Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0016020 membrane	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: Phylogenetic inference placing ATP6V1F as active in membrane context. The V1 F subunit is a peripheral protein on the cytoplasmic face of membranes where V-ATPase is active. Reason: The generic membrane annotation with is_active_in is subsumed by the more specific lysosomal membrane and other organelle membrane annotations. The IBA annotation is overly broad.
GO:0030665 clathrin-coated vesicle membrane	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: UniProt subcellular location vocabulary mapping from ortholog data. V-ATPase is present on clathrin-coated vesicles for endocytic pathway acidification. Reason: Consistent with V-ATPase biology but non-core relative to lysosomal function.
GO:0030672 synaptic vesicle membrane	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: UniProt subcellular location vocabulary mapping for synaptic vesicle membrane. V-ATPase acidifies synaptic vesicles for neurotransmitter loading. Reason: Non-core for this ubiquitously expressed subunit; neuronal context is secondary to the primary lysosomal function.
GO:0033180 proton-transporting V-type ATPase, V1 domain	IEA GO_REF:0000002	ACCEPT	Summary: InterPro-based annotation placing ATP6V1F in the V1 domain. Confirmed by human cryo-EM structural data. Reason: Subunit F is a defining structural component of the V1 domain central rotor, confirmed by cryo-EM (PMID:33065002) and biochemical data (PMID:18752060). Supporting Evidence: PMID:33065002 Vesicular- or vacuolar-type adenosine triphosphatases (V-ATPases) are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer.
GO:0034220 monoatomic ion transmembrane transport	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: InterPro-based annotation for monoatomic ion transmembrane transport, which subsumes proton transport. The more specific proton transmembrane transport annotation is more informative. Reason: The generic monoatomic ion transmembrane transport is subsumed by the more specific proton transmembrane transport annotations. Redundant and less informative.
GO:0046961 proton-transporting ATPase activity, rotational mechanism	IEA GO_REF:0000002	ACCEPT	Summary: InterPro-based annotation for rotational ATPase activity. The F subunit is part of the central rotor essential for this activity. Reason: Core molecular function of the V-ATPase; subunit F is an essential structural component of the rotary mechanism. Supporting Evidence: PMID:18752060 Energy from this reaction drives the rotation of a central stalk consisting of V1 subunits D and F and this is coupled to rotation of the V0 proteolipid ring made up of c, c′ and c″.
GO:1902600 proton transmembrane transport	IEA GO_REF:0000002	ACCEPT	Summary: InterPro-based annotation for proton transmembrane transport. Reason: Core biological process of V-ATPase.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a reference map of the human binary protein interactome. High-throughput; not informative for specific function. Reason: High-throughput interactome protein binding annotation is uninformative for the specific function of ATP6V1F.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a dual proteome-scale interactome network. High-throughput; not informative. Reason: High-throughput interactome data is uninformative for ATP6V1F function.
GO:0005515 protein binding	IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from the OpenCell endogenous tagging study. High-throughput; not informative. Reason: High-throughput protein binding annotation is uninformative.
GO:0015078 proton transmembrane transporter activity	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl ortholog-transfer annotation for proton transmembrane transporter activity. The contributes_to qualifier appropriately acknowledges the whole-complex nature of this activity. Reason: Core molecular function of V-ATPase; contributes_to qualifier is appropriate for a structural subunit that participates in but does not individually perform the activity.
GO:0033176 proton-transporting V-type ATPase complex	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl ortholog-transfer annotation for V-type ATPase complex membership. Consistent with structural evidence. Reason: Core complex membership.
GO:0097401 synaptic vesicle lumen acidification	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl ortholog-transfer annotation for synaptic vesicle lumen acidification. V-ATPase acidifies synaptic vesicles; F subunit would be present as part of the complex in neurons. Reason: Synaptic vesicle acidification is a non-core context for this ubiquitous subunit; primary function is lysosomal/organellar acidification.
GO:0000139 Golgi membrane	NAS PMID:32001091 Structure and Roles of V-type ATPases.	ACCEPT	Summary: NAS from V-ATPase review. V-ATPase acidifies the Golgi; F subunit is part of the complex. Reason: Well-established V-ATPase location in Golgi for glycosylation pathway function.
GO:0005765 lysosomal membrane	NAS PMID:32001091 Structure and Roles of V-type ATPases.	ACCEPT	Summary: NAS from V-ATPase review. Lysosomal membrane is the primary functional location. Reason: Core localization.
GO:0005886 plasma membrane	NAS PMID:32001091 Structure and Roles of V-type ATPases.	KEEP AS NON CORE	Summary: NAS from V-ATPase review. V-ATPase is targeted to plasma membrane in specialized cell types. Reason: Plasma membrane localization is real in specialized contexts but non-core for this ubiquitous subunit.
GO:0007035 vacuolar acidification	NAS PMID:32001091 Structure and Roles of V-type ATPases.	ACCEPT	Summary: NAS from V-ATPase review. Core function of V-ATPase. Reason: Vacuolar acidification is the core biological process.
GO:0007042 lysosomal lumen acidification	NAS PMID:32001091 Structure and Roles of V-type ATPases.	ACCEPT	Summary: NAS from V-ATPase review. More specific than vacuolar acidification. Reason: Core function of V-ATPase.
GO:0007042 lysosomal lumen acidification	NAS PMID:33065002 Structures of a Complete Human V-ATPase Reveal Mechanisms of...	ACCEPT	Summary: NAS from the structural study. Consistent. Reason: Core function.
GO:0010008 endosome membrane	NAS PMID:32001091 Structure and Roles of V-type ATPases.	ACCEPT	Summary: NAS from V-ATPase review. V-ATPase acidifies endosomes. Reason: Endosome membrane is an established V-ATPase location.
GO:0016020 membrane	IDA PMID:33065002 Structures of a Complete Human V-ATPase Reveal Mechanisms of...	MARK AS OVER ANNOTATED	Summary: IDA from the cryo-EM study. F subunit is associated with membrane as part of the V-ATPase complex. Reason: Generic membrane annotation subsumed by more specific lysosomal/Golgi/endosome membrane annotations.
GO:0033176 proton-transporting V-type ATPase complex	NAS PMID:33065002 Structures of a Complete Human V-ATPase Reveal Mechanisms of...	ACCEPT	Summary: NAS from the structural study. Consistent with IDA annotation from PMID:18752060. Reason: Core complex membership.
GO:0048388 endosomal lumen acidification	NAS PMID:32001091 Structure and Roles of V-type ATPases.	ACCEPT	Summary: NAS from V-ATPase review. Endosomal lumen acidification is a core function. Reason: Core V-ATPase function.
GO:0051452 intracellular pH reduction	NAS PMID:32001091 Structure and Roles of V-type ATPases.	MARK AS OVER ANNOTATED	Summary: NAS from V-ATPase review. Generic term for the acidification function. Reason: Less specific than the individual lumen acidification terms; redundant and subsumed by more precise annotations.
GO:0061795 Golgi lumen acidification	NAS PMID:32001091 Structure and Roles of V-type ATPases.	ACCEPT	Summary: NAS from V-ATPase review. Golgi lumen acidification is important for glycosylation. Reason: Core V-ATPase function in Golgi.
GO:1902600 proton transmembrane transport	NAS PMID:33065002 Structures of a Complete Human V-ATPase Reveal Mechanisms of...	ACCEPT	Summary: NAS from the structural study. Reason: Core biological process.
GO:0000221 vacuolar proton-transporting V-type ATPase, V1 domain	ISS GO_REF:0000024	ACCEPT	Summary: Ortholog-based annotation for V1 domain membership. Confirmed by cryo-EM structural data. Reason: Core structural membership of V1 domain confirmed by PMID:33065002. Supporting Evidence: PMID:33065002 Vesicular- or vacuolar-type adenosine triphosphatases (V-ATPases) are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer.
GO:0042625 ATPase-coupled ion transmembrane transporter activity	NAS PMID:8581736 Cloning, sequencing and expression of a novel cDNA encoding ...	ACCEPT	Summary: NAS from the original cloning paper (Fujiwara et al. 1995). ATP6V1F is a component of an ATPase-coupled ion transporter complex. Reason: The ATPase-coupled ion transmembrane transporter activity is an appropriate molecular function annotation for a V-ATPase subunit. Supporting Evidence: PMID:8581736 A cDNA encoding the 14-kDa subunit of vacuolar ATPase was cloned from human fetal brain. The sequence was composed of 680 nucleotides containing an open reading frame of 357 nucleotides.
GO:0070062 extracellular exosome	HDA PMID:19199708 Proteomic analysis of human parotid gland exosomes by multid...	MARK AS OVER ANNOTATED	Summary: High-throughput proteomics detection in parotid gland exosomes. Likely reflects membrane co-purification. Reason: Exosome detection is likely artifactual; not informative for core function.
GO:0070062 extracellular exosome	HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos...	MARK AS OVER ANNOTATED	Summary: High-throughput proteomics detection in urinary exosomes. Reason: Same reasoning as parotid exosome; likely artifactual.
GO:0005829 cytosol	TAS Reactome:R-HSA-1222516	KEEP AS NON CORE	Summary: Reactome TAS annotation. V1 F subunit can be in cytosol during regulated V1-V0 disassembly. Reason: The V1 domain including F subunit can exist as a soluble complex in cytosol.
GO:0005829 cytosol	TAS Reactome:R-HSA-5252133	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol. Reason: Consistent.
GO:0005829 cytosol	TAS Reactome:R-HSA-74723	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol. Reason: Consistent.
GO:0005829 cytosol	TAS Reactome:R-HSA-917841	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol. Reason: Consistent.
GO:0005829 cytosol	TAS Reactome:R-HSA-9639286	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol. Reason: Consistent.
GO:0005829 cytosol	TAS Reactome:R-HSA-9640167	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol. Reason: Consistent.
GO:0005829 cytosol	TAS Reactome:R-HSA-9640168	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol. Reason: Consistent.
GO:0005829 cytosol	TAS Reactome:R-HSA-9640175	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol. Reason: Consistent.
GO:0005829 cytosol	TAS Reactome:R-HSA-9640195	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol. Reason: Consistent.
GO:0005829 cytosol	TAS Reactome:R-HSA-9645598	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol. Reason: Consistent.
GO:0005829 cytosol	TAS Reactome:R-HSA-9645608	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol. Reason: Consistent.
GO:0005829 cytosol	TAS Reactome:R-HSA-9646468	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol. Reason: Consistent.
GO:0005515 protein binding	IPI PMID:18752060 The d subunit plays a central role in human vacuolar H(+)-AT...	MARK AS OVER ANNOTATED	Summary: The specific interaction underlying this annotation is the F subunit-V0 d subunit (ATP6V0D1) interaction, which is mechanistically central to the rotary pump mechanism. However, generic protein binding is not informative. Reason: Generic protein binding is uninformative; the specific D-F and F-d interactions are the mechanistically meaningful interaction, but no specific GO term captures this subunit-rotor interaction. Supporting Evidence: PMID:18752060 each can pull down the central stalk's D and F subunits from human kidney membrane, and in vitro studies using D and F further showed that the interactions between these proteins and the d subunit is direct.
GO:0016020 membrane	IDA PMID:18752060 The d subunit plays a central role in human vacuolar H(+)-AT...	MARK AS OVER ANNOTATED	Summary: IDA from Smith et al. (2008) showing F subunit in membrane preparations. Reason: Generic membrane is subsumed by more specific lysosomal/Golgi/endosome membrane annotations.
GO:0016471 vacuolar proton-transporting V-type ATPase complex	IDA PMID:18752060 The d subunit plays a central role in human vacuolar H(+)-AT...	ACCEPT	Summary: IDA from Smith et al. (2008) demonstrating F subunit co-purification with the V-ATPase complex. Direct biochemical evidence for complex membership. Reason: Direct experimental evidence for V-ATPase complex membership. This is the core complex membership annotation. Supporting Evidence: PMID:18752060 each can pull down the central stalk's D and F subunits from human kidney membrane, and in vitro studies using D and F further showed that the interactions between these proteins and the d subunit is direct.
GO:0015078 proton transmembrane transporter activity	NAS PMID:8581736 Cloning, sequencing and expression of a novel cDNA encoding ...	ACCEPT	Summary: NAS from the original cloning paper. Reason: Appropriate molecular function for a V-ATPase subunit.
GO:1902600 proton transmembrane transport	NAS PMID:8581736 Cloning, sequencing and expression of a novel cDNA encoding ...	ACCEPT	Summary: NAS from the original cloning paper. Reason: Core biological process of V-ATPase. Supporting Evidence: PMID:8581736 A cDNA encoding the 14-kDa subunit of vacuolar ATPase was cloned from human fetal brain. The sequence was composed of 680 nucleotides containing an open reading frame of 357 nucleotides.

