Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0046961 proton-transporting ATPase activity, rotational mechanism	IBA GO_REF:0000033	ACCEPT	Summary: V-ATPase enables proton-transporting ATPase activity by the rotational mechanism. The C1 subunit is required for V1 assembly and function. The IBA annotation from a phylogenetic tree is consistent with the established V-ATPase function. Reason: Proton-transporting ATPase activity, rotational mechanism is the core molecular function of V-ATPase; the C subunit is required for V1 assembly and function. Supporting Evidence: PMID:8250920 are regulated by accessory subunits C, D and E. cDNAs encoding subunits C, D, and E were cloned from human osteoclastoma PMID:33065002 The V 1 ATPase is composed of three copies of subunits A, B, E, and G, and one copy of subunit C, D, F, and H
GO:0015078 proton transmembrane transporter activity	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Proton transmembrane transporter activity is the broader transporter activity term. V-ATPase does translocate protons; this IEA annotation is consistent but is less specific than GO:0046961 (rotational mechanism). Reason: Valid but redundant with the more specific GO:0046961 annotation; IEA evidence is automated and the more specific term is preferred. Supporting Evidence: file:human/ATP6V1C1/ATP6V1C1-uniprot.txt Subunit of the V1 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons
GO:0016020 membrane	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: The term 'membrane' is too broad and does not specify which membrane. ATP6V1C1 is localized to specific membranes (synaptic vesicle, clathrin-coated vesicle, lysosomal membrane). Reason: Too broad; the specific membrane compartment annotations (lysosomal membrane, synaptic vesicle membrane) are more informative. IEA evidence from automated annotation. Supporting Evidence: file:human/ATP6V1C1/ATP6V1C1-uniprot.txt Cytoplasmic vesicle, secretory vesicle, synaptic vesicle membrane
GO:0030665 clathrin-coated vesicle membrane	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: ATP6V1C1 is annotated to clathrin-coated vesicle membrane by similarity with rat C subunit (UniProt by similarity). V-ATPase is present on clathrin-coated vesicles to acidify the maturing endosome. Reason: Supported by UniProt similarity annotation with rat C subunit; functionally coherent given V-ATPase role in endosomal acidification. Not a primary functional location but valid. Supporting Evidence: file:human/ATP6V1C1/ATP6V1C1-uniprot.txt Cytoplasmic vesicle, clathrin-coated vesicle membrane
GO:0030672 synaptic vesicle membrane	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: ATP6V1C1 is annotated to synaptic vesicle membrane by similarity with rat C subunit. V-ATPase on synaptic vesicles drives neurotransmitter loading by acidifying vesicle lumen. Reason: Supported by UniProt similarity annotation; functionally coherent. Synaptic vesicle localization is cell-type-specific (neurons) rather than core ubiquitous function. Supporting Evidence: file:human/ATP6V1C1/ATP6V1C1-uniprot.txt Cytoplasmic vesicle, secretory vesicle, synaptic vesicle membrane
GO:0033180 proton-transporting V-type ATPase, V1 domain	IEA GO_REF:0000120	ACCEPT	Summary: ATP6V1C1 is a subunit of the V1 domain by definition; C subunit is present in a single copy per V1 complex. Reason: Definitionally correct; C1 is a component of the V1 domain as established by biochemical and structural studies. Supporting Evidence: PMID:33065002 The V 1 ATPase is composed of three copies of subunits A, B, E, and G, and one copy of subunit C, D, F, and H
GO:0046961 proton-transporting ATPase activity, rotational mechanism	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Duplicate of the IBA annotation above. IEA from automated annotation pipeline. Reason: Redundant with the IBA annotation (GO_REF:0000033) for the same term. IBA is higher confidence than IEA. Supporting Evidence: PMID:8250920 are regulated by accessory subunits C, D and E. cDNAs encoding subunits C, D, and E were cloned from human osteoclastoma
GO:1902600 proton transmembrane transport	IEA GO_REF:0000002	ACCEPT	Summary: Proton transmembrane transport is the core biological process of V-ATPase. The IEA annotation is consistent with the established function. Reason: Core biological process of V-ATPase; the C1 subunit is required for V1 assembly and thus for proton transport. 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:0005515 protein binding	IPI PMID:16415858 V-ATPase interacts with ARNO and Arf6 in early endosomes and...	MARK AS OVER ANNOTATED	Summary: The PMID:16415858 paper reports that Arf6 interacts with the V0 c-subunit and ARNO interacts with the a2 isoform of V-ATPase. The protein binding annotation for ATP6V1C1 appears to reflect the broader V-ATPase complex interaction rather than a specific direct interaction of V1 C subunit with ARF6/ARNO. Reason: The paper demonstrates that Arf6 interacts with the V0 c-subunit (not V1 C subunit) and ARNO with the a2-isoform of V-ATPase. Protein binding (GO:0005515) is too uninformative and the specific interaction is attributed to different V-ATPase subunits. Supporting Evidence: PMID:16415858 Arf6 interacts with the c-subunit, and ARNO with the a2-isoform of V-ATPase
GO:0005886 plasma membrane	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Plasma membrane localization of V-ATPase occurs in specialized cells (osteoclasts, renal intercalated cells). The IEA from Ensembl is based on ortholog transfer. Reason: Valid for specialized cell types where V-ATPase operates at the plasma membrane, but not a ubiquitous primary location for ATP6V1C1. Supporting Evidence: file:human/ATP6V1C1/ATP6V1C1-uniprot.txt V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments and in some cell types, is targeted to the plasma membrane, where it is responsible for acidifying the extracellular environment
GO:0033176 proton-transporting V-type ATPase complex	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: ATP6V1C1 is part of the complete V-ATPase complex (V1+V0). This IEA is from Ensembl ortholog transfer. Reason: Valid but redundant with more specific complex annotations (V1 domain, GO:0033180). The broader complex term is less informative about C1 subunit's specific domain. Supporting Evidence: file:human/ATP6V1C1/ATP6V1C1-uniprot.txt V-ATPase is a heteromultimeric enzyme made up of two complexes: the ATP-hydrolytic V1 complex and the proton translocation V0 complex
GO:0045177 apical part of cell	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: In specialized epithelial cells (renal intercalated cells), V-ATPase is targeted to the apical membrane. This is cell-type-specific and based on ortholog transfer. Reason: Cell-type-specific localization; valid in specialized cells but not the core ubiquitous location of ATP6V1C1. Supporting Evidence: file:human/ATP6V1C1/ATP6V1C1-uniprot.txt V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments and in some cell types, is targeted to the plasma membrane
GO:0097401 synaptic vesicle lumen acidification	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: V-ATPase acidifies synaptic vesicles to drive neurotransmitter loading. This IEA from Ensembl is based on ortholog transfer. Reason: A valid downstream process of V-ATPase in neurons, but cell-type-specific (neurons) rather than the core ubiquitous function of ATP6V1C1. Supporting Evidence: file:human/ATP6V1C1/ATP6V1C1-uniprot.txt Cytoplasmic vesicle, secretory vesicle, synaptic vesicle membrane
GO:0098850 extrinsic component of synaptic vesicle membrane	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: V1 subunits are peripheral (extrinsic) components of the synaptic vesicle membrane when the V1 complex is assembled on V0. IEA from Ensembl ortholog transfer. Reason: Accurate description of the topology of V1 subunits on vesicle membranes but neuron-specific. Redundant with synaptic vesicle membrane annotation. Supporting Evidence: file:human/ATP6V1C1/ATP6V1C1-uniprot.txt Cytoplasmic vesicle, secretory vesicle, synaptic vesicle membrane
GO:0000221 vacuolar proton-transporting V-type ATPase, V1 domain	ISS GO_REF:0000024	ACCEPT	Summary: ATP6V1C1 is a subunit of the V1 domain. ISS annotation by manual transfer from rat or other species. Reason: Definitionally correct; C1 is a component of the V1 domain. Consistent with structural evidence from cryo-EM. Supporting Evidence: PMID:33065002 The V 1 ATPase is composed of three copies of subunits A, B, E, and G, and one copy of subunit C, D, F, and H file:human/ATP6V1C1/ATP6V1C1-uniprot.txt Subunit C is necessary for the assembly of the catalytic sector of the enzyme and is likely to have a specific function in its catalytic activity
GO:0016241 regulation of macroautophagy	NAS PMID:22982048 Lipofuscin is formed independently of macroautophagy and lys...	MARK AS OVER ANNOTATED	Summary: The PMID:22982048 paper (lipofuscin study) concerns lysosomal and autophagic activity in senescent fibroblasts. V-ATPase maintains lysosomal acidification which is required for autophagy. The NAS annotation connects ATP6V1C1 to regulation of macroautophagy indirectly through lysosomal acidification. Reason: Regulation of macroautophagy is an indirect downstream consequence of lysosomal acidification; ATP6V1C1 is not directly or specifically a regulator of macroautophagy. The paper does not study ATP6V1C1 directly. NAS evidence code reflects no direct experimental evidence. Supporting Evidence: PMID:22982048 both the autophagosomes and the lysosomal system are not mandatory for the formation of lipofuscin
GO:0070062 extracellular exosome	HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos...	MARK AS OVER ANNOTATED	Summary: ATP6V1C1 was detected in urinary exosomes by mass spectrometry (PMID:19056867), a large-scale proteomics study of human urinary exosomes. Detection of V-ATPase subunits in exosomes likely reflects contamination from lysosomes or other compartments during exosome isolation. Reason: HDA evidence from high-throughput proteomics of urinary exosomes; likely contamination during exosome isolation. V-ATPase subunits are not established as true exosome residents. Supporting Evidence: PMID:19056867 Normal human urine contains large numbers of exosomes, which are 40- to 100-nm vesicles that originate as the internal vesicles in multivesicular bodies from every renal epithelial cell type facing the urinary space.
GO:0005765 lysosomal membrane	HDA PMID:17897319 Integral and associated lysosomal membrane proteins.	ACCEPT	Summary: ATP6V1C1 was detected in lysosomal membrane fractions by mass spectrometry in PMID:17897319. This is consistent with V-ATPase function in lysosomal acidification; V-ATPase is a major component of the lysosomal membrane proteome. Reason: Lysosomal membrane is the primary functional location of assembled V-ATPase in most cell types. Proteomic detection supports the localization. Supporting Evidence: PMID:17897319 In membranes purified from placental lysosomes, we identified 58 proteins, known to reside at least partially in the lysosomal membrane. These included 17 polypeptides comprising or associated with the vacuolar adenosine triphosphatase.
GO:0005829 cytosol	TAS Reactome:R-HSA-1222516	KEEP AS NON CORE	Summary: Cytosol localization reflects the regulated disassembly of V1 from V0. When V-ATPase disassembles in response to nutrient starvation, the free V1 complex (including C subunit) is released into the cytosol. This is biologically real. Reason: Valid but non-core; cytosolic V1 represents a regulated disassembly state rather than the primary functional location. Multiple Reactome entries annotate this for different contexts. Supporting Evidence: Reactome:R-HSA-1222516 Intraphagosomal pH is lowered to 5 by V-ATPase
GO:0005829 cytosol	TAS Reactome:R-HSA-5252133	KEEP AS NON CORE	Summary: Duplicate cytosol annotation from a different Reactome pathway (ATP6AP1 binds V-ATPase). Same reasoning applies. Reason: Valid; cytosolic V1 is a known state during V1-V0 disassembly. Reactome TAS evidence from multiple pathways. Supporting Evidence: Reactome:R-HSA-5252133 ATP6AP1 binds V-ATPase
GO:0005829 cytosol	TAS Reactome:R-HSA-74723	KEEP AS NON CORE	Summary: Duplicate cytosol annotation from Reactome endosome acidification pathway. Reason: Same as other cytosol TAS annotations; valid but non-core. Supporting Evidence: Reactome:R-HSA-74723 Endosome acidification
GO:0005829 cytosol	TAS Reactome:R-HSA-917841	KEEP AS NON CORE	Summary: Duplicate cytosol annotation from Reactome transferrin endocytosis pathway. Reason: Same as other cytosol TAS annotations; valid but non-core. Supporting Evidence: Reactome:R-HSA-917841 Acidification of Tf:TfR1 containing endosome
GO:0005829 cytosol	TAS Reactome:R-HSA-9639286	KEEP AS NON CORE	Summary: Duplicate cytosol annotation from Reactome mTORC1 amino acid sensing pathway. Reason: Same as other cytosol TAS annotations; valid but non-core. Supporting Evidence: Reactome:R-HSA-9639286 RRAGC,D exchanges GTP for GDP
GO:0005829 cytosol	TAS Reactome:R-HSA-9640167	KEEP AS NON CORE	Summary: Duplicate cytosol annotation from Reactome mTORC1 pathway (RRAGA,B GDP exchange). Reason: Same as other cytosol TAS annotations; valid but non-core. Supporting Evidence: Reactome:R-HSA-9640167 RRAGA,B exchanges GDP for GTP
GO:0005829 cytosol	TAS Reactome:R-HSA-9640168	KEEP AS NON CORE	Summary: Duplicate cytosol annotation from Reactome v-ATPase/Ragulator pathway. Reason: Same as other cytosol TAS annotations; valid but non-core. Supporting Evidence: 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
GO:0005829 cytosol	TAS Reactome:R-HSA-9640175	KEEP AS NON CORE	Summary: Duplicate cytosol annotation from Reactome v-ATPase/Ragulator/SLC38A9 pathway. Reason: Same as other cytosol TAS annotations; valid but non-core. Supporting Evidence: Reactome:R-HSA-9640175 v-ATPase:Ragulator:RagA,B:GDP:RagC,D:GDP binds SLC38A9:Arginine
GO:0005829 cytosol	TAS Reactome:R-HSA-9640195	KEEP AS NON CORE	Summary: Duplicate cytosol annotation from Reactome mTORC1 pathway. Reason: Same as other cytosol TAS annotations; valid but non-core. Supporting Evidence: Reactome:R-HSA-9640195 RRAGA,B hydrolyzes GTP
GO:0005829 cytosol	TAS Reactome:R-HSA-9645598	KEEP AS NON CORE	Summary: Duplicate cytosol annotation from Reactome mTORC1 pathway. Reason: Same as other cytosol TAS annotations; valid but non-core. Supporting Evidence: Reactome:R-HSA-9645598 RRAGC,D hydrolyzes GTP
GO:0005829 cytosol	TAS Reactome:R-HSA-9645608	KEEP AS NON CORE	Summary: Duplicate cytosol annotation from Reactome v-ATPase/mTORC1 pathway. Reason: Same as other cytosol TAS annotations; valid but non-core. Supporting Evidence: Reactome:R-HSA-9645608 v-ATPase:Ragulator:RRAGA,B:GTP:RRAGC,D:GDP binds mTORC1
GO:0005829 cytosol	TAS Reactome:R-HSA-9646468	KEEP AS NON CORE	Summary: Duplicate cytosol annotation from Reactome mTORC1/RHEB pathway. Reason: Same as other cytosol TAS annotations; valid but non-core. Supporting Evidence: Reactome:R-HSA-9646468 mTORC1 binds RHEB:GTP
GO:0005829 cytosol	TAS Reactome:R-HSA-9858912	KEEP AS NON CORE	Summary: Duplicate cytosol annotation from Reactome MITF-M-dependent ATP6V1C1 gene expression pathway. Reason: Same as other cytosol TAS annotations; valid but non-core. Supporting Evidence: Reactome:R-HSA-9858912 MITF-M-dependent ATP6V1C1 gene expression
GO:0005886 plasma membrane	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Plasma membrane localization by similarity transfer. V-ATPase operates at the plasma membrane in specialized cells (osteoclasts, renal intercalated cells). Reason: Cell-type-specific; valid for specialized cells but not the primary ubiquitous location. Supported by UniProt by similarity annotation. Supporting Evidence: file:human/ATP6V1C1/ATP6V1C1-uniprot.txt V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments and in some cell types, is targeted to the plasma membrane, where it is responsible for acidifying the extracellular environment
GO:0016469 proton-transporting two-sector ATPase complex	TAS PMID:8250920 Cloning and tissue distribution of subunits C, D, and E of t...	ACCEPT	Summary: The original cloning paper for the human C subunit established it as a component of the V-ATPase (two-sector ATPase complex). TAS evidence from the foundational paper. Reason: Established by the original cloning and characterization paper; the C subunit is definitionally a component of the two-sector ATPase complex. Supporting Evidence: PMID:8250920 are regulated by accessory subunits C, D and E. cDNAs encoding subunits C, D, and E were cloned from human osteoclastoma
GO:0046961 proton-transporting ATPase activity, rotational mechanism	TAS PMID:8250920 Cloning and tissue distribution of subunits C, D, and E of t...	ACCEPT	Summary: Proton-transporting ATPase activity, rotational mechanism, established by the original cloning paper TAS annotation. Reason: Core molecular function of V-ATPase; established by TAS from the foundational cloning paper. The C subunit is required for V1 assembly and function. Supporting Evidence: PMID:8250920 are regulated by accessory subunits C, D and E. cDNAs encoding subunits C, D, and E were cloned from human osteoclastoma
GO:1902600 proton transmembrane transport	TAS PMID:8250920 Cloning and tissue distribution of subunits C, D, and E of t...	ACCEPT	Summary: Proton transmembrane transport is the core biological process of V-ATPase. TAS from the original cloning paper. Reason: Core biological process; established by TAS from the foundational cloning paper. Supporting Evidence: PMID:8250920 The vacuolar proton ATPase (V-ATPase) translocates protons into intracellular organelles or across the plasma membrane of specialised cells such as osteoclast and renal intercalated cells.

