents synaptic rearrangement upon plasticity induction [PMID:38837572, PMID:29668857].\",\n  \"teleology\": [\n    {\n      \"year\": 1988,\n      \"claim\": \"Establishing that the V-ATPase subunit A contains the catalytic ATP hydrolysis site resolved a key question about which subunit drives proton pumping, grounding all subsequent functional studies of ATP6V1A.\",\n      \"evidence\": \"Gene cloning and sequence homology analysis of Neurospora crassa vma-1 revealing a conserved nucleotide-binding region\",\n      \"pmids\": [\"2971651\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No direct biochemical demonstration of ATP hydrolysis by purified subunit A alone\", \"Mammalian ortholog not yet characterized\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Defining the protein splicing mechanism of the yeast VMA1 intein established that specific cysteine residues catalyze an autocatalytic excision reaction required to generate the functional 69-kDa subunit A — a unique post-translational processing event among ATPase subunits.\",\n      \"evidence\": \"Site-directed mutagenesis of Cys-284 and Cys-738 in yeast, in vitro reconstitution of splicing, and X-ray crystallography (2.1 Å) of the intein precursor revealing the N→S acyl shift mechanism\",\n      \"pmids\": [\"1417861\", \"8651930\", \"11884132\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Intein splicing is specific to yeast/fungal VMA1 and does not occur in metazoan ATP6V1A\", \"Regulation of splicing efficiency in vivo not fully understood\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrating that atp6v1a knockdown in zebrafish abolishes acid secretion and disrupts ion homeostasis in vivo established the subunit's non-redundant role in organismal physiology beyond yeast genetics.\",\n      \"evidence\": \"Morpholino antisense knockdown in zebrafish with in vivo acid secretion and ion measurements\",\n      \"pmids\": [\"17272665\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Morpholino approach cannot distinguish cell-autonomous from systemic effects\", \"Mammalian in vivo loss-of-function not yet performed at this stage\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identifying AMPK as a direct kinase phosphorylating ATP6V1A at Ser-384 revealed the first post-translational regulatory switch controlling V-ATPase membrane targeting and proton secretion, linking cellular energy sensing to pump activity.\",\n      \"evidence\": \"In vitro kinase assay, mass spectrometry site identification, S384A mutagenesis, H+ secretion assay in perfused kidney collecting duct and HEK-293 cells\",\n      \"pmids\": [\"23863464\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Ser-384 phosphorylation regulates V-ATPase in non-renal tissues was untested\", \"Structural basis for how phosphorylation disrupts membrane association unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linking biallelic ATP6V1A missense mutations to autosomal-recessive cutis laxa — with complexome profiling showing disrupted V-ATPase assembly and functional assays revealing impaired Golgi retrograde trafficking — established ATP6V1A as a disease gene and connected it to vesicular trafficking beyond lysosomes.\",\n      \"evidence\": \"Whole-exome sequencing, BN-PAGE/LC-MS/MS complexome profiling, brefeldin A transport assay, electron microscopy in patient fibroblasts\",\n      \"pmids\": [\"28065471\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How specific missense mutations differentially affect V1–V0 assembly versus catalytic activity not resolved\", \"No animal model recapitulating cutis laxa phenotype at this time\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Characterizing de novo heterozygous ATP6V1A mutations revealed that gain-of-function and loss-of-function variants cause opposing lysosomal pH changes yet both impair autophagosome recruitment and neuronal function, establishing the mechanistic basis of developmental epileptic encephalopathy and showing that precise V-ATPase activity is required for neuronal health.\",\n      \"evidence\": \"LysoTracker/LysoSensor fluorescence, cycloheximide chase, autophagosome recruitment assay, neurite morphology and synaptic input measurements in HEK293T cells, patient lymphoblasts, and primary rat neurons\",\n      \"pmids\": [\"29668857\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How gain-of-function mutations mechanistically increase proton pumping not defined\", \"Patient-specific neuronal models (iPSC) not yet fully developed at this stage\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Discovery that mTORC1 phosphorylates ATP6V1A at Ser-441 to promote αB-crystallin binding and protect it from proteasomal degradation established a second signaling axis (mTORC1–αB-crystallin) controlling V-ATPase stability at lysosomes, complementing the AMPK pathway.\",\n      \"evidence\": \"GST pull-down, co-immunoprecipitation, S441A mutagenesis, rapamycin treatment, lysosome fractionation, zebrafish HSF4 knockdown model\",\n      \"pmids\": [\"31786107\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether mTORC1-mediated stabilization operates in neurons or immune cells not tested\", \"E3 ligase mediating ATP6V1A ubiquitination in this context not identified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extending genotype–phenotype correlations across multiple ATP6V1A variants in patient fibroblasts and iPSC-derived neurons confirmed that phenotype severity scales with the direction and magnitude of lysosomal pH disruption, and revealed ultrastructural pathology (electron-dense inclusions, small lysosomes) in human neurons.\",\n      \"evidence\": \"LysoTracker staining, LAMP1 immunoblotting, organelle pH measurement, substrate accumulation assay, electron microscopy in patient fibroblasts and iPSC-derived neurons\",\n      \"pmids\": [\"35675510\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis for differential assembly defects of individual variants not structurally resolved\", \"Whether lysosomal storage material composition differs between variants unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrating that Atp6v1a depletion in primary hippocampal neurons blocks autophagy progression, causes aberrant lysosome accumulation, and prevents synaptic rearrangement upon plasticity induction directly linked V-ATPase catalytic subunit function to synaptic plasticity mechanisms.\",\n      \"evidence\": \"shRNA knockdown in murine hippocampal neurons, electrophysiology, electron microscopy, autophagy flux assays\",\n      \"pmids\": [\"38837572\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether synaptic phenotypes are cell-autonomous or involve non-cell-autonomous signaling not determined\", \"In vivo conditional knockout model in brain not yet reported\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identifying CISH as an E3 ligase adaptor that ubiquitinates ATP6V1A for proteasomal degradation, downstream of AHR transcriptional activation, defined a third regulatory axis controlling V-ATPase protein levels and connected ATP6V1A turnover to immune microenvironment signaling.\",\n      \"evidence\": \"ChIP for AHR binding to CISH promoter, CISH siRNA, ubiquitination assay, lysosomal pH measurement, in vivo mouse pregnancy model\",\n      \"pmids\": [\"41522347\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CISH directly ubiquitinates ATP6V1A or acts through a complex is not distinguished\", \"Relevance outside decidual macrophages not established\", \"Single study without independent replication\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis for how specific disease-causing missense mutations alter V-ATPase catalytic activity or assembly, whether the multiple regulatory phosphorylation and ubiquitination pathways converge on a common mechanism of V1–V0 dissociation, and whether in vivo conditional knockout in mammalian brain recapitulates the synaptic and epileptic phenotypes seen in patients.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of mammalian V-ATPase with disease mutations\", \"No conditional brain-specific Atp6v1a knockout mouse model reported\", \"Crosstalk between AMPK, mTORC1, and CISH regulatory axes on the same subunit unexplored\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [10, 11, 14, 15]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [7, 10]},\n      {\"term_id\": \"GO:0005773\", \"supporting_discovery_ids\": [0, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [7, 8, 10, 15]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [10, 15]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [9, 13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [9, 10, 14]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [7, 11, 18]}\n    ],\n    \"complexes\": [\n      \"V-ATPase V1 domain\"\n    ],\n    \"partners\": [\n      \"CRYAB\",\n      \"PRKAA1\",\n      \"MTOR\",\n      \"CISH\",\n      \"GPNMB\",\n      \"YY1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}