Core Functions

Central rotor component of the V1 sector of the vacuolar-type H+-ATPase. Together with subunit D, forms the DF central stalk that transmits ATP hydrolysis energy from the catalytic A3B3 hexamer to the V0 c-ring, enabling proton translocation across organelle membranes. Essential for lysosomal, endosomal, and Golgi acidification. The smallest V1 subunit (13 kDa; 119 amino acids) and ubiquitously expressed.

Directly Involved In:

proton transmembrane transport

Cellular Locations:

lysosomal membrane

Supporting Evidence:

PMID:33065002
Vesicular- or vacuolar-type adenosine triphosphatases (V-ATPases) are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer.
PMID:18752060
Energy from this reaction drives the rotation of a central stalk consisting of V1 subunits D and F and this is coupled to rotation of the V0 proteolipid ring made up of c, c′ and c″.

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000107

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

PMID:18752060

The d subunit plays a central role in human vacuolar H(+)-ATPases.

Human V-ATPase F subunit directly interacts with d1 and d2 V0 subunits; F and D are pulled down by d1/d2 from human kidney membrane; confirmed direct D-F and F-d interactions; F forms part of the central stalk.

PMID:19056867

Large-scale proteomics and phosphoproteomics of urinary exosomes.

ATP6V1F detected in urinary exosomes by mass spectrometry.

PMID:19199708

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

ATP6V1F detected in parotid gland exosome proteome.

PMID:32001091

Structure and Roles of V-type ATPases.

Comprehensive review of V-ATPase structure; F subunit is part of central rotor.

PMID:32296183

A reference map of the human binary protein interactome.

ATP6V1F detected in binary interactome map.

PMID:33065002

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

Cryo-EM structures of complete human V-ATPase; F subunit resolved as part of the central DF rotor at near-atomic resolution.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

ATP6V1F detected in proteome-scale interactome study.

PMID:35271311

OpenCell: Endogenous tagging for the cartography of human cellular organization.

ATP6V1F localization mapped by endogenous tagging.

PMID:8581736

Cloning, sequencing and expression of a novel cDNA encoding human vacuolar ATPase (14-kDa subunit).

Human V-ATPase F subunit (14 kDa) cloned from fetal brain; ubiquitous expression in human tissues; high sequence conservation with insect orthologs.

Reactome:R-HSA-1222516

Intraphagosomal pH is lowered to 5 by V-ATPase

Reactome:R-HSA-5252133

ATP6AP1 binds V-ATPase

Reactome:R-HSA-74723

Endosome acidification

Reactome:R-HSA-917841

Acidification of Tf:TfR1 containing endosome

Reactome:R-HSA-9639286

RRAGC,D exchanges GTP for GDP

Reactome:R-HSA-9640167

RRAGA,B exchanges GDP for GTP

Reactome:R-HSA-9640168

v-ATPase:Ragulator:RRAGA,B:GTP:RRAGC,D:GDP:SLC38A9:Arginine dissociates yielding v-ATPase:Ragulator:RRAGA,B:GTP:RRAGC,D:GDP and SLC38A9:Arginine

Reactome:R-HSA-9640175

v-ATPase:Ragulator:RagA,B:GDP:RagC,D:GDP binds SLC38A9:Arginine

Reactome:R-HSA-9640195

RRAGA,B hydrolyzes GTP

Reactome:R-HSA-9645598

RRAGC,D hydrolyzes GTP

Reactome:R-HSA-9645608

v-ATPase:Ragulator:RRAGA,B:GTP:RRAGC,D:GDP binds mTORC1

Reactome:R-HSA-9646468

mTORC1 binds RHEB:GTP

Suggested Experiments

Experiment: Cryo-EM analysis of V-ATPase in multiple rotational states at higher resolution to define the precise contacts between F subunit and the V0 d subunit at different stages of the catalytic cycle.

Hypothesis: The F subunit makes distinct contacts with V0 d subunit at different stages of the rotary catalytic cycle.

Type: structural biology

Experiment: Identification of post-translational modifications on the F subunit using quantitative mass spectrometry under varying nutrient conditions to assess regulation of V-ATPase activity.

Hypothesis: Post-translational modifications on the F subunit regulate V-ATPase assembly or activity.

Type: quantitative mass spectrometry

Experiment: CRISPR-based isoform knockout combined with rescue experiments using individual isoforms to determine whether either isoform has a distinct functional role in V-ATPase biology.

Hypothesis: ATP6V1F isoforms differ in V-ATPase incorporation or subcellular function.

Type: CRISPR functional genomics

Deep Research

Falcon

(ATP6V1F-deep-research-falcon.md)

Comprehensive Research Report: ATP6V1F (V-Type Proton ATPase Subunit F) Falcon

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Comprehensive Research Report: ATP6V1F (V-Type Proton ATPase Subunit F)

Gene and Protein Identity

ATP6V1F (UniProt: Q16864) encodes the V-type proton ATPase subunit F in humans, a critical component of the vacuolar H+-ATPase (V-ATPase) complex (wang2020structuresofa pages 3-5, abbas2020structureofvatpase pages 1-2). This gene belongs to the V-ATPase F subunit family and contains an ATP-synt_F domain characteristic of this protein family (wang2020structuresofa pages 3-5). The protein has been definitively identified in purified mammalian V-ATPase preparations through mass spectrometry analysis of brain-derived enzyme complexes (abbas2020structureofvatpase pages 1-2, abbas2020structureofvatpase pages 2-4).

Structural Organization and Primary Function

V-ATPase Complex Architecture

V-ATPase is a large multi-subunit proton pump consisting of two major domains: the cytosolic V1 domain responsible for ATP hydrolysis, and the membrane-embedded V0 domain that translocates protons (wang2020structuresofa pages 1-3, eaton2021theh+atpase(vatpase) pages 1-5, chen2024vatpaseincancer pages 1-3). The human V1 complex comprises eight different subunit types (A, B, C, D, E, F, G, and H), while the V0 complex contains subunits a, c, d, e, and accessory proteins including ATP6AP1 and ATP6AP2 (wang2020structuresofa pages 3-5, chen2024vatpaseincancer pages 1-3).

Central Stalk Formation and Torque Transmission

ATP6V1F serves a critical structural and mechanical role as part of the central stalk, which it forms together with subunit D (the DF stalk) (wang2020structuresofa pages 3-5, wang2020structuresofa pages 5-7). Recent cryo-electron microscopy (cryo-EM) structures of human V-ATPase at 2.9-3.1 Å resolution have revealed the precise architecture of this central stalk (wang2020structuresofa pages 1-3, wang2020structuresofa pages 3-5). The central stalk connects the ATP-hydrolyzing A3B3 hexameric head in the V1 domain to the proton-translocating machinery in the V0 domain, specifically linking to subunit d and the c-ring (wang2020structuresofa pages 3-5, wang2020structuresofa pages 5-7).

The primary mechanistic function of ATP6V1F is to enable mechanical coupling between ATP hydrolysis and proton pumping. When ATP is hydrolyzed at the interfaces of the A and B subunits in the A3B3 head, conformational changes drive rotation of the DF central stalk (wang2020structuresofa pages 3-5, wang2020structuresofa pages 5-7). This rotation is transmitted through the stalk to the membrane-embedded c-ring, which rotates relative to the stationary subunit a, enabling cycles of protonation and deprotonation of glutamic acid residues in the c subunits for coupled proton transfer across the membrane (wang2020structuresofa pages 1-3, wang2020structuresofa pages 3-5).

Substrate Specificity and Enzymatic Reaction

ATP6V1F does not directly catalyze ATP hydrolysis or determine substrate specificity on its own. Rather, as a structural component of the rotary motor, it enables the V-ATPase holoenzyme to perform its overall catalytic function: ATP-driven proton transport (wang2020structuresofa pages 1-3, eaton2021theh+atpase(vatpase) pages 1-5, chen2024vatpaseincancer pages 1-3). The chemical reaction catalyzed by the complete V-ATPase complex is:

ATP + H2O + H+ (cytosolic side) → ADP + Pi + H+ (luminal/extracellular side)

The ATP:proton stoichiometry has been defined as 3:10 based on the structural composition of the enzyme, with three catalytic sites in the A3B3 head and ten proton-binding sites in the c-ring (wang2020structuresofa pages 1-3, abbas2020structureofvatpase pages 1-2).