Core Functions

ATP6V1C1 is the ubiquitously expressed C1 regulatory subunit of the V1 domain of the vacuolar-type H+-ATPase. As a single-copy subunit of the V1 complex, C1 is necessary for assembly of the catalytic V1 sector and is required for V-ATPase function. The assembled V-ATPase complex acidifies lysosomes, endosomes, and other intracellular compartments using its proton-transporting ATPase activity via a rotational mechanism.

Directly Involved In:

proton transmembrane transport

Cellular Locations:

lysosomal membrane

In Complex:

vacuolar proton-transporting V-type ATPase, V1 domain

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

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:8250920

Cloning and tissue distribution of subunits C, D, and E of the human vacuolar H(+)-ATPase.

The vacuolar proton ATPase (V-ATPase) translocates protons into intracellular organelles or across the plasma membrane of specialised cells such as osteoclast and renal intercalated cells.

"The vacuolar proton ATPase (V-ATPase) translocates protons into intracellular organelles or across the plasma membrane of specialised cells such as osteoclast and renal intercalated cells."
The catalytic site of the V-ATPase consists of a hexamer of three A subunits and three B subunits which bind and hydrolyse ATP and are regulated by accessory subunits C, D and E.

"are regulated by accessory subunits C, D and E. cDNAs encoding subunits C, D, and E were cloned from human osteoclastoma"

PMID:12384298

Molecular cloning and characterization of novel tissue-specific isoforms of the human vacuolar H(+)-ATPase C, G and d subunits, and their evaluation in autosomal recessive distal renal tubular acidosis.

ATP6V1C1 is ubiquitously expressed; a second isoform ATP6V1C2 is expressed specifically in testes.

"Molecular cloning and characterization of novel tissue-specific isoforms of the human vacuolar H(+)-ATPase C, G and d subunits, and their evaluation in autosomal recessive distal renal tubular acidosis."

PMID:16415858

V-ATPase interacts with ARNO and Arf6 in early endosomes and regulates the protein degradative pathway.

Arf6 interacts with the V0 c-subunit and ARNO with the a2-isoform of V-ATPase; the V1 C subunit is not the direct binding partner.

"Arf6 interacts with the c-subunit, and ARNO with the a2-isoform of V-ATPase"

PMID:17897319

Integral and associated lysosomal membrane proteins.

ATP6V1C1 was detected among 17 polypeptides comprising or associated with the vacuolar adenosine triphosphatase in lysosomal membrane fractions.

"In membranes purified from placental lysosomes, we identified 58 proteins, known to reside at least partially in the lysosomal membrane. These included 17 polypeptides comprising or associated with the vacuolar adenosine triphosphatase."

PMID:19056867

Large-scale proteomics and phosphoproteomics of urinary exosomes.

ATP6V1C1 detected in urinary exosomes by large-scale MS/MS proteomics; likely contamination from lysosomes.

"Normal human urine contains large numbers of exosomes, which are 40- to 100-nm vesicles that originate as the internal vesicles in multivesicular bodies from every renal epithelial cell type facing the urinary space."

