Affinage

ATP6V1F

V-type proton ATPase subunit F · UniProt Q16864

Round 2 corrected
Length
119 aa
Mass
13.4 kDa
Annotated
2026-04-28
48 papers in source corpus 6 papers cited in narrative 6 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ATP6V1F encodes subunit F of the V1 catalytic sector of the vacuolar H⁺-ATPase (V-ATPase), a proton pump essential for organelle acidification, and is required for proper V1–V0 holoenzyme assembly and proton-pumping activity. Deletion of the yeast ortholog VMA7 abolishes V-ATPase activity, prevents V1 subunit association with the vacuolar membrane, and reduces V0 complex subunit levels, indicating that subunit F bridges the V1 and V0 sectors and stabilizes the assembled complex (PMID:7929308, PMID:7929071). In zebrafish, loss-of-function mutations in atp6v1f cause oculocutaneous albinism with defective melanosome biogenesis, impaired retinal pigmented epithelium integrity, sustained retinoblast proliferation, photoreceptor degeneration, and accumulation of undigested outer segment material, demonstrating an essential in vivo role in RPE-mediated lysosomal degradation and eye development (PMID:18836173). In hepatocellular carcinoma cells, ATP6V1F protein levels are positively regulated by the ER chaperone calnexin (CANX), linking V-ATPase expression to ER proteostasis and energy metabolism (PMID:39161338).

Mechanistic history

Synthesis pass · year-by-year structured walk · 4 steps
  1. 1994 High

    The identity of V-ATPase subunit F as a novel V1-sector component required for holoenzyme assembly was established, resolving how the catalytic sector attaches to the membrane-integral V0 domain.

    Evidence Yeast VMA7 deletion mutants analyzed by Western blotting, density gradient fractionation, membrane stripping, quinacrine acidification assays, and antibody-mediated inhibition of proton uptake

    PMID:7929071 PMID:7929308

    Open questions at the time
    • Structural basis of subunit F contacts with other V1 and V0 subunits not resolved
    • Post-translational regulation of subunit F not addressed
    • Whether subunit F has roles beyond structural scaffolding (e.g., regulatory) was unknown
  2. 2005 Medium

    Extension of subunit F function to a pathogenic organism showed that Vma7p is required for vacuole acidification, alkaline-pH tolerance, and full virulence, reinforcing its non-redundant role in V-ATPase-dependent processes.

    Evidence Candida albicans VMA7 null mutant phenotyping including vacuole acidification, metal sensitivity, and mouse systemic candidiasis model with VPS34 epistasis

    PMID:15870472

    Open questions at the time
    • Whether loss of virulence is solely via defective acidification or involves additional Vma7p-dependent pathways is unclear
    • Interaction between Vma7p and Vps34p was not demonstrated to be direct
  3. 2008 High

    A vertebrate in vivo requirement for ATP6V1F was defined: loss of function in zebrafish revealed that subunit F is essential for RPE melanosome biogenesis, retinoblast cell cycle regulation, and photoreceptor outer segment turnover, connecting V-ATPase-mediated acidification to eye development.

    Evidence Zebrafish forward genetic screen with histology, BrdU, TUNEL, TEM ultrastructure, and in situ hybridization

    PMID:18836173

    Open questions at the time
    • Whether the proliferation defect is cell-autonomous to RPE or secondary to impaired signaling was not resolved
    • Mammalian confirmation of these phenotypes is lacking
    • Molecular partners of ATP6V1F in the RPE context were not identified
  4. 2024 Medium

    An upstream transcriptional/post-transcriptional regulator of ATP6V1F was identified: calnexin (CANX) positively controls ATP6V1F protein levels in hepatocellular carcinoma cells, linking ER proteostasis to V-ATPase abundance and mitochondrial energy metabolism.

    Evidence siRNA knockdown and overexpression of CANX with Western blot for ATP6V1F/ATP6V0B, ATP, JC-1, and ROS assays in HCC cell lines

    PMID:39161338

    Open questions at the time
    • Mechanism of CANX-mediated regulation of ATP6V1F (transcriptional vs. protein stability) not distinguished
    • Single-lab finding without independent replication
    • Whether this regulatory axis operates outside hepatocellular carcinoma is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • A high-resolution structural model of subunit F within the mammalian V-ATPase holoenzyme, the regulatory signals (e.g., phosphorylation) controlling reversible V1–V0 dissociation at subunit F, and the physiological relevance of ATP6V1F in mammalian disease remain to be determined.
  • No mammalian loss-of-function model for ATP6V1F has been reported
  • Predicted phosphorylation sites on subunit F have not been functionally validated
  • Whether subunit F participates in regulated V-ATPase disassembly in response to nutrient signals is untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 2 GO:0140657 ATP-dependent activity 2
Localization
GO:0005773 vacuole 3 GO:0005764 lysosome 1
Pathway
R-HSA-382551 Transport of small molecules 3 R-HSA-392499 Metabolism of proteins 2
Partners
CANX
Complex memberships
V-ATPase (V1 sector)