Subcellular Localization and Functional Context

Intracellular Distribution

ATP6V1F functions as part of V-ATPase complexes distributed across multiple intracellular membranes. The enzyme is localized to lysosomes, endosomes, the trans-Golgi network, secretory vesicles, and synaptic vesicles (eaton2021theh+atpase(vatpase) pages 1-5, abbas2020structureofvatpase pages 1-2, chen2024vatpaseincancer pages 1-3). In neurons, V-ATPase is particularly enriched in synaptic vesicles, where mass spectrometry studies have confirmed the presence of ATP6V1F in brain-derived enzyme preparations (abbas2020structureofvatpase pages 1-2, abbas2020structureofvatpase pages 2-4).

Specialized Plasma Membrane Functions

In addition to intracellular roles, V-ATPase containing ATP6V1F can localize to the plasma membrane in specialized cell types where it performs extracellular acidification functions (eaton2021theh+atpase(vatpase) pages 1-5, chen2024vatpaseincancer pages 1-3). These include:

Osteoclasts: V-ATPase pumps protons into the bone resorption lacuna, enabling bone remodeling (eaton2021theh+atpase(vatpase) pages 1-5, chen2024vatpaseincancer pages 1-3)
Kidney intercalated cells: The enzyme secretes protons for systemic acid-base balance (eaton2021theh+atpase(vatpase) pages 1-5, chen2024vatpaseincancer pages 1-3)
Epididymal cells: V-ATPase contributes to sperm maturation through luminal acidification (eaton2021theh+atpase(vatpase) pages 1-5)

Physiological Roles Dependent on Acidification

Through its contribution to V-ATPase-mediated acidification, ATP6V1F indirectly supports numerous cellular processes (eaton2021theh+atpase(vatpase) pages 1-5, chen2024vatpaseincancer pages 1-3):

Lysosomal proteolysis: Acidification activates lysosomal hydrolases for degradation of proteins and organelles
Endosomal trafficking: pH gradients enable receptor sorting and vesicle maturation
Neurotransmitter loading: Synaptic vesicle acidification provides the electrochemical gradient for neurotransmitter uptake
Protein processing: Golgi acidification supports protein modification and sorting

Signaling and Biochemical Pathways

Nutrient Sensing Platform

Beyond its canonical role as a proton pump, V-ATPase serves as a central scaffold for nutrient-sensing signaling complexes at the lysosomal membrane (ratto2022directcontrolof pages 1-2, leprivier2020howdoesmtor pages 1-2, yang2025vatpaseandlysosomal pages 1-2). ATP6V1F, as an integral V1 component, participates in this signaling platform.

mTORC1 Pathway Regulation

V-ATPase directly interacts with mechanistic target of rapamycin complex 1 (mTORC1) through the Ragulator-RAG GTPase complex at lysosomes (ratto2022directcontrolof pages 1-2, leprivier2020howdoesmtor pages 1-2, yang2025vatpaseandlysosomal pages 1-2). During amino acid sufficiency, V-ATPase recruits and activates mTORC1 at the lysosomal surface, promoting anabolic processes and cell growth (ratto2022directcontrolof pages 1-2, yang2025vatpaseandlysosomal pages 1-2). Recent work has shown that mTORC1 activity also reciprocally controls V-ATPase assembly: when mTORC1 is active, V1 domains (including ATP6V1F) are stabilized in the cytosol by interaction with the chaperonin TRiC, keeping lysosomes in a low-activity state (ratto2022directcontrolof pages 1-2). Upon mTORC1 inactivation during nutrient stress, V1 domains rapidly assemble with V0 domains at lysosomes, increasing acidification and catabolic activity (ratto2022directcontrolof pages 1-2).

AMPK Pathway Interactions

V-ATPase also serves as a core component for lysosomal AMP-activated protein kinase (L-AMPK) signaling (leprivier2020howdoesmtor pages 1-2, yang2025vatpaseandlysosomal pages 1-2). The enzyme physically interacts with AMPK complexes at lysosomes, and this interaction is regulated by nutrient availability, particularly glucose (leprivier2020howdoesmtor pages 1-2, yang2025vatpaseandlysosomal pages 1-2). During energy stress, AMPK activation leads to mTORC1 inhibition, coordinating catabolic responses including autophagy induction (leprivier2020howdoesmtor pages 1-2, yang2025vatpaseandlysosomal pages 1-2).

Recent studies have also revealed direct phosphorylation of V-ATPase subunits by kinases including ABL1, which phosphorylates ATP6V1B2 to regulate V-ATPase assembly and lysosomal acidification (song2025nonreceptortyrosinekinase pages 1-2, song2025nonreceptortyrosinekinase pages 2-5). While direct phosphorylation of ATP6V1F has not been extensively characterized, the central stalk positioning makes it a potential target for regulatory modifications.

Autophagy Regulation

V-ATPase-dependent lysosomal acidification is essential for autophagy, the major cellular degradation pathway (song2025nonreceptortyrosinekinase pages 1-2, ratto2022directcontrolof pages 1-2, zhang2022ionchannelsand pages 1-3). ATP6V1F contributes to this process by enabling functional proton pumping required for:

Autophagosome-lysosome fusion competence
Lysosomal hydrolase activation
Degradation of autophagic cargo
Nutrient recycling

The regulation of V-ATPase assembly in response to nutrient status represents a rapid mechanism for cells to modulate autophagic flux (ratto2022directcontrolof pages 1-2, zhang2022ionchannelsand pages 1-3).

Additional Signaling Interactions

V-ATPase has been implicated in other signaling pathways including Wnt signaling, Notch signaling, and interactions with various ion channels and transporters (eaton2021theh+atpase(vatpase) pages 1-5, chen2024vatpaseincancer pages 1-3, zhang2022ionchannelsand pages 1-3). These interactions often occur at the level of the holoenzyme rather than through subunit-specific mechanisms.

Experimental Evidence and Structural Data

High-Resolution Structural Studies

The most definitive structural information for ATP6V1F comes from cryo-EM studies of intact mammalian V-ATPase complexes. Wang et al. (2020) determined structures of human V-ATPase purified from HEK293F cells at resolutions of 2.9-3.1 Å for different rotational states (wang2020structuresofa pages 1-3, wang2020structuresofa pages 3-5). Abbas et al. (2020) independently solved structures of rat brain V-ATPase at 3.6-3.9 Å resolution (abbas2020structureofvatpase pages 1-2, abbas2020structureofvatpase pages 2-4). These studies revealed:

The precise positioning of subunit F within the central stalk
Interactions between subunit F and subunit D in the stalk assembly
The insertion of the DF stalk into the A3B3 head and its connection to the c-ring
Conformational changes during the catalytic cycle showing stalk rotation

Biochemical Characterization

Mass spectrometry analysis of purified V-ATPase preparations from rat brain confirmed the presence of subunit F, along with other V1 and V0 components (abbas2020structureofvatpase pages 1-2, abbas2020structureofvatpase pages 2-4). The homogeneity of these preparations was verified by native mass spectrometry, which showed the V1 region with a composition consistent with A3B23C1DE13FG23 (abbas2020structureofvatpase pages 2-4).

Functional Assembly Studies

Experiments on V-ATPase assembly and disassembly have demonstrated that the V1 domain (including ATP6V1F) can reversibly dissociate from the V0 domain in response to various stimuli including glucose deprivation, amino acid starvation, and hormonal signals (eaton2021theh+atpase(vatpase) pages 5-9, eaton2021theh+atpase(vatpase) pages 9-12, ratto2022directcontrolof pages 1-2). When dissociated, the isolated V1 complex lacks ATPase activity, and the V0 complex cannot transport protons, preventing futile ATP hydrolysis and proton leak (eaton2021theh+atpase(vatpase) pages 5-9, eaton2021theh+atpase(vatpase) pages 9-12). The central stalk position of ATP6V1F makes it essential for maintaining the V1-V0 interaction when the holoenzyme is assembled.

Evolutionary Conservation

V-ATPase is highly conserved across eukaryotes from yeast to mammals, indicating ancient origins and fundamental importance (eaton2021theh+atpase(vatpase) pages 1-5, yang2025vatpaseandlysosomal pages 1-2). The central stalk architecture including subunit F orthologs is conserved, with the yeast F subunit sharing significant structural similarity with mammalian ATP6V1F despite sequence divergence (wang2020structuresofa pages 1-3, eaton2021theh+atpase(vatpase) pages 1-5). This conservation supports the inference that the mechanical coupling role of ATP6V1F in the rotary motor represents a core, evolutionarily ancient function.

Disease Relevance and Clinical Implications

While direct disease-causing mutations in ATP6V1F are not extensively documented in the current literature, dysfunction of V-ATPase subunits is implicated in various pathological conditions (eaton2021theh+atpase(vatpase) pages 1-5, chen2024vatpaseincancer pages 1-3, chen2022thevatpasesin pages 1-2). These include:

Cancer: Altered V-ATPase expression and localization contributes to tumor cell survival, metastasis, and drug resistance through effects on intracellular pH homeostasis and signaling (chen2024vatpaseincancer pages 1-3, liu2024ubiquitinligasesubunit pages 1-2, chen2022thevatpasesin pages 1-2)
Neurodegenerative diseases: Impaired V-ATPase function affects autophagy and lysosomal degradation, contributing to protein aggregate accumulation (eaton2021theh+atpase(vatpase) pages 1-5, chen2022thevatpasesin pages 1-2)
Osteopetrosis: Mutations in other V-ATPase subunits (particularly a3 and d2) cause defective osteoclast function and increased bone density (eaton2021theh+atpase(vatpase) pages 1-5)
Renal tubular acidosis: Defects in specific V-ATPase isoforms impair urinary acidification (eaton2021theh+atpase(vatpase) pages 1-5)

