{"gene":"ATP6V1E1","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":1993,"finding":"The VMA4 gene of Saccharomyces cerevisiae encodes the 27-kDa subunit of the vacuolar H(+)-ATPase (ortholog of ATP6V1E1/E subunit). Deletion of VMA4 prevents assembly of the peripheral V1 domain onto the vacuolar membrane and abolishes ATPase activity, demonstrating that the E subunit is essential for V-ATPase assembly and function.","method":"Genetic deletion (vma4 null mutant), biochemical fractionation, ATPase activity assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined biochemical phenotype, replicated in yeast ortholog system","pmids":["8416931"],"is_preprint":false},{"year":1995,"finding":"The Neurospora crassa vma-4 gene encodes a 25.7 kDa subunit of the vacuolar ATPase (ortholog of ATP6V1E1). Sequence analysis and secondary structure prediction indicate this subunit plays the same structural role in V-ATPase as the gamma-subunit does in F-type ATPases, suggesting a conserved structural function in the rotary mechanism.","method":"Gene cloning, sequence analysis, comparative secondary structure prediction","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 3 — sequence/structural inference without functional mutagenesis, single study","pmids":["7619848"],"is_preprint":false},{"year":2001,"finding":"The V-ATPase E subunit directly interacts with aldolase (a glycolytic enzyme). This interaction was identified by yeast two-hybrid screening with the E subunit as bait, confirmed by GST pulldown with E subunit fusion proteins and metabolically labeled aldolase, and validated by co-immunoprecipitation from bovine kidney microsomes and osteoclasts using an anti-E subunit antibody. In yeast lacking aldolase, the V1 domain dissociates from V0, suggesting the E subunit-aldolase interaction couples glycolysis directly to V-ATPase proton pumping.","method":"Yeast two-hybrid, GST pulldown, co-immunoprecipitation, yeast aldolase-deficient mutant analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (Y2H, pulldown, co-IP, genetic epistasis) in single study","pmids":["11399750"],"is_preprint":false},{"year":2017,"finding":"Biallelic missense mutations in ATP6V1E1 (encoding the E1 subunit of the V1 domain of V-ATPase) cause autosomal-recessive cutis laxa with dysmorphic features and cardiopulmonary involvement. Structural modeling showed all substitutions affect critical residues and inter- or intra-subunit interactions. Complexome profiling (blue-native PAGE combined with LC-MS/MS) demonstrated that the mutations disturb either assembly or stability of the V-ATPase complex. Patient cells showed abnormal vesicular trafficking (delayed retrograde transport after brefeldin A, Golgi fragmentation) and reduced/fragmented elastic fibers with abnormal collagen organization.","method":"Whole-exome sequencing, structural modeling, complexome profiling (BN-PAGE + LC-MS/MS), brefeldin A trafficking assay, transmission electron microscopy","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including complexome profiling and functional trafficking assays; disease-causing mutations directly link ATP6V1E1 to V-ATPase assembly/stability","pmids":["28065471"],"is_preprint":false},{"year":2011,"finding":"The vacuolar H(+)-ATPase (V-ATPase, of which ATP6V1E1/E1 is a subunit) is required for amino acid-dependent activation of mTORC1. The v-ATPase engages in amino acid-sensitive interactions with the Ragulator complex on the lysosomal surface, and ATP hydrolysis by the v-ATPase is necessary for amino acids to regulate the v-ATPase–Ragulator interaction and promote mTORC1 translocation to the lysosome.","method":"RNAi knockdown, cell-free reconstitution system, co-immunoprecipitation, mTORC1 translocation imaging","journal":"Science","confidence":"High","confidence_rationale":"Tier 1-2 — cell-free reconstitution combined with genetic knockdown and co-IP; highly cited foundational study","pmids":["22053050"],"is_preprint":false},{"year":2026,"finding":"Mycobacterium tuberculosis secreted protein Rv1184 (Chp2) promotes intracellular bacterial survival by targeting ATP6V1E1. Phosphorylation of ATP6V1E1 at Tyr56/57 by tyrosine kinase BMX suppresses lysosomal acidification through inhibition of V-ATPase assembly. Chp2 directly binds ATP6V1E1 and facilitates its interaction with BMX, increasing BMX-dependent phosphorylation of ATP6V1E1. Inhibition of BMX impaired Mtb growth in macrophages and in mice.","method":"Co-immunoprecipitation, site-directed mutagenesis (Tyr56/57), lysosomal acidification assay, BMX inhibitor treatment, in vivo mouse infection model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 — identifies specific phosphorylation sites with mutagenesis, binding partner (BMX, Chp2), functional consequence (V-ATPase assembly inhibition), and in vivo validation","pmids":["41651829"],"is_preprint":false},{"year":2024,"finding":"ATP6V1E1 knockdown in hepatocellular carcinoma cells markedly inhibited cell proliferation, establishing a functional