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 VMA7 (the yeast ortholog of ATP6V1F) encodes a novel 14-kDa subunit of the V-ATPase V1 catalytic sector. Deletion of VMA7 abolishes V-ATPase activity, prevents V1 subunit association with the vacuolar membrane, and causes greatly reduced V0 complex subunit levels. Unlike integral V0 subunits, Vma7p is easily stripped from membranes and associates only with the fully assembled V-ATPase, not with a separate V0 subcomplex fraction, suggesting it stabilizes V0 and bridges V1 and V0 complexes. Genetic null mutant analysis, Western blotting, density gradient fractionation, membrane stripping assay The Journal of biological chemistry High 7929308
1994 VMA7 (yeast ortholog of ATP6V1F) encodes subunit F of the V-ATPase catalytic sector. In its absence, other V1 catalytic subunits fail to assemble onto the vacuolar membrane and vacuoles cannot acidify. A monoclonal antibody against epitope-tagged Vma7p markedly inhibits proton uptake activity of isolated vacuoles. Cold inactivation experiments confirm Vma7p is a genuine subunit of the V1 catalytic sector. Null mutant generation, quinacrine accumulation assay, epitope-tagged protein inhibition with monoclonal antibody, cold inactivation experiment, proton uptake assay The Journal of biological chemistry High 7929071
2005 The Candida albicans ortholog of ATP6V1F (Vma7p) is required for vacuole acidification; its deletion causes defective growth at alkaline pH, impaired degradation of intravacuolar endosomal structures, sensitivity to metal ions, and complete avirulence in a mouse model of systemic candidiasis. The Vma7p-interacting phosphatidylinositol 3-kinase Vps34p null mutant shows similar phenotypes, placing Vma7p in the same pathway. Null mutant generation in C. albicans, vacuole acidification assay, mouse virulence model, genetic epistasis with VPS34 deletion Microbiology (Reading, England) Medium 15870472
2008 Loss-of-function mutations in atp6v1f in zebrafish cause microphthalmic, oculocutaneous albino phenotypes including defects in melanosome formation/survival, malformation of the retinal pigmented epithelium, impaired retinoblast cell cycle exit, sustained ciliary marginal zone proliferation, elevated retinal and brain apoptosis, photoreceptor outer segment rosette formation, and accumulation of membrane-bounded vacuoles containing undigested outer segment material in RPE cells. In situ hybridization localized atp6v1f transcripts to the RPE. Zebrafish forward genetics, histology, BrdU incorporation assay, TUNEL apoptosis assay, ultrastructural (TEM) analysis, in situ hybridization Investigative ophthalmology & visual science High 18836173
2012 The ATP6V1F gene was cloned from Giant Panda; the encoded protein contains one protein kinase C phosphorylation site, two casein kinase II phosphorylation sites, and one N-myristoylation site as predicted by topology analysis. Overexpression in E. coli produced an expected ~17 kDa His-tagged fusion protein, confirming the predicted molecular weight of the subunit F polypeptide. RT-PCR cloning, genomic PCR, sequence alignment, topology/motif prediction, recombinant overexpression in E. coli Molecular biology reports Low 22212708
2024 In hepatocellular carcinoma cells, dihydroartemisinin (DHA) decreased expression of CANX (calnexin), and both ATP6V1F (V1 domain subunit F) and ATP6V0B (V0 domain subunit B) protein levels were reduced upon DHA treatment or CANX knockdown. CANX overexpression increased ATP6V1F and ATP6V0B levels and promoted mitochondrial function and energy metabolism, establishing CANX as an upstream regulator of V-ATPase subunit expression including ATP6V1F. siRNA knockdown and overexpression of CANX, Western blotting for ATP6V1F/ATP6V0B, ATP production assay, mitochondrial membrane potential (JC-1), ROS measurement, cell proliferation/apoptosis/migration assays Oncology letters Medium 39161338