Summary and Key Findings

Feature/Property	Description	Evidence/Citation
Verified identity	ATP6V1F is the human V-type proton ATPase subunit F, a component of the cytosolic V1 sector of the vacuolar ATPase complex; human structural studies identified one copy of subunit F in purified mammalian V-ATPase preparations.	(wang2020structuresofa pages 3-5, abbas2020structureofvatpase pages 1-2)
Protein domain structure	UniProt annotation places ATP6V1F in the V-ATPase F-subunit family and notes an ATP-synt_F domain; structurally, mammalian subunit F is part of the central stalk associated with subunit D in cryo-EM reconstructions of intact V-ATPase.	(wang2020structuresofa pages 3-5, chen2022thevatpasesin pages 1-2)
Role in V-ATPase complex	V-ATPase consists of a cytosolic V1 ATP-hydrolysis sector and membrane-embedded V0 proton-translocating sector; ATP6V1F belongs to V1 and is one of the single-copy subunits that contribute to the rotary motor architecture.	(wang2020structuresofa pages 1-3, eaton2021theh+atpase(vatpase) pages 1-5, chen2022thevatpasesin pages 1-2)
Central stalk function	Subunit F forms the central stalk together with subunit D, linking the A3B3 catalytic head of V1 to the membrane sector for mechanical transmission. This places ATP6V1F at the core of the rotor that couples ATP hydrolysis to proton pumping.	(wang2020structuresofa pages 3-5, chen2022thevatpasesin pages 1-2)
Molecular interactions with other subunits	In human cryo-EM structures, subunit F is directly associated with subunit D in the DF stalk; this stalk interfaces with the A3B3 head above and with subunit d/c-ring machinery below through the rotary axis, enabling force transmission across the holoenzyme.	(wang2020structuresofa pages 3-5, wang2020structuresofa pages 5-7)
Role in ATP hydrolysis coupling	ATP hydrolysis occurs in the V1 head, and the resulting conformational changes drive rotation of the DF central stalk. Because F is part of this stalk, its primary mechanistic role is coupling ATP hydrolysis in V1 to rotation of V0 for proton translocation rather than directly catalyzing ATP cleavage itself.	(wang2020structuresofa pages 1-3, wang2020structuresofa pages 3-5, chen2022thevatpasesin pages 1-2)
Substrate/process specificity	ATP6V1F does not define substrate specificity on its own; as part of V-ATPase, it contributes to transport of H+ across organelle or plasma membranes using energy derived from ATP hydrolysis. The chemical reaction of the holoenzyme is ATP hydrolysis coupled to proton pumping.	(wang2020structuresofa pages 1-3, eaton2021theh+atpase(vatpase) pages 1-5, chen2024vatpaseincancer pages 1-3)
Subcellular localization	ATP6V1F functions where assembled V-ATPase holoenzymes are located: lysosomes, endosomes, Golgi/trans-Golgi network, synaptic vesicles, secretory vesicles, and in certain specialized cells the plasma membrane. Brain-derived mammalian complexes containing subunit F were purified from synaptic-vesicle-rich fractions.	(eaton2021theh+atpase(vatpase) pages 1-5, abbas2020structureofvatpase pages 1-2, chen2024vatpaseincancer pages 1-3)
Physiologic cellular roles	Through V-ATPase activity, ATP6V1F contributes indirectly to acidification-dependent processes such as lysosomal proteolysis, endosomal trafficking, neurotransmitter loading into synaptic vesicles, receptor trafficking, bone resorption, renal acid secretion, and sperm maturation.	(wang2020structuresofa pages 1-3, eaton2021theh+atpase(vatpase) pages 1-5, chen2024vatpaseincancer pages 1-3)
mTORC1 pathway relevance	V-ATPase acts as a lysosomal nutrient-sensing platform for mTORC1. Although these signaling studies are typically at the holoenzyme level rather than subunit-F-specific, ATP6V1F is part of the V1 module whose assembly onto V0 is regulated by nutrient state and is therefore part of the machinery through which V-ATPase influences mTORC1 activity.	(ratto2022directcontrolof pages 1-2, leprivier2020howdoesmtor pages 1-2, yang2025vatpaseandlysosomal pages 1-2)
AMPK pathway relevance	V-ATPase also participates in lysosomal AMPK signaling platforms. Reviews describe the V-ATPase as a physical and functional core for lysosomal AMPK regulation; thus ATP6V1F contributes as a constitutive structural element of the V1 sector required for that signaling-competent complex.	(leprivier2020howdoesmtor pages 1-2, yang2025vatpaseandlysosomal pages 1-2)
Autophagy relevance	V-ATPase-driven lysosomal acidification is essential for autophagic degradation. By enabling functional V-ATPase assembly and proton pumping, ATP6V1F indirectly supports autophagosome-lysosome fusion competence and lysosomal hydrolase activity needed for autophagic flux.	(song2025nonreceptortyrosinekinase pages 1-2, ratto2022directcontrolof pages 1-2, zhang2022ionchannelsand pages 1-3)
Regulation through assembly/disassembly	V-ATPase activity is regulated by reversible dissociation of V1 from V0. Because ATP6V1F is a V1 central-stalk subunit, its function depends on proper assembly of the V1 sector with V0; nutrient stress and signaling pathways can shift this assembly state to modulate acidification.	(eaton2021theh+atpase(vatpase) pages 5-9, song2025nonreceptortyrosinekinase pages 1-2, ratto2022directcontrolof pages 1-2)
Structural evidence base	Human V-ATPase cryo-EM studies resolved the V1 complex to near-atomic resolution and identified subunit F in the intact human and mammalian complexes, supporting a structure-based assignment of its position and role in the rotary axis.	(wang2020structuresofa pages 1-3, wang2020structuresofa pages 3-5, abbas2020structureofvatpase pages 2-4)
Evolutionary conservation	V-ATPase is evolutionarily conserved from yeast to mammals, and ATP6V1F is part of the conserved V1 architecture. Recent comparative review material also shows strong conservation of ATP6V1F across eukaryotes, supporting inference that its central-stalk role is ancient and fundamental.	(eaton2021theh+atpase(vatpase) pages 1-5, yang2025vatpaseandlysosomal pages 1-2)
Evidence limitations specific to ATP6V1F	Direct ATP6V1F-specific mechanistic or disease literature in humans is limited compared with data on the whole V-ATPase or on other subunits. Most confident functional annotation for ATP6V1F comes from high-resolution holoenzyme structures, biochemical composition studies, and conserved V-ATPase mechanism rather than subunit-F-only perturbation studies.	(wang2020structuresofa pages 3-5, abbas2020structureofvatpase pages 1-2, chen2022thevatpasesin pages 1-2)

Table: This table summarizes the best-supported structural and functional annotations for human ATP6V1F within the V-ATPase complex. It is useful for quickly separating subunit-specific evidence from broader holoenzyme-level inference, especially for function, localization, and signaling roles.

ATP6V1F (subunit F) is an essential structural component of the V-type H+-ATPase, where it forms the central rotary stalk together with subunit D. This stalk mechanically couples ATP hydrolysis in the cytosolic V1 domain to proton translocation through the membrane-embedded V0 domain. The protein functions across multiple intracellular compartments—including lysosomes, endosomes, Golgi, and synaptic vesicles—as well as at the plasma membrane in specialized cells. Beyond its canonical role in acidification, ATP6V1F participates in V-ATPase-based nutrient sensing platforms that regulate mTORC1 and AMPK signaling at lysosomes, thereby influencing autophagy, metabolism, and cell growth.

High-resolution cryo-EM structures (2.9-3.1 Å) have defined the precise molecular architecture and rotational mechanism of the enzyme. Functional studies demonstrate that V-ATPase activity is regulated through reversible V1-V0 assembly, with ATP6V1F being critical for maintaining holoenzyme integrity and function. The evolutionary conservation of this subunit across eukaryotes underscores its fundamental importance to cellular physiology.

While ATP6V1F-specific disease mutations are not well characterized, the broader V-ATPase complex is implicated in cancer, neurodegeneration, metabolic disorders, and bone diseases, highlighting the clinical relevance of understanding this essential proton pump component.