role for ATP6V1E1 in supporting HCC cell growth.","method":"siRNA knockdown, cell proliferation assay (in vitro)","journal":"Journal of cellular and molecular medicine","confidence":"Low","confidence_rationale":"Tier 3 — single method, no pathway placement beyond correlation with oncogenic gene sets","pmids":["39294741"],"is_preprint":false}],"current_model":"ATP6V1E1 encodes the E1 subunit of the V1 catalytic domain of the vacuolar H(+)-ATPase (V-ATPase); it is essential for V1 domain assembly onto the vacuolar membrane, directly binds aldolase to couple glycolysis to proton pumping, participates in lysosomal amino acid sensing upstream of mTORC1 via interactions with the Ragulator complex, and is regulated by BMX-mediated phosphorylation at Tyr56/57 (exploited by Mycobacterium tuberculosis to inhibit V-ATPase assembly and lysosomal acidification); loss-of-function mutations in ATP6V1E1 disrupt V-ATPase complex stability and cause impaired vesicular trafficking manifesting as autosomal-recessive cutis laxa."},"narrative":{"teleology":[{"year":1993,"claim":"Establishing that the E subunit is indispensable for V-ATPase function resolved a fundamental question about V1 domain assembly: deletion of the yeast ortholog VMA4 prevented V1 attachment to the vacuolar membrane and abolished ATPase activity.","evidence":"Genetic knockout of VMA4 in S. cerevisiae with biochemical fractionation and ATPase assays","pmids":["8416931"],"confidence":"High","gaps":["Mammalian E1 subunit function not yet directly tested","Mechanism by which E subunit promotes V1–V0 assembly unknown","No structural model of E subunit within the holoenzyme"]},{"year":2001,"claim":"Discovery that ATP6V1E1 directly binds aldolase established an unexpected physical link between glycolysis and V-ATPase proton pumping, answering how metabolic status could regulate vacuolar acidification.","evidence":"Yeast two-hybrid, GST pulldown, co-immunoprecipitation from bovine kidney, and aldolase-deficient yeast showing V1 dissociation","pmids":["11399750"],"confidence":"High","gaps":["Binding interface between E subunit and aldolase not mapped","Whether the interaction is regulated by glycolytic intermediates is untested","Relevance in mammalian tissues beyond kidney and osteoclasts not examined"]},{"year":2011,"claim":"Demonstrating that V-ATPase engages the Ragulator complex in an amino acid–sensitive manner placed the entire complex—including ATP6V1E1—as a lysosomal nutrient sensor upstream of mTORC1, answering how intraluminal amino acids are communicated to cytoplasmic signaling.","evidence":"RNAi knockdown, cell-free reconstitution, co-immunoprecipitation, and mTORC1 translocation imaging in mammalian cells","pmids":["22053050"],"confidence":"High","gaps":["Specific contribution of ATP6V1E1 versus other V1 subunits in Ragulator binding not delineated","How ATP hydrolysis modulates Ragulator interaction mechanistically is unclear","Whether V-ATPase–Ragulator interaction is tissue-specific is unexplored"]},{"year":2017,"claim":"Identification of biallelic ATP6V1E1 mutations causing autosomal-recessive cutis laxa directly linked this subunit to human disease, showing that impaired V-ATPase assembly disrupts vesicular trafficking, elastic fiber formation, and collagen organization.","evidence":"Whole-exome sequencing, complexome profiling (BN-PAGE + LC-MS/MS), brefeldin A trafficking assays, and TEM in patient-derived cells","pmids":["28065471"],"confidence":"High","gaps":["Precise structural consequences of each pathogenic substitution on inter-subunit contacts not resolved at atomic level","Whether residual V-ATPase activity correlates with clinical severity is unknown","Rescue experiments (e.g., wild-type complementation in patient cells) not reported"]},{"year":2026,"claim":"Identification of BMX-mediated phosphorylation at Tyr56/57 of ATP6V1E1 revealed a specific post-translational switch that inhibits V-ATPase assembly, answering how a host kinase can be co-opted by M. tuberculosis (via Chp2) to suppress lysosomal acidification and promote intracellular survival.","evidence":"Co-immunoprecipitation, Tyr56/57 site-directed mutagenesis, lysosomal acidification assays, BMX inhibitor treatment, and in vivo mouse infection model","pmids":["41651829"],"confidence":"High","gaps":["Whether BMX phosphorylation of ATP6V1E1 occurs under non-infectious physiological conditions is untested","Structural basis for how Tyr56/57 phosphorylation disrupts V1–V0 assembly not determined","Whether other kinases target the same residues is unknown"]},{"year":null,"claim":"The structural basis for ATP6V1E1's dual roles—as a V1 assembly scaffold and as a metabolic/signaling integrator (via aldolase and Ragulator interactions)—remains unresolved, and how post-translational regulation at Tyr56/57 is integrated with the reversible V1–V0 dissociation cycle under normal physiology is unknown.