PMID:22982048

Lipofuscin is formed independently of macroautophagy and lysosomal activity in stress-induced prematurely senescent human fibroblasts.

The lipofuscin paper does not study ATP6V1C1 directly; regulation of macroautophagy is an indirect consequence of lysosomal acidification.

"both the autophagosomes and the lysosomal system are not mandatory for the formation of lipofuscin"

PMID:33065002

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

The V1 complex contains subunit C in a single copy: The V 1 ATPase is composed of three copies of subunits A, B, E, and G, and one copy of subunit C, D, F, and H.

"The V 1 ATPase is composed of three copies of subunits A, B, E, and G, and one copy of subunit C, D, F, and H"
V-ATPase subunit C is necessary for assembly of the V1 catalytic sector.

"Subunit C is necessary for the assembly of the catalytic sector of the enzyme and is likely to have a specific function in its catalytic activity"

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

Reactome:R-HSA-9858912

MITF-M-dependent ATP6V1C1 gene expression

file:human/ATP6V1C1/ATP6V1C1-uniprot.txt

UniProtKB entry for ATP6V1C1 (P21283)

ATP6V1C1 subunit C is necessary for V1 assembly and has a specific function in catalytic activity.

"Subunit C is necessary for the assembly of the catalytic sector of the enzyme and is likely to have a specific function in its catalytic activity"
ATP6V1C1 is ubiquitously expressed.

"Ubiquitous."

Suggested Experiments

Experiment: Use site-specific crosslinking mass spectrometry combined with cryo-EM to map direct contacts of C1 within the assembled V-ATPase and during V1-V0 assembly intermediates.

Hypothesis: Subunit C1 directly contacts the EG peripheral stalk subunits and the a-subunit of V0 during V1-V0 assembly.

Type: STRUCTURAL_BIOLOGY

Experiment: Generate ATP6V1C1 knockout human cell lines using CRISPR-Cas9 and measure lysosomal pH by ratiometric fluorescent probes and mTORC1 activity by S6K1 phosphorylation.

Hypothesis: Loss of ATP6V1C1 impairs lysosomal acidification and mTORC1 signaling in human cells.

Type: CELL_BIOLOGY

Experiment: Express ATP6V1C2 ectopically in ATP6V1C1-knockout cells and assess rescue of lysosomal acidification and V-ATPase assembly by blue native PAGE and lysosomal pH measurements.

Hypothesis: ATP6V1C2 can compensate for loss of ATP6V1C1 in non-testicular cell types.

Type: CELL_BIOLOGY

Deep Research

Falcon

(ATP6V1C1-deep-research-falcon.md)

Comprehensive Research Report on ATP6V1C1 (V-type proton ATPase subunit C1, UniProt: P21283) in Homo sapiens 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 on ATP6V1C1 (V-type proton ATPase subunit C1, UniProt: P21283) in Homo sapiens

1. Gene/Protein Identity and Verification

ATP6V1C1 encodes the V-type proton ATPase subunit C1 in Homo sapiens. This subunit is a core component of the V1 domain of the vacuolar (H+) ATPase (V-ATPase) complex, which is evolutionarily conserved and essential for cellular pH regulation. The gene and protein annotation match UniProt P21283, and all literature investigated was specific for Homo sapiens (not a different species or ambiguous symbol). The protein belongs to the V-ATPase C subunit family, with the "V-ATPase_C" domain (wang2020structuresofa pages 3-5, carpentieri2024dominantlyactingvariants pages 1-2).

2. Structural Features and Molecular Function

ATP6V1C1 is a single-copy, highly conserved component of the cytosolic V1 domain of V-ATPase. The V1 domain mediates ATP hydrolysis, and C1 forms a key part of the collar/stator architecture. It interacts with peripheral stalks and the a-subunit (Vo) to stabilize energy transmission from ATP hydrolysis to proton pumping. While ATP6V1C1 is not directly responsible for catalyzing ATP hydrolysis, it is essential for structural assembly, proper holoenzyme function, and the coupling of chemical to mechanical energy for H+ translocation (wang2020structuresofa pages 3-5, wang2020structuresofa pages 1-3, eaton2021theh+atpase(vatpase) pages 1-5).

Mechanistically, ATP hydrolysis in the V1 A3B3 hexamer drives rotation of central stalk components, enabling proton movement through the Vo membrane domain. ATP6V1C1 forms part of the stator, ensuring the non-rotating components remain fixed, enabling efficient energy transmission (wang2020structuresofa pages 1-3, eaton2021theh+atpase(vatpase) pages 1-5, indrawinata2023structuralandfunctional pages 1-2).

3. Subcellular Localization

ATP6V1C1 is found wherever V-ATPase complexes assemble:
- Lysosomes and late endosomes: Critical for acidification and cargo degradation
- Golgi apparatus: Controls pH for vesicle trafficking and post-translational modification
- Secretory vesicles/granules: Enables neurotransmitter/hormone loading in neurons/endocrine cells
- Plasma membrane in specialized cells: Found at bone-resorbing ruffled border in osteoclasts; renal intercalated cells for acid secretion
- Autolysosomes: Facilitates completion of autophagy (eaton2021theh+atpase(vatpase) pages 1-5, song2020theemergingroles pages 2-3, chu2021thevatpasea3 pages 1-2, carpentieri2024dominantlyactingvariants pages 1-2, zhang2024defectivelamtor5leads pages 1-3)

4. Key Biological Processes and Pathways

Lysosomal Acidification: Required for proteolytic enzyme function, substrate degradation, and cargo trafficking
Autophagy and Autophagic Flux: Supports fusion and degradation of autophagosomes
Endocytosis/Membrane Trafficking: Controls pH-dependent steps in cargo sorting and receptor processing
mTORC1 Signaling: Essential for amino-acid sensing and nutrient-responsive TOR activation at the lysosomal surface; integrates cell metabolism with environmental cues
Wnt, Notch, AMPK, and other cell signaling pathways: Via holoenzyme roles in endomembrane function and pH sensing (song2020theemergingroles pages 1-2, song2020theemergingroles pages 2-3, eaton2021theh+atpase(vatpase) pages 1-5, chen2024vatpaseincancer pages 1-3, zhang2024defectivelamtor5leads pages 1-3, tuli2023thecytosolicnterminal pages 1-2, indrawinata2023structuralandfunctional pages 1-2)

5. Disease Associations and Recent Research

Mendelian/Monogenic Disease

2024 evidence demonstrates that dominantly acting ATP6V1C1 variants cause a spectrum of multisystem/lysosomal diseases, including neurodevelopmental syndromes with features of DOORS syndrome. Gain-of-function mutations can upregulate V-ATPase function, resulting in abnormal lysosomal acidification, defective autophagic flux, accumulation of substrates, and impaired cilium biogenesis (Carpentieri et al., 2024; https://doi.org/10.1016/j.xhgg.2024.100349).

Autoimmunity/Immune Tolerance

Defective v-ATPase assembly (in which ATP6V1C1 is a component) impairs lysosomal acidification, disrupts Ragulator-mTORC1 immune signaling, and is associated with lupus-like autoimmunity in model organisms and human patient cells (Zhang et al., 2024; https://doi.org/10.1002/advs.202400446).

Cancer and Other Pathologies

ATP6V1C1/V-ATPase activity affects cancer cell proliferation, drug resistance (notably androgen receptor in prostate cancer), and tumor invasion. C1 isoform balance is implicated in tissue/cancer specificity, and is under investigation as a biomarker and therapeutic node (whitton2021vatpaseinhibitiondecreases pages 1-3, chen2024vatpaseincancer pages 1-3).

Renal and Bone Disorders

While classic disease mutations often affect other subunits, ATP6V1C1 is part of plasma membrane V-ATPases driving acid secretion in renal and osteoclast cells, with functional importance for bone resorption and systemic acid-base balance (chu2021thevatpasea3 pages 1-2, eaton2021theh+atpase(vatpase) pages 1-5).

6. Recent Developments and Expert Analysis (2023–2024 Focus)

Establishment of ATP6V1C1 as a monogenic disease gene with direct human genetics evidence (2024).
Molecular mechanisms of disease (gain and loss of function) and links to autophagic/lysosomal and ciliary disorders are better characterized than ever before.
Roles in mTORC1-amino acid sensing and immune cellular homeostasis identified as critical, with implications for lupus and related autoimmune diseases.
Structural/functional insight into V1–Vo assembly/disassembly and localization provides framework for targeted therapies or biomarker development.
V-ATPase (including C1) is being evaluated as a target for cancer therapy, though toxicity of global inhibition remains an obstacle; research is focused on isoform- or cell-type-specific targeting.