References

(wang2020structuresofa pages 3-5): Longfei Wang, Di Wu, Carol V. Robinson, Hao Wu, and Tian-Min Fu. Structures of a complete human v-atpase reveal mechanisms of its assembly. Molecular Cell, 80:501-511.e3, Nov 2020. URL: https://doi.org/10.1016/j.molcel.2020.09.029, doi:10.1016/j.molcel.2020.09.029. This article has 184 citations and is from a highest quality peer-reviewed journal.
(abbas2020structureofvatpase pages 1-2): Yazan M. Abbas, Di Wu, Stephanie A. Bueler, Carol V. Robinson, and John L. Rubinstein. Structure of v-atpase from the mammalian brain. Mar 2020. URL: https://doi.org/10.1126/science.aaz2924, doi:10.1126/science.aaz2924. This article has 278 citations and is from a highest quality peer-reviewed journal.
(abbas2020structureofvatpase pages 2-4): Yazan M. Abbas, Di Wu, Stephanie A. Bueler, Carol V. Robinson, and John L. Rubinstein. Structure of v-atpase from the mammalian brain. Mar 2020. URL: https://doi.org/10.1126/science.aaz2924, doi:10.1126/science.aaz2924. This article has 278 citations and is from a highest quality peer-reviewed journal.
(wang2020structuresofa pages 1-3): Longfei Wang, Di Wu, Carol V. Robinson, Hao Wu, and Tian-Min Fu. Structures of a complete human v-atpase reveal mechanisms of its assembly. Molecular Cell, 80:501-511.e3, Nov 2020. URL: https://doi.org/10.1016/j.molcel.2020.09.029, doi:10.1016/j.molcel.2020.09.029. This article has 184 citations and is from a highest quality peer-reviewed journal.
(eaton2021theh+atpase(vatpase) pages 1-5): Amity F. Eaton, Maria Merkulova, and Dennis Brown. The h⁺-atpase (v-atpase): from proton pump to signaling complex in health and disease. Mar 2021. URL: https://doi.org/10.1152/ajpcell.00442.2020, doi:10.1152/ajpcell.00442.2020. This article has 188 citations.
(chen2024vatpaseincancer pages 1-3): Tingting Chen, Xiaotan Lin, Shuo Lu, and Bo Li. V-atpase in cancer: mechanistic insights and therapeutic potentials. Cell Communication and Signaling : CCS, Dec 2024. URL: https://doi.org/10.1186/s12964-024-01998-9, doi:10.1186/s12964-024-01998-9. This article has 25 citations.
(wang2020structuresofa pages 5-7): Longfei Wang, Di Wu, Carol V. Robinson, Hao Wu, and Tian-Min Fu. Structures of a complete human v-atpase reveal mechanisms of its assembly. Molecular Cell, 80:501-511.e3, Nov 2020. URL: https://doi.org/10.1016/j.molcel.2020.09.029, doi:10.1016/j.molcel.2020.09.029. This article has 184 citations and is from a highest quality peer-reviewed journal.
(ratto2022directcontrolof pages 1-2): Edoardo Ratto, S. Roy Chowdhury, Nora S. Siefert, Martin Schneider, Marten Wittmann, Dominic Helm, and Wilhelm Palm. Direct control of lysosomal catabolic activity by mtorc1 through regulation of v-atpase assembly. Nature Communications, Aug 2022. URL: https://doi.org/10.1038/s41467-022-32515-6, doi:10.1038/s41467-022-32515-6. This article has 179 citations and is from a highest quality peer-reviewed journal.
(leprivier2020howdoesmtor pages 1-2): Gabriel Leprivier and Barak Rotblat. How does mtor sense glucose starvation? ampk is the usual suspect. Cell Death Discovery, Apr 2020. URL: https://doi.org/10.1038/s41420-020-0260-9, doi:10.1038/s41420-020-0260-9. This article has 150 citations and is from a peer-reviewed journal.
(yang2025vatpaseandlysosomal pages 1-2): Xianrui Yang and Lexie Shannon Holliday. V-atpase and lysosomal energy sensing in periodontitis and medicine-related osteonecrosis of the jaw. Biomolecules, 15:997, Jul 2025. URL: https://doi.org/10.3390/biom15070997, doi:10.3390/biom15070997. This article has 2 citations.
(song2025nonreceptortyrosinekinase pages 1-2): Caiwei Song, Qincai Dong, Yi Yao, Yan Cui, Chunmei Zhang, Lijun Lin, Lin Zhu, Yong Hu, Hainan Liu, Yanwen Jin, Ping Li, Xuan Liu, and Cheng Cao. Nonreceptor tyrosine kinase abl1 regulates lysosomal acidification by phosphorylating the atp6v1b2 subunit of the vacuolar-type h ⁺ -atpase. Autophagy, pages 1-20, Jan 2025. URL: https://doi.org/10.1080/15548627.2024.2448913, doi:10.1080/15548627.2024.2448913. This article has 12 citations and is from a domain leading peer-reviewed journal.
(song2025nonreceptortyrosinekinase pages 2-5): Caiwei Song, Qincai Dong, Yi Yao, Yan Cui, Chunmei Zhang, Lijun Lin, Lin Zhu, Yong Hu, Hainan Liu, Yanwen Jin, Ping Li, Xuan Liu, and Cheng Cao. Nonreceptor tyrosine kinase abl1 regulates lysosomal acidification by phosphorylating the atp6v1b2 subunit of the vacuolar-type h ⁺ -atpase. Autophagy, pages 1-20, Jan 2025. URL: https://doi.org/10.1080/15548627.2024.2448913, doi:10.1080/15548627.2024.2448913. This article has 12 citations and is from a domain leading peer-reviewed journal.
(zhang2022ionchannelsand pages 1-3): Ruoxi Zhang, Rui Kang, Daniel J. Klionsky, and Daolin Tang. Ion channels and transporters in autophagy. Autophagy, 18:4-23, Mar 2022. URL: https://doi.org/10.1080/15548627.2021.1885147, doi:10.1080/15548627.2021.1885147. This article has 40 citations and is from a domain leading peer-reviewed journal.
(eaton2021theh+atpase(vatpase) pages 5-9): Amity F. Eaton, Maria Merkulova, and Dennis Brown. The h⁺-atpase (v-atpase): from proton pump to signaling complex in health and disease. Mar 2021. URL: https://doi.org/10.1152/ajpcell.00442.2020, doi:10.1152/ajpcell.00442.2020. This article has 188 citations.
(eaton2021theh+atpase(vatpase) pages 9-12): Amity F. Eaton, Maria Merkulova, and Dennis Brown. The h⁺-atpase (v-atpase): from proton pump to signaling complex in health and disease. Mar 2021. URL: https://doi.org/10.1152/ajpcell.00442.2020, doi:10.1152/ajpcell.00442.2020. This article has 188 citations.
(chen2022thevatpasesin pages 1-2): Fangquan Chen, Rui Kang, Jiao Liu, and Daolin Tang. The v-atpases in cancer and cell death. Cancer Gene Therapy, 29:1529-1541, May 2022. URL: https://doi.org/10.1038/s41417-022-00477-y, doi:10.1038/s41417-022-00477-y. This article has 129 citations and is from a peer-reviewed journal.
(liu2024ubiquitinligasesubunit pages 1-2): Liang Liu, Xiaodong Chen, Leilei Wu, Kaizong Huang, Zhenyi Wang, Yaolin Zheng, Cheng Zheng, Zhenshan Zhang, Jiayan Chen, Jiaming Wei, Song Chen, Weilin Jin, Jinfei Chen, Dongping Wei, and Yaping Xu. Ubiquitin ligase subunit fbxo9 inhibits v-atpase assembly and impedes lung cancer metastasis. Experimental Hematology & Oncology, Mar 2024. URL: https://doi.org/10.1186/s40164-024-00497-4, doi:10.1186/s40164-024-00497-4. This article has 12 citations and is from a peer-reviewed journal.

📚 Additional Documentation

Notes

(ATP6V1F-notes.md)

ATP6V1F Research Notes

Gene Identity

UniProt: Q16864 (VATF_HUMAN)
Gene symbol: ATP6V1F (also known as ATP6S14, VATF)
Protein: V-type proton ATPase subunit F; 119 amino acids, ~13 kDa (the smallest V1 subunit)
Two isoforms from alternative splicing (Q16864-1, Q16864-2)

Core V-ATPase Biology

ATP6V1F encodes the F subunit of the V1 peripheral sector of the vacuolar-type H+-ATPase (V-ATPase). Together with subunit D, subunit F forms the central rotor of V1 that transmits ATP hydrolysis energy to rotate the V0 proteolipid ring, driving proton translocation.

PMID:18752060

PMID:33065002

Smith et al. (2008) directly demonstrated that human subunit F interacts with the V0 d subunit, confirming its central stalk position:

PMID:18752060

Original Cloning

Subunit F (14 kDa) was cloned from human fetal brain by Fujiwara et al. (1995). Northern blot analysis showed ubiquitous expression across human tissues.

PMID:8581736

Subcellular Localization

Primary: lysosomal membrane, as part of the V-ATPase complex on the cytoplasmic face of acidic organelle membranes
Also: Golgi membrane, endosome membrane, plasma membrane (in specialized cells), clathrin-coated vesicle membrane, synaptic vesicle membrane

As a V1 peripheral complex subunit, the cytoplasmic face (cytosol) is the functional location.

Structural Data

Subunit F is present in all four cryo-EM structures of the complete human V-ATPase (PDB: 6WLZ, 6WM2, 6WM3, 6WM4; PMID:33065002), chain N, at near-atomic resolution. The structure confirms its position in the central rotor of V1.

Interaction with ATP6V1D

The F subunit directly interacts with subunit D (ATP6V1D) as shown by IntAct (NbExp=7, EBI-714690 x EBI-2684998) and by biochemical pulldowns (PMID:18752060). This D-F pair constitutes the central stalk of V1.

Curation Notes

"Protein binding" annotations (IPI from PMID:32296183, PMID:33961781, PMID:35271311) are from high-throughput interactome studies and represent generic protein-protein interaction data with no functional specificity.
The protein binding annotation from PMID:18752060 (IPI) reflects a specific, functionally important interaction between subunit F and the V0 d subunit (ATP6V0D1), which is mechanistically central to the rotary pump mechanism.
"Monoatomic ion transmembrane transport" (GO:0034220, IEA) is an appropriate but potentially redundant term given the more specific "proton transmembrane transport" (GO:1902600).
The extracellular exosome (HDA) annotations are from proteomics surveys; subunit F has no known function outside the V-ATPase complex.
There is no dedicated disease association for ATP6V1F specifically (unlike ATP6V1E1 which causes ARCL2C), though V-ATPase dysfunction in general causes multiple disorders.
The ATPase-coupled ion transmembrane transporter activity (GO:0042625, NAS from PMID:8581736) and proton transmembrane transporter activity (GO:0015078, NAS from PMID:8581736) annotations are from the original cloning paper and are appropriate for a V-ATPase subunit contributing to overall complex activity.

Falcon deep research synthesis (2026-06-21)

Falcon deep research has now completed (file:human/ATP6V1F/ATP6V1F-deep-research-falcon.md,
25 citations). It corroborates the central-rotor core above with no new
F-specific function or disease; no change to annotation calls.

Core confirmed. F is the smallest V1 subunit and forms the DF central
stalk with subunit D, mechanically coupling A3B3 ATP hydrolysis to c-ring
rotation/proton translocation (Wang 2020 cryo-EM). Its central-stalk position
makes it essential for maintaining the V1–V0 interaction in the holoenzyme.
Reversible-assembly relevance. On glucose/amino-acid starvation V1
(including F) reversibly dissociates from V0; dissociated V1 lacks ATPase
activity and V0 cannot leak protons — preventing futile hydrolysis. Regulatory
context (not an F-specific MF).
Conservation. F orthologs (yeast↔mammal) are structurally conserved despite
sequence divergence, consistent with an ancient core mechanical-coupling role.
Disease. No ATP6V1F-specific Mendelian disease documented; the section is
generic V-ATPase (cancer, neurodegeneration, osteopetrosis via a3/d2, dRTA).
Non-core context.

Net: no change to calls — F is the small central-rotor (DF) V1 subunit coupling
ATP hydrolysis to proton translocation.