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure of ATP6V1E1 in complex with aldolase or BMX","Tissue-specific functions of E1 versus the E2 paralog are poorly defined","Quantitative contribution of Tyr56/57 phosphorylation to V-ATPase regulation outside infection is untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,3]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,4]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[4,5]},{"term_id":"GO:0005773","term_label":"vacuole","supporting_discovery_ids":[0]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,3,5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,5]}],"complexes":["V-ATPase (V1 peripheral domain)"],"partners":["ALDOA","BMX","RAGULATOR"],"other_free_text":[]},"mechanistic_narrative":"ATP6V1E1 encodes the E1 subunit of the peripheral V1 catalytic domain of the vacuolar H⁺-ATPase (V-ATPase), functioning as an essential structural component required for V1 domain assembly onto the V0 membrane sector and for ATPase-driven proton pumping [PMID:8416931, PMID:28065471]. ATP6V1E1 directly binds the glycolytic enzyme aldolase, coupling glycolytic flux to V-ATPase activity, as loss of aldolase causes V1–V0 dissociation [PMID:11399750]. The V-ATPase complex participates in amino acid sensing at the lysosomal surface through regulated interactions with the Ragulator complex, enabling mTORC1 activation [PMID:22053050], and ATP6V1E1 is subject to BMX-mediated phosphorylation at Tyr56/57, which inhibits V-ATPase assembly and lysosomal acidification—a mechanism exploited by Mycobacterium tuberculosis to promote intracellular survival [PMID:41651829]. Biallelic loss-of-function mutations in ATP6V1E1 disrupt V-ATPase complex stability and vesicular trafficking, causing autosomal-recessive cutis laxa with cardiopulmonary involvement [PMID:28065471]."},"prefetch_data":{"uniprot":{"accession":"P36543","full_name":"V-type proton ATPase subunit E 1","aliases":["V-ATPase 31 kDa subunit","p31","Vacuolar proton pump subunit E 1"],"length_aa":226,"mass_kda":26.1,"function":"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:32001091, PubMed:33065002). 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)","subcellular_location":"Apical cell membrane; Cytoplasmic vesicle, secretory vesicle, synaptic vesicle membrane; Cytoplasmic vesicle, clathrin-coated vesicle membrane","url":"https://www.uniprot.org/uniprotkb/P36543/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/ATP6V1E1","classification":"Common Essential","n_dependent_lines":1191,"n_total_lines":1208,"dependency_fraction":0.9859271523178808},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000131100","cell_line_id":"CID001931","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3},{"compartment":"golgi","grade":1}],"interactors":[{"gene":"ATP6AP2","stoichiometry":10.0},{"gene":"ATP6V1A","stoichiometry":10.0},{"gene":"ATP6V1B2","stoichiometry":10.0},{"gene":"ATP6V1D","stoichiometry":10.0},{"gene":"ATP6V1G1","stoichiometry":10.0},{"gene":"ATP6V1H","stoichiometry":10.0},{"gene":"ATP6V1F","stoichiometry":4.0},{"gene":"ATP6V0A1","stoichiometry":0.2},{"gene":"ATP6V0D1","stoichiometry":0.2},{"gene":"ATP6V1C1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001931","total_profiled":1310},"omim":[{"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":"617385","title":"ATPase, H+ TRANSPORTING, LYSOSOMAL, 31-KD, V1 SUBUNIT E, ISOFORM 1; ATP6V1E2","url":"https://www.omim.org/entry/617385"},{"mim_id":"607027","title":"ATPase, H+ TRANSPORTING, LYSOSOMAL, 70-KD, VI SUBUNIT A; ATP6V1A","url":"https://www.omim.org/entry/607027"},{"mim_id":"219200","title":"CUTIS LAXA, AUTOSOMAL RECESSIVE, TYPE IIA; ARCL2A","url":"https://www.omim.org/entry/219200"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ATP6V1E1"},"hgnc":{"alias_symbol":["P31","Vma4","ATP6E2"],"prev_symbol":["ATP6E","ATP6V1E"]},"alphafold":{"accession":"P36543","domains":[{"cath_id":"3.30.2320.30","chopping":"98-213","consensus_level":"high","plddt":95.2236,"start":98,"end":213}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P36543","model_url":"https://alphafold.ebi.ac.uk/files/AF-P36543-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P36543-F1-predicted_aligned_error_v6.png","plddt_mean":94.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ATP6V1E1","jax_strain_url":"https://www.jax.org/strain/search?query=ATP6V1E1"},"sequence":{"accession":"P36543","fasta_url":"https://rest.uniprot.org/uniprotkb/P36543.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P36543/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P36543"}},"corpus_meta":[{"pmid":"6305755","id":"PMC_6305755","title":"A 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signaling","url":"https://pubmed.ncbi.nlm.nih.gov/21900206","citation_count":258,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10224039","id":"PMC_10224039","title":"Structure and properties of the vacuolar (H+)-ATPases.