Source papers

Stage 0 corpus · 48 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2002 The vacuolar (H+)-ATPases--nature's most versatile proton pumps. Nature reviews. Molecular cell biology 961 11836511
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2008 Large-scale proteomics and phosphoproteomics of urinary exosomes. Journal of the American Society of Nephrology : JASN 607 19056867
2018 High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies. Molecular cell 580 29395067
1997 Structure, function and regulation of the vacuolar (H+)-ATPase. Annual review of cell and developmental biology 488 9442887
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2015 A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface. Cell 433 26638075
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
1996 Normalization and subtraction: two approaches to facilitate gene discovery. Genome research 401 8889548
1994 Purification of CpG islands using a methylated DNA binding column. Nature genetics 363 8012384
1999 Vacuolar and plasma membrane proton-adenosinetriphosphatases. Physiological reviews 348 10221984
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2007 Coupling of rotation and catalysis in F(1)-ATPase revealed by single-molecule imaging and manipulation. Cell 307 17662945
2019 Intrinsically Disordered Protein TEX264 Mediates ER-phagy. Molecular cell 296 31006538
2012 A high-throughput approach for measuring temporal changes in the interactome. Nature methods 273 22863883
1999 Structure and properties of the vacuolar (H+)-ATPases. The Journal of biological chemistry 252 10224039
2009 Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT). Journal of proteome research 237 19199708
1999 Animal plasma membrane energization by proton-motive V-ATPases. BioEssays : news and reviews in molecular, cellular and developmental biology 206 10440860
2018 An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. Nature communications 201 29568061
1997 The vacuolar H+-ATPase: a universal proton pump of eukaryotes. The Biochemical journal 199 9210392
2004 Up-regulated expression of the MAT-8 gene in prostate cancer and its siRNA-mediated inhibition of expression induces a decrease in proliferation of human prostate carcinoma cells. International journal of oncology 82 14654946
2008 The vacuolar-ATPase complex regulates retinoblast proliferation and survival, photoreceptor morphogenesis, and pigmentation in the zebrafish eye. Investigative ophthalmology & visual science 78 18836173
2016 Polygenic analysis and targeted improvement of the complex trait of high acetic acid tolerance in the yeast Saccharomyces cerevisiae. Biotechnology for biofuels 71 26740819
1994 VMA7 encodes a novel 14-kDa subunit of the Saccharomyces cerevisiae vacuolar H(+)-ATPase complex. The Journal of biological chemistry 62 7929308
1994 The Saccharomyces cerevisiae VMA7 gene encodes a 14-kDa subunit of the vacuolar H(+)-ATPase catalytic sector. The Journal of biological chemistry 52 7929071
2005 The putative vacuolar ATPase subunit Vma7p of Candida albicans is involved in vacuole acidification, hyphal development and virulence. Microbiology (Reading, England) 51 15870472
2020 Identification of Antimicrobial Resistance Determinants in Aeromonas veronii Strain MS-17-88 Recovered From Channel Catfish (Ictalurus punctatus). Frontiers in cellular and infection microbiology 32 32766165
2022 Triphenyltin exposure induced abnormal morphological colouration in adult male guppies (Poecilia reticulata). Ecotoxicology and environmental safety 12 35905627
2024 Identification of key regulatory molecules in the early development stage of Alzheimer's disease. Journal of cellular and molecular medicine 11 38429903
2020 RNA-Seq Analysis of Genetic and Transcriptome Network Effects of Dual-Trait Selection for Ethanol Preference and Withdrawal Using SOT and NOT Genetic Models. Alcoholism, clinical and experimental research 11 32090358
2025 Neutrophil-derived serine proteases induce FOXA2-mediated autophagy dysfunction and exacerbate colitis-associated carcinogenesis via protease activated receptor 2. Autophagy 6 40205686
2024 Study on the mechanism of arsenic-induced renal injury based on SWATH proteomics technology. Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS) 6 38266420
2023 Hunted Wild Boars in Sardinia: Prevalence, Antimicrobial Resistance and Genomic Analysis of Salmonella and Yersinia enterocolitica. Foods (Basel, Switzerland) 5 38201093
2025 Phylogenetic relationship, genomic heterogeneity, and population structure of Yersinia enterocolitica biotype 1A isolated from pork and poultry meat. Food research international (Ottawa, Ont.) 3 40382034
2024 Dihydroartemisinin inhibits ATP6 activity, reduces energy metabolism of hepatocellular carcinoma cells, promotes apoptosis and inhibits metastasis via CANX. Oncology letters 3 39161338
2012 Cloning and overexpression of an important functional gene ATP6V1F encoding a component of vacuolar ATPase from the Giant Panda (Ailuropoda melanoleuca). Molecular biology reports 2 22212708
2026 A single-cell derived spheroid approach to dissect intratumoural heterogeneity in colorectal cancer: cell lines show changes in proteomes and therapeutic response to 5-FU. Journal of cancer research and clinical oncology 0 41580526
2025 Genomic characteristics and virulence of common but overlooked Yersinia intermedia, Y. frederiksenii, and Y. kristensenii in food. International journal of food microbiology 0 39798383