Pn Notes

(ATP6V1F-pn-notes.md)

ATP6V1F PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q16864
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-06
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/ATP6V1F/ATP6V1F-ai-review.yaml
AIGR review HTML: present - genes/human/ATP6V1F/ATP6V1F-ai-review.html
Gene notes: present - genes/human/ATP6V1F/ATP6V1F-notes.md
GOA TSV: present - genes/human/ATP6V1F/ATP6V1F-goa.tsv
UniProt record: present - genes/human/ATP6V1F/ATP6V1F-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/ATP6V1F.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/ATP6V1F.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

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

AIGR Review Snapshot

Description: ATP6V1F encodes the F subunit (~13 kDa; 119 aa, 13,441 Da, historically called the "14-kDa subunit") of the V1 peripheral sector of the vacuolar-type H+-ATPase (V-ATPase). Together with subunit D, subunit F forms the central rotor of V1 that is driven by ATP hydrolysis in the catalytic A3B3 hexamer and transmits rotational energy to the V0 proteolipid c-ring to drive proton translocation across organelle membranes. ATP6V1F is the smallest subunit of V1 and is ubiquitously expressed, reflecting the housekeeping role of V-ATPase in acidifying lysosomes, endosomes, Golgi apparatus, and other organelles. The D-F central rotor assembly serves as the mechanical connection between the ATP-hydrolyzing head and the proton-translocating V0 membrane sector. In some cell types, the V-ATPase is targeted to the plasma membrane for extracellular acidification. The protein interacts directly with V0 d subunit (ATP6V0D1), cementing its position in the central stalk. Two alternatively spliced isoforms exist.
Existing/core annotation action counts: ACCEPT: 20; KEEP_AS_NON_CORE: 16; MARK_AS_OVER_ANNOTATED: 11

PN Consistency Summary

Consistency: Consistent. Notes ↔ review agree: F = smallest V1 subunit (13 kDa), central-rotor with D, interacts directly with V0 d subunit (PMID:18752060); ubiquitous housekeeping. Review correctly ACCEPTs complex/MF/process core terms and marks generic membrane/monoatomic-ion/intracellular-pH terms over-annotated. No PN/review contradiction.
PN story / NEW pressure: No over-reach, no unmet pressure. PN's mTORC1-upstream row is generic; the F review correctly does NOT add mTORC1/Ragulator annotations (no F-specific evidence) — defensible. GO:0007042 already in GOA (dossier: already_in_goa_exact; 2 hits) and ACCEPTed. GO:0046612 (verified real, OLS) absent from GOA — defensible more-specific ADD. GO:0033176 already in GOA (2 hits) ACCEPT.
Evidence alignment: Minimal overlap. PN cites generic V-ATPase/mTORC1 review titles; review anchors on F-specific primaries: PMID:8581736 (14-kDa F cloning), 18752060 (central stalk/d-subunit, IDA), 33065002 (cryo-EM), 32001091 (= one PN review, overlap). PN evidence non-F-specific.
Verdict: Consistent / ADD GO:0046612 (verified) as more-specific CC; no contradictions. Recommended edits: none required; mappings sound (broader GO:0033176 acceptable given F GOA lacks a lysosomal-specific complex term).

Full Consistency Review

UniProt: Q16864 · batch: proteostasis-batch-2026-06-06 · review status: COMPLETE (mature; ~45 annotations, full core_functions)
PN placement: Autophagy-Lysosome Pathway|...|V1 lysosomal v-ATPase proton pump component (two rows, identical pattern) ; PN-node mapping: subtype=mapped/ok GO:0046612 + GO:0033176; type=mapped/ok GO:0007042; ancestors no_mapping/context_only.
Consistency: Consistent. Notes ↔ review agree: F = smallest V1 subunit (13 kDa), central-rotor with D, interacts directly with V0 d subunit (PMID:18752060); ubiquitous housekeeping. Review correctly ACCEPTs complex/MF/process core terms and marks generic membrane/monoatomic-ion/intracellular-pH terms over-annotated. No PN/review contradiction.
PN story / NEW pressure: No over-reach, no unmet pressure. PN's mTORC1-upstream row is generic; the F review correctly does NOT add mTORC1/Ragulator annotations (no F-specific evidence) — defensible. GO:0007042 already in GOA (dossier: already_in_goa_exact; 2 hits) and ACCEPTed. GO:0046612 (verified real, OLS) absent from GOA — defensible more-specific ADD. GO:0033176 already in GOA (2 hits) ACCEPT.
Mapping strategy: F does not change node mapping. F GOA lacks lysosomal-specific complex CC (GO:0046611 absent); review's most specific complex term is GO:0016471 (vacuolar V-ATPase complex, IDA/ACCEPT). The subtype-complex projection GO:0033176 is broader; GO:0046612 V1-domain target is correctly specific.
Evidence alignment: Minimal overlap. PN cites generic V-ATPase/mTORC1 review titles; review anchors on F-specific primaries: PMID:8581736 (14-kDa F cloning), 18752060 (central stalk/d-subunit, IDA), 33065002 (cryo-EM), 32001091 (= one PN review, overlap). PN evidence non-F-specific.
Verdict: Consistent / ADD GO:0046612 (verified) as more-specific CC; no contradictions. Recommended edits: none required; mappings sound (broader GO:0033176 acceptable given F GOA lacks a lysosomal-specific complex term).

PN Dossier Context

review_batch: proteostasis-batch-2026-06-06
review_yaml: genes/human/ATP6V1F/ATP6V1F-ai-review.yaml
PN workbook rows: 2

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

UniProt: Q16864
In branches: ALP
Notes: Subunit of the V1 (cytosolic) component of the lysosomal v-ATPase. The V0 and V1 components of the v-ATPase assemble during amino acid starvation creating the active v-ATPase that pumps protons into the lysosome for acidification. The v-ATPase also engages in amino acid-dependent interactions with the Ragulator complex. In the presence of amino acids, the v-ATPase-Ragulator complex undergoes a conformational change that results in Ragulator exerting its GEF activity on RAGA/B.
PN references (titles):
- Regulation of mTORC1 by amino acids - ScienceDirect
- Cells | Free Full-Text | SEA and GATOR 10 Years Later | HTML (mdpi.com)
- Eukaryotic V-ATPase: Novel structural findings and functional insights - ScienceDirect
- The emerging roles of vacuolar-type ATPase-dependent Lysosomal acidification in neurodegenerative diseases | Translational Neurodegeneration | Full Text (biomedcentral.com)
PN-node mapping records (path + ancestors):
- [subtype] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling|mTORC1 pathway, upstream|Nutrient sensing|V1 lysosomal v-ATPase proton pump component
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0046612 lysosomal proton-transporting V-type ATPase, V1 domain]
  rationale: This PN leaf is restricted to V1-sector lysosomal V-ATPase components. The GO lysosomal V1-domain component term is the direct target.
- [type] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling|mTORC1 pathway, upstream|Nutrient sensing
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a contextual PN role. The label is useful for curator triage, but by itself does not support a universal GO assertion for all member genes beyond curated ancestor or child mappings.
- [group] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling|mTORC1 pathway, upstream
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN taxonomy container. The descendants mix components, regulators, context labels, and mechanistic leaves, so propagation should come only from narrower curated nodes.
- [class] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling
  status=context_only scope=too_broad_to_propagate GO=[GO:0010506 regulation of autophagy]
  rationale: This class organizes upstream signaling inputs to autophagy initiation. Because the subtree contains generic insulin, AMPK, mTORC1, nutrient-sensing, and miscellaneous signaling components, class-level propagation to regulation of autophagy would over-annotate many genes.
- [branch] Autophagy-Lysosome Pathway
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

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

UniProt: Q16864
In branches: ALP
Notes: Subunit of the V1 (cytosolic) component of the lysosomal v-ATPase. The V0 and V1 components of the v-ATPase assemble during amino acid starvation creating the active v-ATPase that pumps protons into the lysosome for acidification. The v-ATPase also engages in amino acid-dependent interactions with the Ragulator complex. In the presence of amino acids, the v-ATPase-Ragulator complex undergoes a conformational change that results in Ragulator exerting its GEF activity on RAGA/B.
PN references (titles):
- Regulation of mTORC1 by amino acids - ScienceDirect
- Cells | Free Full-Text | SEA and GATOR 10 Years Later | HTML (mdpi.com)
- Eukaryotic V-ATPase: Novel structural findings and functional insights - ScienceDirect
- The emerging roles of vacuolar-type ATPase-dependent Lysosomal acidification in neurodegenerative diseases | Translational Neurodegeneration | Full Text (biomedcentral.com)
PN-node mapping records (path + ancestors):
- [subtype] Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification|V1 lysosomal v-ATPase proton pump component
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0033176 proton-transporting V-type ATPase complex]
  rationale: This PN subtype denotes the V1-sector component of the lysosomal V-ATPase. In the current GO cache, the broader V-type ATPase complex is the safest validated target for this component role.
- [type] Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0007042 lysosomal lumen acidification]
  rationale: This PN group directly names the lysosomal acidification mechanism. Propagation to the GO lysosomal lumen acidification term is an exact mechanistic match.
- [group] Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN taxonomy container. The descendants mix components, regulators, context labels, and mechanistic leaves, so propagation should come only from narrower curated nodes.
- [class] Autophagy-Lysosome Pathway|Lysosomal catabolism
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad lysosomal-degradation container. The subtree includes carbohydrate, lipid, protein, nuclease, phosphatase, sulfatase, and environment-regulation roles, so mapping should occur at the enzyme or process subtype level.
- [branch] Autophagy-Lysosome Pathway
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

Projected GO annotations (3)

GO:0046612 lysosomal proton-transporting V-type ATPase, V1 domain | scope=ok_for_propagation_to_go | goa_status=more_specific_than_existing_goa | from=Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling|mTORC1 pathway, upstream|Nutrient sensing|V1 lysosomal v-ATPase proton pump component
GO:0007042 lysosomal lumen acidification | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification
GO:0033176 proton-transporting V-type ATPase complex | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification|V1 lysosomal v-ATPase proton pump component

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

id: Q16864
gene_symbol: ATP6V1F
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: ATP6V1F encodes the F subunit (~13 kDa; 119 aa, 13,441 Da, historically
  called the "14-kDa subunit") of the V1 peripheral sector of the
  vacuolar-type H+-ATPase (V-ATPase). Together with subunit D, subunit F forms the central
  rotor of V1 that is driven by ATP hydrolysis in the catalytic A3B3 hexamer and transmits
  rotational energy to the V0 proteolipid c-ring to drive proton translocation across
  organelle membranes. ATP6V1F is the smallest subunit of V1 and is ubiquitously expressed,
  reflecting the housekeeping role of V-ATPase in acidifying lysosomes, endosomes, Golgi
  apparatus, and other organelles. The D-F central rotor assembly serves as the mechanical
  connection between the ATP-hydrolyzing head and the proton-translocating V0 membrane
  sector. In some cell types, the V-ATPase is targeted to the plasma membrane for
  extracellular acidification. The protein interacts directly with V0 d subunit
  (ATP6V0D1), cementing its position in the central stalk. Two alternatively spliced
  isoforms exist.
alternative_products:
- name: '1'
  id: Q16864-1
- name: '2'
  id: Q16864-2
  sequence_note: VSP_045952
existing_annotations:
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic inference placing ATP6V1F as active in membrane context.
      The V1 F subunit is a peripheral protein on the cytoplasmic face of membranes
      where V-ATPase is active.
    action: MARK_AS_OVER_ANNOTATED
    reason: The generic membrane annotation with is_active_in is subsumed by the more
      specific lysosomal membrane and other organelle membrane annotations. The IBA
      annotation is overly broad.