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10224039","citation_count":252,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19199708","id":"PMC_19199708","title":"Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT).","date":"2009","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/19199708","citation_count":237,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25281560","id":"PMC_25281560","title":"Proximity biotinylation and affinity purification are complementary approaches for the interactome mapping of chromatin-associated protein complexes.","date":"2014","source":"Journal of 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journal","url":"https://pubmed.ncbi.nlm.nih.gov/9210392","citation_count":199,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"2874839","id":"PMC_2874839","title":"Receptor-mediated endocytosis: the intracellular journey of transferrin and its receptor.","date":"1986","source":"Biochimie","url":"https://pubmed.ncbi.nlm.nih.gov/2874839","citation_count":169,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17897319","id":"PMC_17897319","title":"Integral and associated lysosomal membrane proteins.","date":"2007","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/17897319","citation_count":163,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"31995728","id":"PMC_31995728","title":"AMPK, a Regulator of Metabolism and Autophagy, Is Activated by Lysosomal Damage via a Novel Galectin-Directed Ubiquitin Signal Transduction System.","date":"2020","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/31995728","citation_count":152,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10915794","id":"PMC_10915794","title":"The amino-terminal domain of the B subunit of vacuolar H+-ATPase contains a filamentous actin binding site.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10915794","citation_count":150,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"11399750","id":"PMC_11399750","title":"Interaction between aldolase and vacuolar H+-ATPase: evidence for direct coupling of glycolysis to the ATP-hydrolyzing proton pump.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11399750","citation_count":146,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":44541,"output_tokens":1310,"usd":0.076636},"stage2":{"model":"claude-opus-4-6","input_tokens":4535,"output_tokens":1407,"usd":0.086775},"total_usd":0.387852,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":56657,"output_tokens":2838,"usd":0.106271},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":5496,"output_tokens":2052,"usd":0.11817}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1993,\n      \"finding\": \"ATP6V1E1 (yeast ortholog VMA4/27-kDa subunit of V-ATPase) is essential for assembly of the peripheral V1 sector onto the vacuolar membrane; deletion of VMA4 prevents proper assembly of V1 subunits and abolishes vacuolar H(+)-ATPase enzyme activity.\",\n      \"method\": \"Genetic deletion (vma4 null mutant) with vacuolar ATPase activity assays and membrane fractionation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined biochemical phenotype (loss of V-ATPase assembly and activity), replicated in same study with multiple subunit mutants\",\n      \"pmids\": [\"8416931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The Neurospora crassa vma-4 gene product (ortholog of ATP6V1E1, 26 kDa subunit of vacuolar ATPase) is predicted to play the same structural role in V-ATPase as the gamma-subunit in F-type ATPases, based on secondary structure predictions and biochemical data.\",\n      \"method\": \"Gene isolation, amino acid sequence comparison, and computer-assisted secondary structure prediction\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — computational/structural prediction only, no direct functional mutagenesis\",\n      \"pmids\": [\"7619848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Biallelic missense mutations in ATP6V1E1 (encoding the E1 subunit of the V1 domain of V-ATPase) disrupt V-ATPase complex assembly or stability, impair acidification of secretory compartments, cause delayed retrograde transport after brefeldin A treatment, abnormal Golgi fragmentation, and defective extracellular matrix assembly, resulting in autosomal-recessive cutis laxa.\",\n      \"method\": \"Whole-exome sequencing, structural modeling, complexome profiling (blue-native PAGE + LC-MS/MS), brefeldin A transport assay, transmission electron microscopy\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (genetic, structural modeling, complexome profiling, cell biology assays) in a single rigorous study\",\n      \"pmids\": [\"28065471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Phosphorylation of ATP6V1E1 at Tyr56/57 by the tyrosine kinase BMX suppresses lysosomal acidification by inhibiting V-ATPase assembly. Mycobacterium tuberculosis secreted protein Chp2 (Rv1184) promotes BMX-dependent phosphorylation of ATP6V1E1 by directly binding ATP6V1E1 and facilitating its interaction with BMX, thereby preventing phagolysosomal acidification to enable intracellular Mtb survival.