For a structured overview with explicit topic-by-topic citations and expanded context, see the following artifact:
| Category | Subtopic | ATP6V1C1-specific summary | Key evidence / recent findings | Sources |
|---|---|---|---|---|
| Gene / protein identity | Core annotation | Gene: ATP6V1C1; Protein: V-type proton ATPase subunit C1; UniProt accession: P21283; Organism: Homo sapiens; Family/domain: V-ATPase C subunit family, V1-sector component of vacuolar H+-ATPase | Human V-ATPase structural work explicitly identified subunit C1 in the V1 complex together with A, B2, E1, G1, D, F, and H; recent human genetics paper directly implicates ATP6V1C1 variants in disease | (wang2020structuresofa pages 3-5, carpentieri2024dominantlyactingvariants pages 1-2) |
| Structural features | Complex position | ATP6V1C1 is a single-copy V1 subunit in the cytosolic/peripheral domain of V-ATPase; it forms part of the bottom collar/stator architecture that helps connect V1 to Vo through interactions with peripheral stalks and the a-subunit N-terminus | Cryo-EM of complete human V-ATPase assigned one copy of C1 and described subunit C as part of the collar with H and a-NTD; reviews describe V1C as important in tethering V1 to Vo and in regulating disassembly | (wang2020structuresofa pages 3-5, whitton2021vatpaseinhibitiondecreases pages 1-3, eaton2021theh+atpase(vatpase) pages 1-5) |
| Molecular function | Primary role | ATP6V1C1 is not the ATP-hydrolytic active site; instead it is a structural/regulatory V1 subunit required for efficient coupling of ATP hydrolysis in V1 to proton translocation in Vo | V1 catalyzes ATP hydrolysis, Vo carries the proton pathway; subunit C is part of the V1 machinery that supports assembly, torque transmission/stator stability, and regulated holoenzyme activity | (wang2020structuresofa pages 1-3, eaton2021theh+atpase(vatpase) pages 1-5, wang2020structuresofa pages 3-5) |
| Mechanism | ATP-driven proton pumping | Overall V-ATPase mechanism: ATP hydrolysis in the A3B3 catalytic head drives rotation of central stalk elements, enabling protonation/deprotonation cycles in the c-ring and proton transfer through Vo. ATP6V1C1 contributes by stabilizing the non-rotating stator/collar needed to couple these events productively | Reviews and structures consistently define V-ATPase as a rotary ATP-driven proton pump; human structural work places C1 in the V1 collar that anchors peripheral stalks during catalysis | (wang2020structuresofa pages 1-3, eaton2021theh+atpase(vatpase) pages 1-5, wang2020structuresofa pages 3-5, indrawinata2023structuralandfunctional pages 1-2) |
| Regulation | Assembly/disassembly | ATP6V1C1 participates in the reversible V1–Vo assembly/disassembly cycle, a conserved regulatory mechanism that turns proton pumping off/on in response to nutrient and cellular signals | V1C is specifically highlighted as important in regulating enzyme disassembly; mammalian and yeast literature describes assembly state as a key determinant of lysosomal/organelle acidification | (whitton2021vatpaseinhibitiondecreases pages 1-3, eaton2021theh+atpase(vatpase) pages 5-9, tuli2023thecytosolicnterminal pages 1-2) |
| Subcellular localization | Endolysosomal system | ATP6V1C1 functions where V-ATPase complexes localize: especially lysosomes, late/early endosomes, and autolysosomal compartments, where luminal acidification is required for degradation and trafficking | Multiple reviews identify V-ATPase as the major proton pump of lysosomes/endosomes; recent disease papers tie ATP6V1C1 dysfunction to lysosomal defects and altered autophagic flux | (song2020theemergingroles pages 1-2, song2020theemergingroles pages 2-3, carpentieri2024dominantlyactingvariants pages 1-2, zhang2024defectivelamtor5leads pages 1-3) |
| Subcellular localization | Golgi / secretory compartments | V-ATPase containing C1 also functions in the Golgi apparatus and secretory vesicles/granules, supporting organellar pH control, protein processing, and vesicular loading | Reviews summarize V-ATPase roles in Golgi acidification and secretory vesicle function; neuronal vesicle acidification is essential for neurotransmitter loading | (eaton2021theh+atpase(vatpase) pages 1-5, song2020theemergingroles pages 2-3, tuli2023thecytosolicnterminal pages 1-2) |
| Subcellular localization | Plasma membrane in specialized cells | In certain specialized cells, V-ATPases containing C1 can be recruited to the plasma membrane for extracellular acidification, including osteoclasts and kidney intercalated cells | Reviews describe plasma-membrane V-ATPase in bone resorption and renal acid secretion; C1 is among subunits highly expressed in kidney intercalated-cell V-ATPase populations | (eaton2021theh+atpase(vatpase) pages 1-5, chu2021thevatpasea3 pages 1-2) |
| Biological processes | Lysosomal acidification | ATP6V1C1 supports the proton-pump activity required to maintain acidic lysosomal pH, enabling maturation/activation of lysosomal hydrolases and substrate breakdown | Lysosomal acidity is described as V-ATPase-dependent across reviews; dysfunction disrupts degradation, causing accumulation of substrates and organelle pathology | (song2020theemergingroles pages 1-2, song2020theemergingroles pages 2-3, zhang2024defectivelamtor5leads pages 1-3) |
| Biological processes | Autophagy / autophagic flux | By enabling lysosomal acidification, ATP6V1C1 is required for autophagosome clearance, autolysosomal degradation, and normal autophagic flux | 2024 ATP6V1C1 disease study reported defective autophagic flux and lysosomal substrate accumulation with pathogenic variants; broader literature links V-ATPase assembly to autophagic degradation | (carpentieri2024dominantlyactingvariants pages 1-2, zhang2025drosophilaauxorchestrates pages 1-2, indrawinata2023structuralandfunctional pages 1-2) |
| Biological processes | Endocytosis / membrane trafficking | ATP6V1C1 contributes to endosome maturation, receptor/cargo processing, and membrane trafficking through its role in organelle acidification | Reviews describe V-ATPase-dependent acidification as central to endocytic trafficking, receptor dissociation, and intracellular transport steps | (song2020theemergingroles pages 1-2, song2020theemergingroles pages 2-3, tuli2023thecytosolicnterminal pages 1-2) |
| Signaling pathways | mTORC1 nutrient sensing | V-ATPase is a lysosomal signaling hub for amino-acid-dependent mTORC1 regulation; ATP6V1C1, as a core V1 subunit, contributes to the holoenzyme required for these lysosome-surface signaling functions | Reviews describe V-ATPase participation in mTORC1 signaling; 2024 Lamtor5 study linked V-ATPase assembly, lysosomal acidification, Rag/mTORC1 interactions, and immune homeostasis | (eaton2021theh+atpase(vatpase) pages 1-5, chen2024vatpaseincancer pages 1-3, zhang2024defectivelamtor5leads pages 1-3) |
| Additional pathways | Other signaling functions | Beyond proton pumping, V-ATPase influences Wnt, Notch, AMPK, pH sensing, and signaling-complex organization; ATP6V1C1 likely participates through its required role in intact holoenzyme assembly | Reviews from 2021–2024 emphasize V-ATPase as both proton pump and signaling complex in health and disease | (eaton2021theh+atpase(vatpase) pages 1-5, chen2024vatpaseincancer pages 1-3, indrawinata2023structuralandfunctional pages 1-2) |
| Disease associations (2024) | Mendelian / multisystem disorder | Dominantly acting ATP6V1C1 variants can cause a multisystem neurodevelopmental phenotype resembling DOORS-spectrum disease, with altered lysosomal/autophagosomal function; paper reports a gain-of-function/upregulated acidification mechanism for some variants | Carpentieri et al., 2024 showed ATP6V1C1/ATP6V1B2 substitutions disrupt lysosomal morphology, localization, function, autophagic flux, and cilium biogenesis; publication date: October 10, 2024 | (carpentieri2024dominantlyactingvariants pages 1-2) |
| Disease associations (2024) | Autoimmunity / immune homeostasis | Although not ATP6V1C1-variant specific, recent evidence shows defective V-ATPase assembly/acidification perturbs lysosome function and mTORC1, contributing to immune dysregulation and lupus-like autoimmunity; mechanistically relevant to ATP6V1C1 as a core V1 subunit | Zhang et al., 2024 linked v-ATPase assembly and lysosomal acidification to immune tolerance via Lamtor5-v-ATPase-mTORC1 regulation; publication date: April 2024 | (zhang2024defectivelamtor5leads pages 1-3) |
| Disease associations | Cancer relevance | ATP6V1C1/V-ATPase dysregulation has been linked to tumor growth, invasion, drug resistance, and subtype-specific expression programs; ATP6V1C1 knockdown reduced androgen receptor function in prostate cancer cells, though compensatory V1C2 expression can occur | Functional prostate cancer study showed ATP6V1C1-targeted siRNA lowered AR protein/function, but CRISPR knockout induced V1C2 compensation; recent review highlights V-ATPase as a therapeutic target in cancer | (whitton2021vatpaseinhibitiondecreases pages 1-3, chen2024vatpaseincancer pages 1-3) |
| Disease associations | Bone and renal physiology | While disease-causing mutations are more classically assigned to other V-ATPase subunits, ATP6V1C1 is mechanistically relevant to osteoclast acid secretion and renal acid-base homeostasis because these processes depend on plasma-membrane V-ATPase assemblies containing V1 subunits including C1 | Reviews summarize specialized plasma membrane V-ATPases in osteoclasts and kidney intercalated cells | (chu2021thevatpasea3 pages 1-2, eaton2021theh+atpase(vatpase) pages 1-5) |
| Recent developments (2023–2024) | Mechanistic advances | Recent work reframed V-ATPase subunits as regulators of both proton pumping and cell signaling, and strengthened the idea that assembly state, isoform composition, and lysosomal positioning are disease-relevant variables | 2023–2024 reviews on a-subunit regulation, cancer, and brain disease emphasize regulated assembly, organelle specificity, and signaling functions relevant to ATP6V1C1-containing complexes | (tuli2023thecytosolicnterminal pages 1-2, chen2024vatpaseincancer pages 1-3, indrawinata2023structuralandfunctional pages 1-2) |
| Recent developments (2024) | Human genetics | ATP6V1C1 moved from a mostly mechanistic/complex-member gene to a directly disease-associated human gene with experimentally characterized pathogenic variants | 2024 genetics paper provides the strongest direct human evidence to date for ATP6V1C1 pathogenicity and mechanism | (carpentieri2024dominantlyactingvariants pages 1-2) |
| Therapeutic implications | Targeting V-ATPase activity | Therapeutic strategies include V-ATPase inhibition (e.g., bafilomycin-class research tools), modulation of assembly/disassembly, and potentially isoform/subunit-selective targeting to reduce toxicity; ATP6V1C1 itself may be a candidate biomarker or mechanistic node rather than an easy direct drug target | Structural inhibitor work explains how bafilomycin blocks proton translocation; cancer reviews highlight opportunities and toxicity challenges of systemic V-ATPase inhibition | (wang2021molecularbasisof pages 1-2, chen2024vatpaseincancer pages 1-3) |
| Therapeutic implications | Precision medicine outlook | For ATP6V1C1-associated disease, future directions include variant-specific functional testing, lysosomal/autophagy biomarkers, and strategies aimed at restoring balanced V-ATPase assembly and organelle pH rather than broad pump blockade | Recent human genetics and mechanistic studies suggest both gain- and context-dependent dysfunction are relevant, supporting a precision rather than one-size-fits-all therapeutic approach | (carpentieri2024dominantlyactingvariants pages 1-2, zhang2024defectivelamtor5leads pages 1-3) |

Table: This table summarizes verified information on human ATP6V1C1, including its identity, structural role in V-ATPase, localization, pathways, disease relevance, and recent 2023-2024 developments. It is useful as a compact evidence map for functional annotation and literature-supported interpretation.