- term:
    id: GO:0030665
    label: clathrin-coated vesicle membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: UniProt subcellular location vocabulary mapping from ortholog data.
      V-ATPase is present on clathrin-coated vesicles for endocytic pathway acidification.
    action: KEEP_AS_NON_CORE
    reason: Consistent with V-ATPase biology but non-core relative to lysosomal function.

- term:
    id: GO:0030672
    label: synaptic vesicle membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: UniProt subcellular location vocabulary mapping for synaptic vesicle membrane.
      V-ATPase acidifies synaptic vesicles for neurotransmitter loading.
    action: KEEP_AS_NON_CORE
    reason: Non-core for this ubiquitously expressed subunit; neuronal context is
      secondary to the primary lysosomal function.

- term:
    id: GO:0033180
    label: proton-transporting V-type ATPase, V1 domain
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: part_of
  review:
    summary: InterPro-based annotation placing ATP6V1F in the V1 domain. Confirmed
      by human cryo-EM structural data.
    action: ACCEPT
    reason: Subunit F is a defining structural component of the V1 domain central rotor,
      confirmed by cryo-EM (PMID:33065002) and biochemical data (PMID:18752060).
    supported_by:
    - reference_id: PMID:33065002
      supporting_text: Vesicular- or vacuolar-type adenosine triphosphatases (V-ATPases)
        are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis
        and a membrane-embedded Vo complex for proton transfer.
      reference_section_type: ABSTRACT

- term:
    id: GO:0034220
    label: monoatomic ion transmembrane transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: InterPro-based annotation for monoatomic ion transmembrane transport, which
      subsumes proton transport. The more specific proton transmembrane transport annotation
      is more informative.
    action: MARK_AS_OVER_ANNOTATED
    reason: The generic monoatomic ion transmembrane transport is subsumed by the more
      specific proton transmembrane transport annotations. Redundant and less informative.

- term:
    id: GO:0046961
    label: proton-transporting ATPase activity, rotational mechanism
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro-based annotation for rotational ATPase activity. The F subunit
      is part of the central rotor essential for this activity.
    action: ACCEPT
    reason: Core molecular function of the V-ATPase; subunit F is an essential structural
      component of the rotary mechanism.
    supported_by:
    - reference_id: PMID:18752060
      supporting_text: Energy from this reaction drives the rotation of a central stalk
        consisting of V1 subunits D and F and this is coupled to rotation of the V0
        proteolipid ring made up of c, c′ and c″.
      reference_section_type: INTRODUCTION

- term:
    id: GO:1902600
    label: proton transmembrane transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: InterPro-based annotation for proton transmembrane transport.
    action: ACCEPT
    reason: Core biological process of V-ATPase.

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Generic protein binding from a reference map of the human binary protein
      interactome. High-throughput; not informative for specific function.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput interactome protein binding annotation is uninformative
      for the specific function of ATP6V1F.

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Generic protein binding from a dual proteome-scale interactome network.
      High-throughput; not informative.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput interactome data is uninformative for ATP6V1F function.

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  qualifier: enables
  review:
    summary: Generic protein binding from the OpenCell endogenous tagging study.
      High-throughput; not informative.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput protein binding annotation is uninformative.

- term:
    id: GO:0015078
    label: proton transmembrane transporter activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: contributes_to
  review:
    summary: Ensembl ortholog-transfer annotation for proton transmembrane transporter
      activity. The contributes_to qualifier appropriately acknowledges the whole-complex
      nature of this activity.
    action: ACCEPT
    reason: Core molecular function of V-ATPase; contributes_to qualifier is appropriate
      for a structural subunit that participates in but does not individually perform
      the activity.

- term:
    id: GO:0033176
    label: proton-transporting V-type ATPase complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: part_of
  review:
    summary: Ensembl ortholog-transfer annotation for V-type ATPase complex membership.
      Consistent with structural evidence.
    action: ACCEPT
    reason: Core complex membership.

- term:
    id: GO:0097401
    label: synaptic vesicle lumen acidification
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ensembl ortholog-transfer annotation for synaptic vesicle lumen acidification.
      V-ATPase acidifies synaptic vesicles; F subunit would be present as part of the
      complex in neurons.
    action: KEEP_AS_NON_CORE
    reason: Synaptic vesicle acidification is a non-core context for this ubiquitous
      subunit; primary function is lysosomal/organellar acidification.

- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: located_in
  review:
    summary: NAS from V-ATPase review. V-ATPase acidifies the Golgi; F subunit is
      part of the complex.
    action: ACCEPT
    reason: Well-established V-ATPase location in Golgi for glycosylation pathway function.

- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: located_in
  review:
    summary: NAS from V-ATPase review. Lysosomal membrane is the primary functional
      location.
    action: ACCEPT
    reason: Core localization.

- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: located_in
  review:
    summary: NAS from V-ATPase review. V-ATPase is targeted to plasma membrane in
      specialized cell types.
    action: KEEP_AS_NON_CORE
    reason: Plasma membrane localization is real in specialized contexts but non-core
      for this ubiquitous subunit.

- term:
    id: GO:0007035
    label: vacuolar acidification
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: involved_in
  review:
    summary: NAS from V-ATPase review. Core function of V-ATPase.
    action: ACCEPT
    reason: Vacuolar acidification is the core biological process.

- term:
    id: GO:0007042
    label: lysosomal lumen acidification
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: involved_in
  review:
    summary: NAS from V-ATPase review. More specific than vacuolar acidification.
    action: ACCEPT
    reason: Core function of V-ATPase.

- term:
    id: GO:0007042
    label: lysosomal lumen acidification
  evidence_type: NAS
  original_reference_id: PMID:33065002
  qualifier: involved_in
  review:
    summary: NAS from the structural study. Consistent.
    action: ACCEPT
    reason: Core function.

- term:
    id: GO:0010008
    label: endosome membrane
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: located_in
  review:
    summary: NAS from V-ATPase review. V-ATPase acidifies endosomes.
    action: ACCEPT
    reason: Endosome membrane is an established V-ATPase location.

- term:
    id: GO:0016020
    label: membrane
  evidence_type: IDA
  original_reference_id: PMID:33065002
  qualifier: located_in
  review:
    summary: IDA from the cryo-EM study. F subunit is associated with membrane as
      part of the V-ATPase complex.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic membrane annotation subsumed by more specific lysosomal/Golgi/endosome
      membrane annotations.

- term:
    id: GO:0033176
    label: proton-transporting V-type ATPase complex
  evidence_type: NAS
  original_reference_id: PMID:33065002
  qualifier: part_of
  review:
    summary: NAS from the structural study. Consistent with IDA annotation from
      PMID:18752060.
    action: ACCEPT
    reason: Core complex membership.

- term:
    id: GO:0048388
    label: endosomal lumen acidification
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: involved_in
  review:
    summary: NAS from V-ATPase review. Endosomal lumen acidification is a core function.
    action: ACCEPT
    reason: Core V-ATPase function.

- term:
    id: GO:0051452
    label: intracellular pH reduction
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: involved_in
  review:
    summary: NAS from V-ATPase review. Generic term for the acidification function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Less specific than the individual lumen acidification terms; redundant and
      subsumed by more precise annotations.

- term:
    id: GO:0061795
    label: Golgi lumen acidification
  evidence_type: NAS
  original_reference_id: PMID:32001091
  qualifier: involved_in
  review:
    summary: NAS from V-ATPase review. Golgi lumen acidification is important for
      glycosylation.
    action: ACCEPT
    reason: Core V-ATPase function in Golgi.

- term:
    id: GO:1902600
    label: proton transmembrane transport
  evidence_type: NAS
  original_reference_id: PMID:33065002
  qualifier: involved_in
  review:
    summary: NAS from the structural study.
    action: ACCEPT
    reason: Core biological process.

- term:
    id: GO:0000221
    label: vacuolar proton-transporting V-type ATPase, V1 domain
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: part_of
  review:
    summary: Ortholog-based annotation for V1 domain membership. Confirmed by cryo-EM
      structural data.
    action: ACCEPT
    reason: Core structural membership of V1 domain confirmed by PMID:33065002.
    supported_by:
    - reference_id: PMID:33065002
      supporting_text: Vesicular- or vacuolar-type adenosine triphosphatases (V-ATPases)
        are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis
        and a membrane-embedded Vo complex for proton transfer.
      reference_section_type: ABSTRACT

- term:
    id: GO:0042625
    label: ATPase-coupled ion transmembrane transporter activity
  evidence_type: NAS
  original_reference_id: PMID:8581736
  qualifier: enables
  review:
    summary: NAS from the original cloning paper (Fujiwara et al. 1995). ATP6V1F is
      a component of an ATPase-coupled ion transporter complex.
    action: ACCEPT
    reason: The ATPase-coupled ion transmembrane transporter activity is an appropriate
      molecular function annotation for a V-ATPase subunit.
    supported_by:
    - reference_id: PMID:8581736
      supporting_text: A cDNA encoding the 14-kDa subunit of vacuolar ATPase was cloned
        from human fetal brain. The sequence was composed of 680 nucleotides containing
        an open reading frame of 357 nucleotides.
      reference_section_type: ABSTRACT

- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19199708
  qualifier: located_in
  review:
    summary: High-throughput proteomics detection in parotid gland exosomes. Likely
      reflects membrane co-purification.
    action: MARK_AS_OVER_ANNOTATED
    reason: Exosome detection is likely artifactual; not informative for core function.

- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  qualifier: located_in
  review:
    summary: High-throughput proteomics detection in urinary exosomes.
    action: MARK_AS_OVER_ANNOTATED
    reason: Same reasoning as parotid exosome; likely artifactual.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1222516
  qualifier: located_in
  review:
    summary: Reactome TAS annotation. V1 F subunit can be in cytosol during regulated
      V1-V0 disassembly.
    action: KEEP_AS_NON_CORE
    reason: The V1 domain including F subunit can exist as a soluble complex in cytosol.