\",\n      \"method\": \"Phosphorylation mapping, BMX kinase assay, Co-immunoprecipitation (Chp2-ATP6V1E1-BMX complex), V-ATPase assembly assay, macrophage infection model, BMX inhibitor treatment in mice\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct identification of phosphorylation site, writer kinase, and mechanism of V-ATPase inhibition with multiple orthogonal methods including in vivo validation\",\n      \"pmids\": [\"41651829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ATP6V1E1 knockdown markedly inhibited the proliferation of hepatocellular carcinoma (HCC) cells in vitro, implicating ATP6V1E1 in supporting HCC cell growth.\",\n      \"method\": \"siRNA knockdown with cell proliferation assay\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single KD with proliferation readout, no pathway placement beyond correlation with oncogenic GSEA signatures\",\n      \"pmids\": [\"39294741\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATP6V1E1 encodes the E1 subunit of the V1 catalytic domain of the vacuolar H(+)-ATPase (V-ATPase); it is essential for V1 sector assembly onto membranes and for lysosomal/endosomal acidification, and its function is regulated by BMX-mediated phosphorylation at Tyr56/57—a mechanism exploited by Mycobacterium tuberculosis to block phagolysosomal killing—while loss-of-function mutations in humans cause impaired vesicular trafficking and autosomal-recessive cutis laxa.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper, then extract discoveries only from KEEP papers.\n\n**Classification Summary:**\n\n**KEEP (about ATP6V1E1 canonical protein):**\n- PMID 28065471: Directly about ATP6V1E1 mutations causing cutis laxa — KEEP\n- PMID 41651829: Mtb targets ATP6V1E1 phosphorylation — KEEP\n- PMID 39294741: ATP6V1E1 in HCC (biological role study with knockdown) — KEEP (has functional KD assay)\n- PMID 41242442: ATP6V1E1 as AD biomarker (expression/correlation only) — EXCLUDE (no mechanistic finding)\n- PMID 40187519: ATP6V1E1 expression in AD blood/brain — EXCLUDE (expression only)\n- PMID 8416931: VMA4/VMA5 yeast V-ATPase (VMA4 = yeast ortholog of ATP6V1E1 E subunit) — KEEP (ortholog)\n- PMID 7619848: Neurospora vma-4 (E subunit ortholog) — KEEP (ortholog)\n- PMID 10224039: V-ATPase structure/properties review — KEEP (foundational mechanistic)\n- PMID 11836511: V-ATPase nature review — KEEP (mechanistic context)\n- PMID 9442887: V-ATPase structure/function review — KEEP\n- PMID 22053050: V-ATPase role in mTORC1/amino acid sensing — KEEP\n- PMID 10399441 (Holliday 2000, PMID 10915794): E subunit binds aldolase — KEEP (E subunit directly)\n- PMID 11399750: Aldolase-E subunit interaction — KEEP\n- PMID 10221984: V-ATPase review — KEEP\n- PMID 9210392: V-ATPase review — KEEP\n- BioPlex/interactome papers (16169070, 26186194, 28514442, 26496610, 33961781, 22939629, 26344197): Large-scale interactome screens — these identify ATP6V1E1 interaction partners but are not targeted mechanistic studies; they provide interaction data. KEEP for interactions if ATP6V1E1 specifically noted.\n- PMID 19056867: Urinary exosomes proteomics — EXCLUDE (no mechanistic finding for ATP6V1E1)\n- PMID 19199708: Parotid exosomes — EXCLUDE\n- PMID 17897319: Lysosomal membrane proteins — EXCLUDE (no specific ATP6V1E1 mechanism)\n- PMID 31995728: AMPK/lysosomal damage — EXCLUDE (not about ATP6V1E1 specifically)\n\n**All p31(comet)/MAD2L1BP papers** — EXCLUDE (alias collision; these are about MAD2L1BP, not ATP6V1E1)\n\n**All gliadin p31-43 peptide papers** — EXCLUDE (alias collision)\n\n**All HBsAg P31 papers** — EXCLUDE\n\n**All chromosome 1p31 papers** — EXCLUDE\n\n**All P-31 MRS/NMR spectroscopy papers** — EXCLUDE\n\n**All other p31 named proteins** — EXCLUDE\n\nNow extracting discoveries from KEEP papers:\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1993,\n      \"finding\": \"The VMA4 gene of Saccharomyces cerevisiae encodes the 27-kDa subunit of the vacuolar H(+)-ATPase (ortholog of ATP6V1E1/E subunit). Deletion of VMA4 prevents assembly of the peripheral V1 domain onto the vacuolar membrane and abolishes ATPase activity, demonstrating that the E subunit is essential for V-ATPase assembly and function.\",\n      \"method\": \"Genetic deletion (vma4 null mutant), biochemical fractionation, ATPase activity assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined biochemical phenotype, replicated in yeast ortholog system\",\n      \"pmids\": [\"8416931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The Neurospora crassa vma-4 gene encodes a 25.7 kDa subunit of the vacuolar ATPase (ortholog of ATP6V1E1). Sequence analysis and secondary structure prediction indicate this subunit plays the same structural role in V-ATPase as the gamma-subunit does in F-type ATPases, suggesting a conserved structural function in the rotary mechanism.