7. References

Carpentieri G, et al. Dominantly acting variants in ATP6V1C1 and ATP6V1B2 cause a multisystem phenotypic spectrum by altering lysosomal and/or autophagosome function. Human Genetics and Genomics Advances. October 10, 2024. doi:10.1016/j.xhgg.2024.100349 (carpentieri2024dominantlyactingvariants pages 1-2)
Zhang W, et al. Defective Lamtor5 Leads to Autoimmunity by Deregulating v-ATPase and Lysosomal Acidiﬁcation. Advanced Science. April 2024. doi:10.1002/advs.202400446 (zhang2024defectivelamtor5leads pages 1-3)
Wang L, et al. Structures of a Complete Human V-ATPase Reveal Mechanisms of Its Assembly. Molecular Cell. November 5, 2020. doi:10.1016/j.molcel.2020.09.029 (wang2020structuresofa pages 3-5)
Chen T, et al. V-ATPase in cancer: mechanistic insights and therapeutic potentials. Cell Communication and Signaling, 2024. doi:10.1186/s12964-024-01998-9 (chen2024vatpaseincancer pages 1-3)
Eaton AF, Merkulova M, Brown D. The H+-ATPase (V-ATPase): from proton pump to signaling complex in health and disease. Am J Physiol Cell Physiol. 2021;320:C392-C414. doi:10.1152/ajpcell.00442.2020 (eaton2021theh+atpase(vatpase) pages 1-5)

Further citations are indexed within the artifact table. All claims have been matched to and can be verified with direct, authoritative literature (2020–2024), prioritizing the most recent mechanistic, clinical, and structural works.

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.
(carpentieri2024dominantlyactingvariants pages 1-2): Giovanna Carpentieri, Serena Cecchetti, Gianfranco Bocchinfuso, Francesca Clementina Radio, Chiara Leoni, Roberta Onesimo, Paolo Calligari, Agostina Pietrantoni, Andrea Ciolfi, Marco Ferilli, Cristina Calderan, Gerarda Cappuccio, Simone Martinelli, Elena Messina, Viviana Caputo, Ulrike Hüffmeier, Cyril Mignot, Stéphane Auvin, Yline Capri, Charles Marques Lourenco, Bianca E. Russell, Ahna Neustad, Nicola Brunetti Pierri, Boris Keren, André Reis, Julie S. Cohen, Alexis Heidlebaugh, Clay Smith, Christian T. Thiel, Leonardo Salviati, Giuseppe Zampino, Philippe M. Campeau, Lorenzo Stella, Marco Tartaglia, and Elisabetta Flex. Dominantly acting variants in atp6v1c1 and atp6v1b2 cause a multisystem phenotypic spectrum by altering lysosomal and/or autophagosome function. Oct 2024. URL: https://doi.org/10.1016/j.xhgg.2024.100349, doi:10.1016/j.xhgg.2024.100349. This article has 14 citations and is from a 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.
(indrawinata2023structuralandfunctional pages 1-2): Karen Indrawinata, Peter Argiropoulos, and Shuzo Sugita. Structural and functional understanding of disease-associated mutations in v-atpase subunit a1 and other isoforms. Frontiers in Molecular Neuroscience, Jul 2023. URL: https://doi.org/10.3389/fnmol.2023.1135015, doi:10.3389/fnmol.2023.1135015. This article has 16 citations.
(song2020theemergingroles pages 2-3): Qiaoyun Song, Bo Meng, Haidong Xu, and Zixu Mao. The emerging roles of vacuolar-type atpase-dependent lysosomal acidification in neurodegenerative diseases. Translational Neurodegeneration, May 2020. URL: https://doi.org/10.1186/s40035-020-00196-0, doi:10.1186/s40035-020-00196-0. This article has 255 citations and is from a domain leading peer-reviewed journal.
(chu2021thevatpasea3 pages 1-2): Anh Chu, Ralph A. Zirngibl, and Morris F. Manolson. The v-atpase a3 subunit: structure, function and therapeutic potential of an essential biomolecule in osteoclastic bone resorption. International Journal of Molecular Sciences, 22:6934, Jun 2021. URL: https://doi.org/10.3390/ijms22136934, doi:10.3390/ijms22136934. This article has 37 citations.
(zhang2024defectivelamtor5leads pages 1-3): Wei Zhang, Zhou Sha, Yunzhe Tang, Cuiyuan Jin, Wenhua Gao, Changmai Chen, Lang Yu, Nianyin Lv, Shijia Liu, Feng Xu, Dandan Wang, and Liyun Shi. Defective lamtor5 leads to autoimmunity by deregulating v‐atpase and lysosomal acidification. Advanced Science, Apr 2024. URL: https://doi.org/10.1002/advs.202400446, doi:10.1002/advs.202400446. This article has 17 citations and is from a peer-reviewed journal.
(song2020theemergingroles pages 1-2): Qiaoyun Song, Bo Meng, Haidong Xu, and Zixu Mao. The emerging roles of vacuolar-type atpase-dependent lysosomal acidification in neurodegenerative diseases. Translational Neurodegeneration, May 2020. URL: https://doi.org/10.1186/s40035-020-00196-0, doi:10.1186/s40035-020-00196-0. This article has 255 citations and is from a domain leading peer-reviewed journal.
(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.
(tuli2023thecytosolicnterminal pages 1-2): Farzana Tuli and Patricia M. Kane. The cytosolic n-terminal domain of v-atpase a-subunits is a regulatory hub targeted by multiple signals. Frontiers in Molecular Biosciences, Jun 2023. URL: https://doi.org/10.3389/fmolb.2023.1168680, doi:10.3389/fmolb.2023.1168680. This article has 10 citations.
(whitton2021vatpaseinhibitiondecreases pages 1-3): Bradleigh Whitton, Haruko Okamoto, Matthew Rose-Zerilli, Graham Packham, and Simon J. Crabb. V-atpase inhibition decreases mutant androgen receptor activity in castrate-resistant prostate cancer. Molecular Cancer Therapeutics, 20:739-748, Feb 2021. URL: https://doi.org/10.1158/1535-7163.mct-20-0662, doi:10.1158/1535-7163.mct-20-0662. This article has 14 citations and is from a 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.
(zhang2025drosophilaauxorchestrates pages 1-2): Shiping Zhang, Linfang Wang, Shuanglong Yi, Yu-Ting Tsai, Yi-Hsuan Cheng, Yu-Tung Lin, Chia-Ching Lin, Yi-Hua Lee, Honglei Wang, Shuhua Li, Ruiqi Wang, Yang Liu, Wei Yan, Chang Liu, Kai-Wen He, and Margaret S. Ho. Drosophila aux orchestrates the phosphorylation-dependent assembly of the lysosomal v-atpase in glia and contributes to snca/α-synuclein degradation. Autophagy, 21:1039-1058, Jan 2025. URL: https://doi.org/10.1080/15548627.2024.2442858, doi:10.1080/15548627.2024.2442858. This article has 7 citations and is from a domain leading peer-reviewed journal.
(wang2021molecularbasisof pages 1-2): Rong Wang, Jin Wang, Abdirahman Hassan, Chia-Hsueh Lee, Xiao-Song Xie, and Xiaochun Li. Molecular basis of v-atpase inhibition by bafilomycin a1. Nature Communications, Mar 2021. URL: https://doi.org/10.1038/s41467-021-22111-5, doi:10.1038/s41467-021-22111-5. This article has 233 citations and is from a highest quality peer-reviewed journal.

📚 Additional Documentation

Notes

(ATP6V1C1-notes.md)

ATP6V1C1 Research Notes

Gene overview

ATP6V1C1 encodes the C1 subunit of the V1 peripheral domain of the vacuolar-type H+-ATPase (V-ATPase). The C subunit (also called subunit C or subunit C1) is a regulatory subunit of the V1 complex, present in a single copy per V1 complex. ATP6V1C1 is one of two isoforms of the C subunit; the other is ATP6V1C2, which is expressed specifically in testes.

Core function — V-ATPase regulatory C subunit

Subunit C is necessary for assembly of the catalytic sector (V1) of V-ATPase and is likely to have a specific function in its catalytic activity. Structural data from the complete human V-ATPase places C in the V1 complex along with subunits A, B, D, E, F, G, and H.

PMID:33065002

[file:human/ATP6V1C1/ATP6V1C1-uniprot.txt "Subunit C is necessary for the assembly of the catalytic sector of the enzyme and is likely to have a specific function in its catalytic activity"]

Tissue specificity

ATP6V1C1 is ubiquitously expressed. The C2 paralog (ATP6V1C2) has a more restricted expression pattern in testes.

[PMID:12384298 - "Molecular cloning and characterization of novel tissue-specific isoforms of the human vacuolar H(+)-ATPase C, G and d subunits"]
[file:human/ATP6V1C1/ATP6V1C1-uniprot.txt "Ubiquitous."]

Discovery and cloning

ATP6V1C1 was originally cloned from human osteoclastoma tissue (PMID:8250920). The abstract notes: "The catalytic site of the V-ATPase consists of a hexamer of three A subunits and three B subunits which bind and hydrolyse ATP and are regulated by accessory subunits C, D and E."

PMID:8250920

Interaction with ARF6/ARNO

ATP6V1C1 interacts with ARF6 (ADP-ribosylation factor 6) as shown in UniProt INTERACTION records (IntAct EBI-988663, EBI-638181; NbExp=4). This interaction was identified in the context of the V-ATPase/ARNO/Arf6 system in early endosomes (PMID:16415858).

Note: The PMID:16415858 paper reports that Arf6 interacts with the c-subunit (V0 c-subunit, not V1 C subunit) and ARNO interacts with the a2-isoform of V-ATPase. The protein binding annotation for ATP6V1C1 from PMID:16415858 may reflect the broader V-ATPase complex interaction rather than a specific direct interaction of V1 C subunit with ARNO/Arf6.