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

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

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

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9639286
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol.
    action: KEEP_AS_NON_CORE
    reason: Consistent.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9640167
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol.
    action: KEEP_AS_NON_CORE
    reason: Consistent.

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

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

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

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

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9645608
  qualifier: located_in
  review:
    summary: Reactome TAS annotation for cytosol.
    action: KEEP_AS_NON_CORE
    reason: Consistent.

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

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18752060
  qualifier: enables
  review:
    summary: The specific interaction underlying this annotation is the F subunit-V0
      d subunit (ATP6V0D1) interaction, which is mechanistically central to the rotary
      pump mechanism. However, generic protein binding is not informative.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding is uninformative; the specific D-F and F-d interactions
      are the mechanistically meaningful interaction, but no specific GO term captures
      this subunit-rotor interaction.
    supported_by:
    - reference_id: PMID:18752060
      supporting_text: each can pull down the central stalk's D and F subunits from
        human kidney membrane, and in vitro studies using D and F further showed that
        the interactions between these proteins and the d subunit is direct.
      reference_section_type: ABSTRACT

- term:
    id: GO:0016020
    label: membrane
  evidence_type: IDA
  original_reference_id: PMID:18752060
  qualifier: located_in
  review:
    summary: IDA from Smith et al. (2008) showing F subunit in membrane preparations.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic membrane is subsumed by more specific lysosomal/Golgi/endosome
      membrane annotations.

- term:
    id: GO:0016471
    label: vacuolar proton-transporting V-type ATPase complex
  evidence_type: IDA
  original_reference_id: PMID:18752060
  qualifier: part_of
  review:
    summary: IDA from Smith et al. (2008) demonstrating F subunit co-purification
      with the V-ATPase complex. Direct biochemical evidence for complex membership.
    action: ACCEPT
    reason: Direct experimental evidence for V-ATPase complex membership. This is the
      core complex membership annotation.
    supported_by:
    - reference_id: PMID:18752060
      supporting_text: each can pull down the central stalk's D and F subunits from
        human kidney membrane, and in vitro studies using D and F further showed that
        the interactions between these proteins and the d subunit is direct.
      reference_section_type: ABSTRACT

- term:
    id: GO:0015078
    label: proton transmembrane transporter activity
  evidence_type: NAS
  original_reference_id: PMID:8581736
  qualifier: enables
  review:
    summary: NAS from the original cloning paper.
    action: ACCEPT
    reason: Appropriate molecular function for a V-ATPase subunit.

- term:
    id: GO:1902600
    label: proton transmembrane transport
  evidence_type: NAS
  original_reference_id: PMID:8581736
  qualifier: involved_in
  review:
    summary: NAS from the original cloning paper.
    action: ACCEPT
    reason: Core biological process of V-ATPase.
    supported_by:
    - reference_id: PMID:8581736
      supporting_text: A cDNA encoding the 14-kDa subunit of vacuolar ATPase was cloned
        from human fetal brain. The sequence was composed of 680 nucleotides containing
        an open reading frame of 357 nucleotides.
      reference_section_type: ABSTRACT

references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: PMID:18752060
  title: The d subunit plays a central role in human vacuolar H(+)-ATPases.
  findings:
  - statement: Human V-ATPase F subunit directly interacts with d1 and d2 V0 subunits;
      F and D are pulled down by d1/d2 from human kidney membrane; confirmed direct
      D-F and F-d interactions; F forms part of the central stalk.
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  findings:
  - statement: ATP6V1F detected in urinary exosomes by mass spectrometry.
- id: PMID:19199708
  title: Proteomic analysis of human parotid gland exosomes by multidimensional protein
    identification technology (MudPIT).
  findings:
  - statement: ATP6V1F detected in parotid gland exosome proteome.
- id: PMID:32001091
  title: Structure and Roles of V-type ATPases.
  findings:
  - statement: Comprehensive review of V-ATPase structure; F subunit is part of central rotor.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings:
  - statement: ATP6V1F detected in binary interactome map.
- id: PMID:33065002
  title: Structures of a Complete Human V-ATPase Reveal Mechanisms of Its Assembly.
  findings:
  - statement: Cryo-EM structures of complete human V-ATPase; F subunit resolved as
      part of the central DF rotor at near-atomic resolution.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings:
  - statement: ATP6V1F detected in proteome-scale interactome study.
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings:
  - statement: ATP6V1F localization mapped by endogenous tagging.
- id: PMID:8581736
  title: Cloning, sequencing and expression of a novel cDNA encoding human vacuolar
    ATPase (14-kDa subunit).
  findings:
  - statement: Human V-ATPase F subunit (14 kDa) cloned from fetal brain; ubiquitous
      expression in human tissues; high sequence conservation with insect orthologs.
- id: Reactome:R-HSA-1222516
  title: Intraphagosomal pH is lowered to 5 by V-ATPase
  findings: []
- id: Reactome:R-HSA-5252133
  title: ATP6AP1 binds V-ATPase
  findings: []
- id: Reactome:R-HSA-74723
  title: Endosome acidification
  findings: []
- id: Reactome:R-HSA-917841
  title: Acidification of Tf:TfR1 containing endosome
  findings: []
- id: Reactome:R-HSA-9639286
  title: RRAGC,D exchanges GTP for GDP
  findings: []
- id: Reactome:R-HSA-9640167
  title: RRAGA,B exchanges GDP for GTP
  findings: []
- id: Reactome:R-HSA-9640168
  title: v-ATPase:Ragulator:RRAGA,B:GTP:RRAGC,D:GDP:SLC38A9:Arginine dissociates yielding
    v-ATPase:Ragulator:RRAGA,B:GTP:RRAGC,D:GDP and SLC38A9:Arginine
  findings: []
- id: Reactome:R-HSA-9640175
  title: v-ATPase:Ragulator:RagA,B:GDP:RagC,D:GDP binds SLC38A9:Arginine
  findings: []
- id: Reactome:R-HSA-9640195
  title: RRAGA,B hydrolyzes GTP
  findings: []
- id: Reactome:R-HSA-9645598
  title: RRAGC,D hydrolyzes GTP
  findings: []
- id: Reactome:R-HSA-9645608
  title: v-ATPase:Ragulator:RRAGA,B:GTP:RRAGC,D:GDP binds mTORC1
  findings: []
- id: Reactome:R-HSA-9646468
  title: mTORC1 binds RHEB:GTP
  findings: []

core_functions:
- description: Central rotor component of the V1 sector of the vacuolar-type H+-ATPase.
    Together with subunit D, forms the DF central stalk that transmits ATP hydrolysis
    energy from the catalytic A3B3 hexamer to the V0 c-ring, enabling proton translocation
    across organelle membranes. Essential for lysosomal, endosomal, and Golgi acidification.
    The smallest V1 subunit (13 kDa; 119 amino acids) and ubiquitously expressed.
  contributes_to_molecular_function:
    id: GO:0046961
    label: proton-transporting ATPase activity, rotational mechanism
  directly_involved_in:
  - id: GO:1902600
    label: proton transmembrane transport
  locations:
  - id: GO:0005765
    label: lysosomal membrane
  supported_by:
  - reference_id: PMID:33065002
    supporting_text: Vesicular- or vacuolar-type adenosine triphosphatases (V-ATPases)
      are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis
      and a membrane-embedded Vo complex for proton transfer.
    reference_section_type: ABSTRACT
  - reference_id: PMID:18752060
    supporting_text: Energy from this reaction drives the rotation of a central stalk
      consisting of V1 subunits D and F and this is coupled to rotation of the V0 proteolipid
      ring made up of c, c′ and c″.
    reference_section_type: INTRODUCTION

suggested_questions:
- question: What is the precise structural role of the F subunit in coordinating the
    DF central rotor with both the A3B3 head and the V0 d subunit at the rotor-stator
    junction?
  experts: []
- question: Are there post-translational modifications on subunit F that regulate
    V-ATPase assembly or activity, particularly in response to nutrient availability?
  experts: []
- question: Do the two alternatively spliced isoforms of ATP6V1F differ in their
    incorporation into the V-ATPase complex or in their subcellular targeting?
  experts: []

suggested_experiments:
- hypothesis: The F subunit makes distinct contacts with V0 d subunit at different
    stages of the rotary catalytic cycle.
  description: Cryo-EM analysis of V-ATPase in multiple rotational states at higher
    resolution to define the precise contacts between F subunit and the V0 d subunit
    at different stages of the catalytic cycle.
  experiment_type: structural biology
- hypothesis: Post-translational modifications on the F subunit regulate V-ATPase
    assembly or activity.
  description: Identification of post-translational modifications on the F subunit
    using quantitative mass spectrometry under varying nutrient conditions to assess
    regulation of V-ATPase activity.
  experiment_type: quantitative mass spectrometry
- hypothesis: ATP6V1F isoforms differ in V-ATPase incorporation or subcellular function.
  description: CRISPR-based isoform knockout combined with rescue experiments using
    individual isoforms to determine whether either isoform has a distinct functional
    role in V-ATPase biology.
  experiment_type: CRISPR functional genomics

ATP6V1F

Gene Description

Existing Annotations Review

Core Functions

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Comprehensive Research Report: ATP6V1F (V-Type Proton ATPase Subunit F)

Gene and Protein Identity

Structural Organization and Primary Function

V-ATPase Complex Architecture

Central Stalk Formation and Torque Transmission

Substrate Specificity and Enzymatic Reaction

Subcellular Localization and Functional Context

Intracellular Distribution

Specialized Plasma Membrane Functions

Physiological Roles Dependent on Acidification

Signaling and Biochemical Pathways

Nutrient Sensing Platform

mTORC1 Pathway Regulation

AMPK Pathway Interactions

Autophagy Regulation

Additional Signaling Interactions

Experimental Evidence and Structural Data

High-Resolution Structural Studies

Biochemical Characterization

Functional Assembly Studies

Evolutionary Conservation

Disease Relevance and Clinical Implications

Summary and Key Findings

📚 Additional Documentation

Notes

ATP6V1F Research Notes

Gene Identity

Core V-ATPase Biology

Original Cloning

Subcellular Localization

Structural Data

Interaction with ATP6V1D

Curation Notes

Falcon deep research synthesis (2026-06-21)

Pn Notes

ATP6V1F PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

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

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

Projected GO annotations (3)

Note

📄 View Raw YAML