\",\n      \"method\": \"Gene cloning, sequence analysis, comparative secondary structure prediction\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — sequence/structural inference without functional mutagenesis, single study\",\n      \"pmids\": [\"7619848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The V-ATPase E subunit directly interacts with aldolase (a glycolytic enzyme). This interaction was identified by yeast two-hybrid screening with the E subunit as bait, confirmed by GST pulldown with E subunit fusion proteins and metabolically labeled aldolase, and validated by co-immunoprecipitation from bovine kidney microsomes and osteoclasts using an anti-E subunit antibody. In yeast lacking aldolase, the V1 domain dissociates from V0, suggesting the E subunit-aldolase interaction couples glycolysis directly to V-ATPase proton pumping.\",\n      \"method\": \"Yeast two-hybrid, GST pulldown, co-immunoprecipitation, yeast aldolase-deficient mutant analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Y2H, pulldown, co-IP, genetic epistasis) in single study\",\n      \"pmids\": [\"11399750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Biallelic missense mutations in ATP6V1E1 (encoding the E1 subunit of the V1 domain of V-ATPase) cause autosomal-recessive cutis laxa with dysmorphic features and cardiopulmonary involvement. Structural modeling showed all substitutions affect critical residues and inter- or intra-subunit interactions. Complexome profiling (blue-native PAGE combined with LC-MS/MS) demonstrated that the mutations disturb either assembly or stability of the V-ATPase complex. Patient cells showed abnormal vesicular trafficking (delayed retrograde transport after brefeldin A, Golgi fragmentation) and reduced/fragmented elastic fibers with abnormal collagen organization.\",\n      \"method\": \"Whole-exome sequencing, structural modeling, complexome profiling (BN-PAGE + LC-MS/MS), brefeldin A trafficking assay, transmission electron microscopy\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including complexome profiling and functional trafficking assays; disease-causing mutations directly link ATP6V1E1 to V-ATPase assembly/stability\",\n      \"pmids\": [\"28065471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The vacuolar H(+)-ATPase (V-ATPase, of which ATP6V1E1/E1 is a subunit) is required for amino acid-dependent activation of mTORC1. The v-ATPase engages in amino acid-sensitive interactions with the Ragulator complex on the lysosomal surface, and ATP hydrolysis by the v-ATPase is necessary for amino acids to regulate the v-ATPase–Ragulator interaction and promote mTORC1 translocation to the lysosome.\",\n      \"method\": \"RNAi knockdown, cell-free reconstitution system, co-immunoprecipitation, mTORC1 translocation imaging\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — cell-free reconstitution combined with genetic knockdown and co-IP; highly cited foundational study\",\n      \"pmids\": [\"22053050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Mycobacterium tuberculosis secreted protein Rv1184 (Chp2) promotes intracellular bacterial survival by targeting ATP6V1E1. Phosphorylation of ATP6V1E1 at Tyr56/57 by tyrosine kinase BMX suppresses lysosomal acidification through inhibition of V-ATPase assembly. Chp2 directly binds ATP6V1E1 and facilitates its interaction with BMX, increasing BMX-dependent phosphorylation of ATP6V1E1. Inhibition of BMX impaired Mtb growth in macrophages and in mice.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis (Tyr56/57), lysosomal acidification assay, BMX inhibitor treatment, in vivo mouse infection model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — identifies specific phosphorylation sites with mutagenesis, binding partner (BMX, Chp2), functional consequence (V-ATPase assembly inhibition), and in vivo validation\",\n      \"pmids\": [\"41651829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ATP6V1E1 knockdown in hepatocellular carcinoma cells markedly inhibited cell proliferation, establishing a functional role for ATP6V1E1 in supporting HCC cell growth.\",\n      \"method\": \"siRNA knockdown, cell proliferation assay (in vitro)\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single method, no pathway placement beyond correlation with oncogenic gene sets\",\n      \"pmids\": [\"39294741\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATP6V1E1 encodes the E1 subunit of the V1 catalytic domain of the vacuolar H(+)-ATPase (V-ATPase); it is essential for V1 domain assembly onto the vacuolar membrane, directly binds aldolase to couple glycolysis to proton pumping, participates in lysosomal amino acid sensing upstream of mTORC1 via interactions with the Ragulator complex, and is regulated by BMX-mediated phosphorylation at Tyr56/57 (exploited by Mycobacterium tuberculosis to inhibit V-ATPase assembly and lysosomal acidification); loss-of-function mutations in ATP6V1E1 disrupt V-ATPase complex stability and cause impaired vesicular trafficking manifesting as autosomal-recessive cutis laxa.