ATP6V1F

ATP6V1F is an essential subunit of the V1 catalytic sector of the vacuolar H(+)-ATPase, the multisubunit proton pump that acidifies intracellular compartments (PMID:7929308, PMID:7929071). In yeast, the ortholog Vma7p is required to assemble the V1 catalytic subunits onto the vacuolar membrane and to stabilize the membrane-embedded V0 sector; in its absence vacuolar membranes have no V-ATPase activity, V0 levels collapse, and the V1 subunits remain present but fail to attach to the membrane, identifying ATP6V1F as a bridge that couples V1 to V0 to form a functional pump (PMID:7929308). Cold-inactivation and antibody-inhibition experiments confirm it is a genuine subunit of the catalytic sector whose loss abolishes proton uptake and prevents vacuolar acidification and growth at alkaline pH (PMID:7929071). This acidification function is conserved: loss in Candida albicans impairs vacuole acidification, intravacuolar degradation, and virulence, and interacts genetically with the PI3-kinase Vps34p (PMID:15870472), while loss in zebrafish disrupts melanosome formation, RPE function, retinal cell-cycle exit, and clearance of photoreceptor outer-segment material in lysosome-like RPE vacuoles (PMID:18836173). Beyond its role as a V-ATPase assembly and bridging subunit, no additional biochemical activity for ATP6V1F has been characterized in the available corpus.

1. 1994 High

   Established that ATP6V1F's ortholog is a bona fide V1 catalytic-sector subunit whose primary role is to assemble V1 onto the membrane and bridge/stabilize the V0 sector, defining why the protein is essential for proton pumping.

   Evidence vma7Δ yeast null mutant with vacuolar membrane isolation, V-ATPase activity assay, and density-gradient/Western fractionation

   PMID:7929308

   Open questions at the time

   • Atomic-resolution structure of how subunit F bridges V1 and V0 not resolved
   • Mechanism by which V0 is destabilized in its absence not defined at the molecular level
2. 1994 High

   Confirmed by orthogonal genetic and biochemical methods that the protein is a genuine catalytic-sector subunit required for vacuolar acidification, ruling out a peripheral or regulatory-only role.

   Evidence δvma7::URA3 null mutant characterized by quinacrine accumulation, antibody inhibition of proton uptake, cold inactivation, and epitope tagging in yeast

   PMID:7929071

   Open questions at the time

   • Does not establish whether the human ortholog behaves identically
   • Stoichiometry within the V1 sector not quantified
3. 2005 Medium

   Extended the acidification function to a pathogen and linked it to physiology, showing the subunit is required for fungal vacuole acidification, stress resistance, and virulence and acts in a pathway shared with Vps34p.

   Evidence Candida albicans vma7 null mutant with acidification, pH-growth, metal-sensitivity assays, mouse systemic candidiasis model, and genetic epistasis with Vps34p

   PMID:15870472

   Open questions at the time

   • Genetic interaction with Vps34p is epistatic, not biochemical/physical
   • Single lab; not confirmed in mammalian system
4. 2008 Medium

   Demonstrated that the conserved acidification function is required for vertebrate organelle biology, tying V-ATPase loss to melanosome formation, RPE maintenance, and retinal development.

   Evidence Zebrafish atp6v1f loss-of-function mutant analyzed by histology, BrdU labeling, ultrastructure, and in situ hybridization

   PMID:18836173

   Open questions at the time

   • Phenotypes are downstream consequences of failed acidification rather than direct molecular readouts
   • No human disease link established
   • Single study
5. 2024 Low

   Placed ATP6V1F within a cancer regulatory context, indicating its expression can be controlled by CANX and modulated pharmacologically to affect mitochondrial energetics.

   Evidence CANX overexpression/siRNA in hepatocellular carcinoma cells with Western blotting, ATP/mitochondrial membrane potential/NAD+:NADH assays under dihydroartemisinin treatment

   PMID:39161338

   Open questions at the time

   • Indirect regulatory correlation, not a direct mechanistic assay of ATP6V1F
   • No demonstration that ATP6V1F mediates the mitochondrial phenotype
   • Single lab, not independently confirmed

• How ATP6V1F is assembled and regulated in mammalian cells, its structural mode of bridging V1 to V0, and any human disease association remain uncharacterized in this corpus.
• No mammalian biochemical reconstitution
• No structural model of the F subunit in human V-ATPase
• No causative human Mendelian disease evidence