PMID:16415858

Subcellular localizations

ATP6V1C1 is found at:
- Synaptic vesicle membrane (by similarity with rat C subunit)
- Clathrin-coated vesicle membrane (by similarity with rat C subunit)
- Lysosomal membrane (detected by proteomics, PMID:17897319)
- Cytosol (during V1-V0 disassembly)

Annotation quality notes

Protein binding (GO:0005515) IPI from PMID:16415858 should be MARK_AS_OVER_ANNOTATED. The specific functional interaction with ARF6/ARNO involves the V0 c-subunit and a2 isoform; the C subunit involvement is via the intact V-ATPase complex.
Membrane (GO:0016020) from ARBA IEA is over-annotated (too broad); better captured by specific compartment terms.
Regulation of macroautophagy (NAS, PMID:22982048) is an indirect effect of lysosomal acidification.
Extracellular exosome (HDA, PMID:19056867) likely reflects contamination.
Multiple Reactome TAS annotations for cytosol reflect V1-V0 disassembly; valid but non-core.
The TAS annotations from PMID:8250920 provide the original characterization of the C subunit as part of V-ATPase.

Falcon deep research synthesis (2026-06-21)

Falcon deep research has now completed (file:human/ATP6V1C1/ATP6V1C1-deep-research-falcon.md,
33 citations). It corroborates the C1 regulatory-subunit core above and adds new
human-genetics evidence.

Core confirmed / sharpened. C1 is a single-copy V1 subunit forming part of
the stator/collar: it interacts with the peripheral stalks and the V0
a-subunit to keep non-rotating components fixed, coupling A3B3 ATP hydrolysis to
rotor-driven proton translocation, and is required for V1 assembly. It is not
catalytic itself. The C subunit is also the classic point of reversible
V1–V0 dissociation regulation. No change to the assembly/regulatory calls.
New: ATP6V1C1 is now a monogenic disease gene (Carpentieri 2024).
Dominantly-acting variants cause a multisystem/lysosomal neurodevelopmental
syndrome with DOORS-like features via gain-of-function over-acidification
(abnormal lysosomal pH, defective autophagic flux, substrate accumulation,
impaired cilium biogenesis) — paralleling the ATP6V1B2 GOF mechanism. Disease
context; does not change normal-function calls.
Other (non-core) context: LAMTOR5/Ragulator–mTORC1 link to lupus-like
autoimmunity (Zhang 2024); cancer roles incl. androgen-receptor handling in
prostate cancer; plasma-membrane V-ATPase in osteoclast/renal acid secretion.

Net: no change to calls — C1 is the single-copy regulatory/stator V1 subunit
essential for V-ATPase assembly and energy coupling.

Pn Notes

(ATP6V1C1-pn-notes.md)

ATP6V1C1 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: P21283
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-06
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/ATP6V1C1/ATP6V1C1-ai-review.yaml
AIGR review HTML: present - genes/human/ATP6V1C1/ATP6V1C1-ai-review.html
Gene notes: present - genes/human/ATP6V1C1/ATP6V1C1-notes.md
GOA TSV: present - genes/human/ATP6V1C1/ATP6V1C1-goa.tsv
UniProt record: present - genes/human/ATP6V1C1/ATP6V1C1-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/ATP6V1C1.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/ATP6V1C1.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

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AIGR Review Snapshot

Description: ATP6V1C1 encodes the C1 subunit of the V1 peripheral domain of the vacuolar-type H+-ATPase (V-ATPase). The V1 complex hydrolyzes ATP to drive proton translocation through the membrane-embedded V0 domain. Subunit C (C1) is a regulatory subunit present in a single copy per V1 complex, where it is necessary for assembly of the catalytic V1 sector and likely has a specific function in its catalytic activity. ATP6V1C1 is ubiquitously expressed in human tissues. The paralog ATP6V1C2 is expressed specifically in testes. V-ATPase acidifies lysosomes, endosomes, Golgi, and secretory vesicles; ATP6V1C1 is found at the lysosomal membrane and at synaptic vesicle and clathrin-coated vesicle membranes (by similarity). During regulated V1-V0 disassembly under nutrient starvation, the V1 complex including C1 is released into the cytosol.
Existing/core annotation action counts: ACCEPT: 8; KEEP_AS_NON_CORE: 23; MARK_AS_OVER_ANNOTATED: 4

PN Consistency Summary

Consistency: Consistent. Notes ↔ review agree: single-copy regulatory C subunit, required for V1 catalytic-sector assembly, ubiquitous (paralog C2 = testis). Review correctly ACCEPTs complex/process/MF core terms and marks regulation-of-macroautophagy and exosome HDA as over-annotated. No PN/review contradiction.
PN story / NEW pressure: No over-reach. The PN mTORC1-upstream row is generic; the C1 review correctly does NOT add mTORC1/Ragulator annotations (no C1-specific evidence). GO:0007042 absent from C1 GOA (dossier: new_to_goa; confirmed 0 hits) — defensible ADD. GO:0046612 (verified real, OLS) absent — defensible more-specific ADD. GO:0033176 already in GOA (1 hit) and ACCEPTed.
Evidence alignment: Minimal overlap. PN cites generic V-ATPase/mTORC1 review titles; review anchors on C1-specific primaries: PMID:8250920 (C/D/E cloning), 12384298 (C/G/d isoforms), 16415858 (ARNO/Arf6 — correctly noted as V0 c-subunit not V1-C), 17897319 (lyso proteomics), 33065002. The 16415858 caveat (interaction attributed to other subunits) is a good catch unique to this review.
Verdict: Consistent / ADD GO:0007042 + GO:0046612 (verified, new to C1 GOA); no contradictions. Recommended edits: none required; mappings sound.

Full Consistency Review

UniProt: P21283 · batch: proteostasis-batch-2026-06-06 · review status: COMPLETE (mature; ~35 annotations, no core_functions block but full annotation review)
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: single-copy regulatory C subunit, required for V1 catalytic-sector assembly, ubiquitous (paralog C2 = testis). Review correctly ACCEPTs complex/process/MF core terms and marks regulation-of-macroautophagy and exosome HDA as over-annotated. No PN/review contradiction.
PN story / NEW pressure: No over-reach. The PN mTORC1-upstream row is generic; the C1 review correctly does NOT add mTORC1/Ragulator annotations (no C1-specific evidence). GO:0007042 absent from C1 GOA (dossier: new_to_goa; confirmed 0 hits) — defensible ADD. GO:0046612 (verified real, OLS) absent — defensible more-specific ADD. GO:0033176 already in GOA (1 hit) and ACCEPTed.
Mapping strategy: C1 does not change node mapping. C1's GOA lacks lysosomal-specific CC (GO:0046611 absent), so the broader GO:0033176 subtype-complex target is the correct safest choice here; the V1-domain projection GO:0046612 adds lysosomal specificity. Both projections additive and appropriate.
Evidence alignment: Minimal overlap. PN cites generic V-ATPase/mTORC1 review titles; review anchors on C1-specific primaries: PMID:8250920 (C/D/E cloning), 12384298 (C/G/d isoforms), 16415858 (ARNO/Arf6 — correctly noted as V0 c-subunit not V1-C), 17897319 (lyso proteomics), 33065002. The 16415858 caveat (interaction attributed to other subunits) is a good catch unique to this review.
Verdict: Consistent / ADD GO:0007042 + GO:0046612 (verified, new to C1 GOA); no contradictions. Recommended edits: none required; mappings sound.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-06
review_yaml: genes/human/ATP6V1C1/ATP6V1C1-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: P21283
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: P21283
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=new_to_goa | 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: P21283
gene_symbol: ATP6V1C1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 'ATP6V1C1 encodes the C1 subunit of the V1 peripheral domain of the
  vacuolar-type H+-ATPase (V-ATPase). The V1 complex hydrolyzes ATP to drive proton
  translocation through the membrane-embedded V0 domain. Subunit C (C1) is a regulatory
  subunit present in a single copy per V1 complex, where it is necessary for assembly
  of the catalytic V1 sector and likely has a specific function in its catalytic activity.
  ATP6V1C1 is ubiquitously expressed in human tissues. The paralog ATP6V1C2 is expressed
  specifically in testes. V-ATPase acidifies lysosomes, endosomes, Golgi, and secretory
  vesicles; ATP6V1C1 is found at the lysosomal membrane and at synaptic vesicle and
  clathrin-coated vesicle membranes (by similarity). During regulated V1-V0 disassembly
  under nutrient starvation, the V1 complex including C1 is released into the cytosol.'
existing_annotations:
- term:
    id: GO:0046961
    label: proton-transporting ATPase activity, rotational mechanism
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: V-ATPase enables proton-transporting ATPase activity by the rotational
      mechanism. The C1 subunit is required for V1 assembly and function. The IBA
      annotation from a phylogenetic tree is consistent with the established V-ATPase
      function.
    action: ACCEPT
    reason: Proton-transporting ATPase activity, rotational mechanism is the core
      molecular function of V-ATPase; the C subunit is required for V1 assembly and
      function.
    supported_by:
    - reference_id: PMID:8250920
      supporting_text: are regulated by accessory subunits C, D and E. cDNAs encoding
        subunits C, D, and E were cloned from human osteoclastoma
      reference_section_type: ABSTRACT
    - reference_id: PMID:33065002
      supporting_text: 'The V 1 ATPase is composed of three copies of subunits A,
        B, E, and G, and one copy of subunit C, D, F, and H'
      reference_section_type: INTRODUCTION

- term:
    id: GO:0015078
    label: proton transmembrane transporter activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Proton transmembrane transporter activity is the broader transporter
      activity term. V-ATPase does translocate protons; this IEA annotation is consistent
      but is less specific than GO:0046961 (rotational mechanism).
    action: KEEP_AS_NON_CORE
    reason: Valid but redundant with the more specific GO:0046961 annotation; IEA
      evidence is automated and the more specific term is preferred.
    supported_by:
    - reference_id: file:human/ATP6V1C1/ATP6V1C1-uniprot.txt
      supporting_text: Subunit of the V1 complex of vacuolar(H+)-ATPase (V-ATPase),
        a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes
        ATP and a membrane integral complex (V0) that translocates protons
      reference_section_type: DATABASE_ENTRY

- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: The term 'membrane' is too broad and does not specify which membrane.
      ATP6V1C1 is localized to specific membranes (synaptic vesicle, clathrin-coated
      vesicle, lysosomal membrane).
    action: MARK_AS_OVER_ANNOTATED
    reason: Too broad; the specific membrane compartment annotations (lysosomal membrane,
      synaptic vesicle membrane) are more informative. IEA evidence from automated
      annotation.
    supported_by:
    - reference_id: file:human/ATP6V1C1/ATP6V1C1-uniprot.txt
      supporting_text: Cytoplasmic vesicle, secretory vesicle, synaptic vesicle membrane
      reference_section_type: DATABASE_ENTRY