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ATP6V1E1 encodes the E1 subunit of the V1 catalytic domain of the vacuolar H⁺-ATPase (V-ATPase), functioning as an essential structural component required for assembly of the peripheral V1 sector onto membranes and for V-ATPase proton-pumping activity [PMID:8416931]. V-ATPase assembly and consequent organellar acidification are negatively regulated by BMX kinase-mediated phosphorylation of ATP6V1E1 at Tyr56/57, a mechanism exploited by Mycobacterium tuberculosis effector Chp2 to block phagolysosomal killing and promote intracellular survival [PMID:41651829]. Biallelic loss-of-function mutations in ATP6V1E1 disrupt V-ATPase complex stability, impair secretory pathway acidification, delay retrograde vesicular transport, and cause autosomal-recessive cutis laxa with defective extracellular matrix assembly [PMID:28065471].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Establishing that the E subunit is indispensable for V-ATPase function resolved its role as a structural requirement for V1 sector assembly rather than a dispensable accessory factor.\",\n      \"evidence\": \"Genetic deletion of yeast VMA4 (ATP6V1E1 ortholog) with vacuolar ATPase activity assays and membrane fractionation\",\n      \"pmids\": [\"8416931\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which subunit E promotes V1 assembly was not defined\",\n        \"No mammalian data at this stage\",\n        \"No structural model of subunit E within the V1 complex\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linking human ATP6V1E1 mutations to cutis laxa demonstrated that V-ATPase assembly defects translate into impaired vesicular trafficking, Golgi integrity, and extracellular matrix homeostasis in patients.\",\n      \"evidence\": \"Whole-exome sequencing, complexome profiling (BN-PAGE + LC-MS/MS), brefeldin A transport assay, and electron microscopy in patient fibroblasts\",\n      \"pmids\": [\"28065471\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Genotype-phenotype relationship across different missense variants not fully resolved\",\n        \"Whether partial V-ATPase assembly rescue can ameliorate disease is untested\",\n        \"Tissue-specific consequences beyond fibroblasts not characterized\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identifying BMX-mediated Tyr56/57 phosphorylation as an inhibitory switch for V-ATPase assembly revealed the first post-translational regulatory mechanism acting directly on subunit E1 and explained how M. tuberculosis subverts phagolysosomal acidification.\",\n      \"evidence\": \"Phosphorylation mapping, in vitro BMX kinase assay, co-immunoprecipitation of Chp2–ATP6V1E1–BMX complex, V-ATPase assembly assays, macrophage infection model, and BMX inhibitor treatment in mice\",\n      \"pmids\": [\"41651829\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether endogenous host signals also activate BMX-dependent phosphorylation of ATP6V1E1 outside infection is unknown\",\n        \"Structural basis of how Tyr56/57 phosphorylation blocks V1 assembly is not determined\",\n        \"Whether other kinases or phosphatases regulate this site remains unaddressed\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ATP6V1E1 phosphorylation status is dynamically regulated under physiological (non-infection) conditions, which phosphatase(s) reverse Tyr56/57 modification, and the high-resolution structural basis of E1's role in V1 assembly remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No phosphatase for Tyr56/57 identified\",\n        \"No high-resolution structure of human V-ATPase focusing on E1 subunit contacts\",\n        \"Tissue-specific roles of ATP6V1E1 versus ATP6V1E2 isoform not systematically addressed\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005773\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [\n      \"V-ATPase V1 domain\"\n    ],\n    \"partners\": [\n      \"BMX\",\n      \"Chp2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"ATP6V1E1 encodes the E1 subunit of the peripheral V1 catalytic domain of the vacuolar H⁺-ATPase (V-ATPase), functioning as an essential structural component required for V1 domain assembly onto the V0 membrane sector and for ATPase-driven proton pumping [PMID:8416931, PMID:28065471]. ATP6V1E1 directly binds the glycolytic enzyme aldolase, coupling glycolytic flux to V-ATPase activity, as loss of aldolase causes V1–V0 dissociation [PMID:11399750]. The V-ATPase complex participates in amino acid sensing at the lysosomal surface through regulated interactions with the Ragulator complex, enabling mTORC1 activation [PMID:22053050], and ATP6V1E1 is subject to BMX-mediated phosphorylation at Tyr56/57, which inhibits V-ATPase assembly and lysosomal acidification—a mechanism exploited by Mycobacterium tuberculosis to promote intracellular survival [PMID:41651829]. Biallelic loss-of-function mutations in ATP6V1E1 disrupt V-ATPase complex stability and vesicular trafficking, causing autosomal-recessive cutis laxa with cardiopulmonary involvement [PMID:28065471].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Establishing that the E subunit is indispensable for V-ATPase function resolved a fundamental question about V1 domain assembly: deletion of the yeast ortholog VMA4 prevented V1 attachment to the vacuolar membrane and abolished ATPase activity.\",\n      \"evidence\": \"Genetic knockout of VMA4 in S. cerevisiae with biochemical fractionation and ATPase assays\",\n      \"pmids\": [\"8416931\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mammalian E1 subunit function not yet directly tested\",\n        \"Mechanism by which E subunit promotes V1–V0 assembly unknown\",\n        \"No structural model of E subunit within the holoenzyme\"\n      ]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Discovery that ATP6V1E1 directly binds aldolase established an unexpected physical link between glycolysis and V-ATPase proton pumping, answering how metabolic status could regulate vacuolar acidification.\",\n      \"evidence\": \"Yeast two-hybrid, GST pulldown, co-immunoprecipitation from bovine kidney, and aldolase-deficient yeast showing V1 dissociation\",\n      \"pmids\": [\"11399750\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Binding interface between E subunit and aldolase not mapped\",\n        \"Whether the interaction is regulated by glycolytic intermediates is untested\",\n        \"Relevance in mammalian tissues beyond kidney and osteoclasts not examined\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrating that V-ATPase engages the Ragulator complex in an amino acid–sensitive manner placed the entire complex—including ATP6V1E1—as a lysosomal nutrient sensor upstream of mTORC1, answering how intraluminal amino acids are communicated to cytoplasmic signaling.\",\n      \"evidence\": \"RNAi knockdown, cell-free reconstitution, co-immunoprecipitation, and mTORC1 translocation imaging in mammalian cells\",\n      \"pmids\": [\"22053050\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Specific contribution of ATP6V1E1 versus other V1 subunits in Ragulator binding not delineated\",\n        \"How ATP hydrolysis modulates Ragulator interaction mechanistically is unclear\",\n        \"Whether V-ATPase–Ragulator interaction is tissue-specific is unexplored\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identification of biallelic ATP6V1E1 mutations causing autosomal-recessive cutis laxa directly linked this subunit to human disease, showing that impaired V-ATPase assembly disrupts vesicular trafficking, elastic fiber formation, and collagen organization.\",\n      \"evidence\": \"Whole-exome sequencing, complexome profiling (BN-PAGE + LC-MS/MS), brefeldin A trafficking assays, and TEM in patient-derived cells\",\n      \"pmids\": [\"28065471\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Precise structural consequences of each pathogenic substitution on inter-subunit contacts not resolved at atomic level\",\n        \"Whether residual V-ATPase activity correlates with clinical severity is unknown\",\n        \"Rescue experiments (e.g., wild-type complementation in patient cells) not reported\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identification of BMX-mediated phosphorylation at Tyr56/57 of ATP6V1E1 revealed a specific post-translational switch that inhibits V-ATPase assembly, answering how a host kinase can be co-opted by M. tuberculosis (via Chp2) to suppress lysosomal acidification and promote intracellular survival.\",\n      \"evidence\": \"Co-immunoprecipitation, Tyr56/57 site-directed mutagenesis, lysosomal acidification assays, BMX inhibitor treatment, and in vivo mouse infection model\",\n      \"pmids\": [\"41651829\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether BMX phosphorylation of ATP6V1E1 occurs under non-infectious physiological conditions is untested\",\n        \"Structural basis for how Tyr56/57 phosphorylation disrupts V1–V0 assembly not determined\",\n        \"Whether other kinases target the same residues is unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis for ATP6V1E1's dual roles—as a V1 assembly scaffold and as a metabolic/signaling integrator (via aldolase and Ragulator interactions)—remains unresolved, and how post-translational regulation at Tyr56/57 is integrated with the reversible V1–V0 dissociation cycle under normal physiology is unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No high-resolution structure of ATP6V1E1 in complex with aldolase or BMX\",\n        \"Tissue-specific functions of E1 versus the E2 paralog are poorly defined\",\n        \"Quantitative contribution of Tyr56/57 phosphorylation to V-ATPase regulation outside infection is untested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"GO:0005773\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 3, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 5]}\n    ],\n    \"complexes\": [\n      \"V-ATPase (V1 peripheral domain)\"\n    ],\n    \"partners\": [\n      \"ALDOA\",\n      \"BMX\",\n      \"Ragulator\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}