- term:
    id: GO:0030665
    label: clathrin-coated vesicle membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: ATP6V1C1 is annotated to clathrin-coated vesicle membrane by similarity
      with rat C subunit (UniProt by similarity). V-ATPase is present on clathrin-coated
      vesicles to acidify the maturing endosome.
    action: KEEP_AS_NON_CORE
    reason: Supported by UniProt similarity annotation with rat C subunit; functionally
      coherent given V-ATPase role in endosomal acidification. Not a primary functional
      location but valid.
    supported_by:
    - reference_id: file:human/ATP6V1C1/ATP6V1C1-uniprot.txt
      supporting_text: Cytoplasmic vesicle, clathrin-coated vesicle membrane
      reference_section_type: DATABASE_ENTRY

- term:
    id: GO:0030672
    label: synaptic vesicle membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: ATP6V1C1 is annotated to synaptic vesicle membrane by similarity with
      rat C subunit. V-ATPase on synaptic vesicles drives neurotransmitter loading
      by acidifying vesicle lumen.
    action: KEEP_AS_NON_CORE
    reason: Supported by UniProt similarity annotation; functionally coherent. Synaptic
      vesicle localization is cell-type-specific (neurons) rather than core ubiquitous
      function.
    supported_by:
    - reference_id: file:human/ATP6V1C1/ATP6V1C1-uniprot.txt
      supporting_text: Cytoplasmic vesicle, secretory vesicle, synaptic vesicle membrane
      reference_section_type: DATABASE_ENTRY

- term:
    id: GO:0033180
    label: proton-transporting V-type ATPase, V1 domain
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: part_of
  review:
    summary: ATP6V1C1 is a subunit of the V1 domain by definition; C subunit is present
      in a single copy per V1 complex.
    action: ACCEPT
    reason: Definitionally correct; C1 is a component of the V1 domain as established
      by biochemical and structural studies.
    supported_by:
    - reference_id: PMID:33065002
      supporting_text: 'The V 1 ATPase is composed of three copies of subunits A,
        B, E, and G, and one copy of subunit C, D, F, and H'
      reference_section_type: INTRODUCTION

- term:
    id: GO:0046961
    label: proton-transporting ATPase activity, rotational mechanism
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Duplicate of the IBA annotation above. IEA from automated annotation
      pipeline.
    action: KEEP_AS_NON_CORE
    reason: Redundant with the IBA annotation (GO_REF:0000033) for the same term.
      IBA is higher confidence than IEA.
    supported_by:
    - reference_id: PMID:8250920
      supporting_text: are regulated by accessory subunits C, D and E. cDNAs encoding
        subunits C, D, and E were cloned from human osteoclastoma
      reference_section_type: ABSTRACT

- term:
    id: GO:1902600
    label: proton transmembrane transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: Proton transmembrane transport is the core biological process of V-ATPase.
      The IEA annotation is consistent with the established function.
    action: ACCEPT
    reason: Core biological process of V-ATPase; the C1 subunit is required for V1
      assembly and thus for proton transport.
    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:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16415858
  qualifier: enables
  review:
    summary: 'The PMID:16415858 paper reports that Arf6 interacts with the V0 c-subunit
      and ARNO interacts with the a2 isoform of V-ATPase. The protein binding annotation
      for ATP6V1C1 appears to reflect the broader V-ATPase complex interaction rather
      than a specific direct interaction of V1 C subunit with ARF6/ARNO.'
    action: MARK_AS_OVER_ANNOTATED
    reason: 'The paper demonstrates that Arf6 interacts with the V0 c-subunit (not
      V1 C subunit) and ARNO with the a2-isoform of V-ATPase. Protein binding (GO:0005515)
      is too uninformative and the specific interaction is attributed to different
      V-ATPase subunits.'
    supported_by:
    - reference_id: PMID:16415858
      supporting_text: Arf6 interacts with the c-subunit, and ARNO with the a2-isoform
        of V-ATPase
      reference_section_type: ABSTRACT

- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Plasma membrane localization of V-ATPase occurs in specialized cells
      (osteoclasts, renal intercalated cells). The IEA from Ensembl is based on ortholog
      transfer.
    action: KEEP_AS_NON_CORE
    reason: Valid for specialized cell types where V-ATPase operates at the plasma
      membrane, but not a ubiquitous primary location for ATP6V1C1.
    supported_by:
    - reference_id: file:human/ATP6V1C1/ATP6V1C1-uniprot.txt
      supporting_text: V-ATPase is responsible for acidifying and maintaining the
        pH of intracellular compartments and in some cell types, is targeted to the
        plasma membrane, where it is responsible for acidifying the extracellular
        environment
      reference_section_type: DATABASE_ENTRY

- 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: ATP6V1C1 is part of the complete V-ATPase complex (V1+V0). This IEA
      is from Ensembl ortholog transfer.
    action: KEEP_AS_NON_CORE
    reason: Valid but redundant with more specific complex annotations (V1 domain,
      GO:0033180). The broader complex term is less informative about C1 subunit's
      specific domain.
    supported_by:
    - reference_id: file:human/ATP6V1C1/ATP6V1C1-uniprot.txt
      supporting_text: 'V-ATPase is a heteromultimeric enzyme made up of two complexes:
        the ATP-hydrolytic V1 complex and the proton translocation V0 complex'
      reference_section_type: DATABASE_ENTRY

- term:
    id: GO:0045177
    label: apical part of cell
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: In specialized epithelial cells (renal intercalated cells), V-ATPase
      is targeted to the apical membrane. This is cell-type-specific and based on
      ortholog transfer.
    action: KEEP_AS_NON_CORE
    reason: Cell-type-specific localization; valid in specialized cells but not the
      core ubiquitous location of ATP6V1C1.
    supported_by:
    - reference_id: file:human/ATP6V1C1/ATP6V1C1-uniprot.txt
      supporting_text: V-ATPase is responsible for acidifying and maintaining the
        pH of intracellular compartments and in some cell types, is targeted to the
        plasma membrane
      reference_section_type: DATABASE_ENTRY

- term:
    id: GO:0097401
    label: synaptic vesicle lumen acidification
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: V-ATPase acidifies synaptic vesicles to drive neurotransmitter loading.
      This IEA from Ensembl is based on ortholog transfer.
    action: KEEP_AS_NON_CORE
    reason: A valid downstream process of V-ATPase in neurons, but cell-type-specific
      (neurons) rather than the core ubiquitous function of ATP6V1C1.
    supported_by:
    - reference_id: file:human/ATP6V1C1/ATP6V1C1-uniprot.txt
      supporting_text: Cytoplasmic vesicle, secretory vesicle, synaptic vesicle membrane
      reference_section_type: DATABASE_ENTRY

- term:
    id: GO:0098850
    label: extrinsic component of synaptic vesicle membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: V1 subunits are peripheral (extrinsic) components of the synaptic vesicle
      membrane when the V1 complex is assembled on V0. IEA from Ensembl ortholog
      transfer.
    action: KEEP_AS_NON_CORE
    reason: Accurate description of the topology of V1 subunits on vesicle membranes
      but neuron-specific. Redundant with synaptic vesicle membrane annotation.
    supported_by:
    - reference_id: file:human/ATP6V1C1/ATP6V1C1-uniprot.txt
      supporting_text: Cytoplasmic vesicle, secretory vesicle, synaptic vesicle membrane
      reference_section_type: DATABASE_ENTRY

- 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: ATP6V1C1 is a subunit of the V1 domain. ISS annotation by manual transfer
      from rat or other species.
    action: ACCEPT
    reason: Definitionally correct; C1 is a component of the V1 domain. Consistent
      with structural evidence from cryo-EM.
    supported_by:
    - reference_id: PMID:33065002
      supporting_text: 'The V 1 ATPase is composed of three copies of subunits A,
        B, E, and G, and one copy of subunit C, D, F, and H'
      reference_section_type: INTRODUCTION
    - reference_id: file:human/ATP6V1C1/ATP6V1C1-uniprot.txt
      supporting_text: Subunit C is necessary for the assembly of the catalytic sector
        of the enzyme and is likely to have a specific function in its catalytic activity
      reference_section_type: DATABASE_ENTRY

- term:
    id: GO:0016241
    label: regulation of macroautophagy
  evidence_type: NAS
  original_reference_id: PMID:22982048
  qualifier: involved_in
  review:
    summary: The PMID:22982048 paper (lipofuscin study) concerns lysosomal and autophagic
      activity in senescent fibroblasts. V-ATPase maintains lysosomal acidification
      which is required for autophagy. The NAS annotation connects ATP6V1C1 to regulation
      of macroautophagy indirectly through lysosomal acidification.
    action: MARK_AS_OVER_ANNOTATED
    reason: Regulation of macroautophagy is an indirect downstream consequence of
      lysosomal acidification; ATP6V1C1 is not directly or specifically a regulator
      of macroautophagy. The paper does not study ATP6V1C1 directly. NAS evidence
      code reflects no direct experimental evidence.
    supported_by:
    - reference_id: PMID:22982048
      supporting_text: both the autophagosomes and the lysosomal system are not mandatory
        for the formation of lipofuscin
      reference_section_type: ABSTRACT

- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  qualifier: located_in
  review:
    summary: ATP6V1C1 was detected in urinary exosomes by mass spectrometry (PMID:19056867),
      a large-scale proteomics study of human urinary exosomes. Detection of V-ATPase
      subunits in exosomes likely reflects contamination from lysosomes or other compartments
      during exosome isolation.
    action: MARK_AS_OVER_ANNOTATED
    reason: HDA evidence from high-throughput proteomics of urinary exosomes; likely
      contamination during exosome isolation. V-ATPase subunits are not established
      as true exosome residents.
    supported_by:
    - reference_id: PMID:19056867
      supporting_text: Normal human urine contains large numbers of exosomes, which
        are 40- to 100-nm vesicles that originate as the internal vesicles in multivesicular
        bodies from every renal epithelial cell type facing the urinary space.
      reference_section_type: ABSTRACT

- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: HDA
  original_reference_id: PMID:17897319
  qualifier: located_in
  review:
    summary: ATP6V1C1 was detected in lysosomal membrane fractions by mass spectrometry
      in PMID:17897319. This is consistent with V-ATPase function in lysosomal acidification;
      V-ATPase is a major component of the lysosomal membrane proteome.
    action: ACCEPT
    reason: Lysosomal membrane is the primary functional location of assembled V-ATPase
      in most cell types. Proteomic detection supports the localization.
    supported_by:
    - reference_id: PMID:17897319
      supporting_text: In membranes purified from placental lysosomes, we identified
        58 proteins, known to reside at least partially in the lysosomal membrane.
        These included 17 polypeptides comprising or associated with the vacuolar
        adenosine triphosphatase.
      reference_section_type: ABSTRACT

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1222516
  qualifier: located_in
  review:
    summary: Cytosol localization reflects the regulated disassembly of V1 from V0.
      When V-ATPase disassembles in response to nutrient starvation, the free V1 complex
      (including C subunit) is released into the cytosol. This is biologically real.
    action: KEEP_AS_NON_CORE
    reason: Valid but non-core; cytosolic V1 represents a regulated disassembly state
      rather than the primary functional location. Multiple Reactome entries annotate
      this for different contexts.
    supported_by:
    - reference_id: Reactome:R-HSA-1222516
      supporting_text: Intraphagosomal pH is lowered to 5 by V-ATPase
      reference_section_type: OTHER

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5252133
  qualifier: located_in
  review:
    summary: Duplicate cytosol annotation from a different Reactome pathway (ATP6AP1
      binds V-ATPase). Same reasoning applies.
    action: KEEP_AS_NON_CORE
    reason: Valid; cytosolic V1 is a known state during V1-V0 disassembly. Reactome
      TAS evidence from multiple pathways.
    supported_by:
    - reference_id: Reactome:R-HSA-5252133
      supporting_text: ATP6AP1 binds V-ATPase
      reference_section_type: OTHER

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-74723
  qualifier: located_in
  review:
    summary: Duplicate cytosol annotation from Reactome endosome acidification pathway.
    action: KEEP_AS_NON_CORE
    reason: Same as other cytosol TAS annotations; valid but non-core.
    supported_by:
    - reference_id: Reactome:R-HSA-74723
      supporting_text: Endosome acidification
      reference_section_type: OTHER

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-917841
  qualifier: located_in
  review:
    summary: Duplicate cytosol annotation from Reactome transferrin endocytosis pathway.
    action: KEEP_AS_NON_CORE
    reason: Same as other cytosol TAS annotations; valid but non-core.
    supported_by:
    - reference_id: Reactome:R-HSA-917841
      supporting_text: Acidification of Tf:TfR1 containing endosome
      reference_section_type: OTHER

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9639286
  qualifier: located_in
  review:
    summary: Duplicate cytosol annotation from Reactome mTORC1 amino acid sensing
      pathway.
    action: KEEP_AS_NON_CORE
    reason: Same as other cytosol TAS annotations; valid but non-core.
    supported_by:
    - reference_id: Reactome:R-HSA-9639286
      supporting_text: RRAGC,D exchanges GTP for GDP
      reference_section_type: OTHER

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9640167
  qualifier: located_in
  review:
    summary: Duplicate cytosol annotation from Reactome mTORC1 pathway (RRAGA,B
      GDP exchange).
    action: KEEP_AS_NON_CORE
    reason: Same as other cytosol TAS annotations; valid but non-core.
    supported_by:
    - reference_id: Reactome:R-HSA-9640167
      supporting_text: RRAGA,B exchanges GDP for GTP
      reference_section_type: OTHER

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9640168
  qualifier: located_in
  review:
    summary: Duplicate cytosol annotation from Reactome v-ATPase/Ragulator pathway.
    action: KEEP_AS_NON_CORE
    reason: Same as other cytosol TAS annotations; valid but non-core.
    supported_by:
    - reference_id: Reactome:R-HSA-9640168
      supporting_text: 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
      reference_section_type: OTHER

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9640175
  qualifier: located_in
  review:
    summary: Duplicate cytosol annotation from Reactome v-ATPase/Ragulator/SLC38A9
      pathway.
    action: KEEP_AS_NON_CORE
    reason: Same as other cytosol TAS annotations; valid but non-core.
    supported_by:
    - reference_id: Reactome:R-HSA-9640175
      supporting_text: v-ATPase:Ragulator:RagA,B:GDP:RagC,D:GDP binds SLC38A9:Arginine
      reference_section_type: OTHER

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9640195
  qualifier: located_in
  review:
    summary: Duplicate cytosol annotation from Reactome mTORC1 pathway.
    action: KEEP_AS_NON_CORE
    reason: Same as other cytosol TAS annotations; valid but non-core.
    supported_by:
    - reference_id: Reactome:R-HSA-9640195
      supporting_text: RRAGA,B hydrolyzes GTP
      reference_section_type: OTHER

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9645598
  qualifier: located_in
  review:
    summary: Duplicate cytosol annotation from Reactome mTORC1 pathway.
    action: KEEP_AS_NON_CORE
    reason: Same as other cytosol TAS annotations; valid but non-core.
    supported_by:
    - reference_id: Reactome:R-HSA-9645598
      supporting_text: RRAGC,D hydrolyzes GTP
      reference_section_type: OTHER

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9645608
  qualifier: located_in
  review:
    summary: Duplicate cytosol annotation from Reactome v-ATPase/mTORC1 pathway.
    action: KEEP_AS_NON_CORE
    reason: Same as other cytosol TAS annotations; valid but non-core.
    supported_by:
    - reference_id: Reactome:R-HSA-9645608
      supporting_text: v-ATPase:Ragulator:RRAGA,B:GTP:RRAGC,D:GDP binds mTORC1
      reference_section_type: OTHER

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9646468
  qualifier: located_in
  review:
    summary: Duplicate cytosol annotation from Reactome mTORC1/RHEB pathway.
    action: KEEP_AS_NON_CORE
    reason: Same as other cytosol TAS annotations; valid but non-core.
    supported_by:
    - reference_id: Reactome:R-HSA-9646468
      supporting_text: mTORC1 binds RHEB:GTP
      reference_section_type: OTHER

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9858912
  qualifier: located_in
  review:
    summary: Duplicate cytosol annotation from Reactome MITF-M-dependent ATP6V1C1
      gene expression pathway.
    action: KEEP_AS_NON_CORE
    reason: Same as other cytosol TAS annotations; valid but non-core.
    supported_by:
    - reference_id: Reactome:R-HSA-9858912
      supporting_text: MITF-M-dependent ATP6V1C1 gene expression
      reference_section_type: OTHER

- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Plasma membrane localization by similarity transfer. V-ATPase operates
      at the plasma membrane in specialized cells (osteoclasts, renal intercalated
      cells).
    action: KEEP_AS_NON_CORE
    reason: Cell-type-specific; valid for specialized cells but not the primary ubiquitous
      location. Supported by UniProt by similarity annotation.
    supported_by:
    - reference_id: file:human/ATP6V1C1/ATP6V1C1-uniprot.txt
      supporting_text: V-ATPase is responsible for acidifying and maintaining the
        pH of intracellular compartments and in some cell types, is targeted to the
        plasma membrane, where it is responsible for acidifying the extracellular
        environment
      reference_section_type: DATABASE_ENTRY

- term:
    id: GO:0016469
    label: proton-transporting two-sector ATPase complex
  evidence_type: TAS
  original_reference_id: PMID:8250920
  qualifier: part_of
  review:
    summary: The original cloning paper for the human C subunit established it as
      a component of the V-ATPase (two-sector ATPase complex). TAS evidence from
      the foundational paper.
    action: ACCEPT
    reason: Established by the original cloning and characterization paper; the C
      subunit is definitionally a component of the two-sector ATPase complex.
    supported_by:
    - reference_id: PMID:8250920
      supporting_text: are regulated by accessory subunits C, D and E. cDNAs encoding
        subunits C, D, and E were cloned from human osteoclastoma
      reference_section_type: ABSTRACT

- term:
    id: GO:0046961
    label: proton-transporting ATPase activity, rotational mechanism
  evidence_type: TAS
  original_reference_id: PMID:8250920
  qualifier: enables
  review:
    summary: Proton-transporting ATPase activity, rotational mechanism, established
      by the original cloning paper TAS annotation.
    action: ACCEPT
    reason: Core molecular function of V-ATPase; established by TAS from the foundational
      cloning paper. The C subunit is required for V1 assembly and function.
    supported_by:
    - reference_id: PMID:8250920
      supporting_text: are regulated by accessory subunits C, D and E. cDNAs encoding
        subunits C, D, and E were cloned from human osteoclastoma
      reference_section_type: ABSTRACT

- term:
    id: GO:1902600
    label: proton transmembrane transport
  evidence_type: TAS
  original_reference_id: PMID:8250920
  qualifier: involved_in
  review:
    summary: Proton transmembrane transport is the core biological process of V-ATPase.
      TAS from the original cloning paper.
    action: ACCEPT
    reason: Core biological process; established by TAS from the foundational cloning
      paper.
    supported_by:
    - reference_id: PMID:8250920
      supporting_text: The vacuolar proton ATPase (V-ATPase) translocates protons
        into intracellular organelles or across the plasma membrane of specialised
        cells such as osteoclast and renal intercalated cells.
      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: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:8250920
  title: Cloning and tissue distribution of subunits C, D, and E of the human vacuolar
    H(+)-ATPase.
  findings:
  - statement: The vacuolar proton ATPase (V-ATPase) translocates protons into intracellular
      organelles or across the plasma membrane of specialised cells such as osteoclast
      and renal intercalated cells.
    supporting_text: The vacuolar proton ATPase (V-ATPase) translocates protons into
      intracellular organelles or across the plasma membrane of specialised cells
      such as osteoclast and renal intercalated cells.
    reference_section_type: ABSTRACT
  - statement: The catalytic site of the V-ATPase consists of a hexamer of three
      A subunits and three B subunits which bind and hydrolyse ATP and are regulated
      by accessory subunits C, D and E.
    supporting_text: are regulated by accessory subunits C, D and E. cDNAs encoding
      subunits C, D, and E were cloned from human osteoclastoma
    reference_section_type: ABSTRACT
- id: PMID:12384298
  title: Molecular cloning and characterization of novel tissue-specific isoforms
    of the human vacuolar H(+)-ATPase C, G and d subunits, and their evaluation in
    autosomal recessive distal renal tubular acidosis.
  findings:
  - statement: ATP6V1C1 is ubiquitously expressed; a second isoform ATP6V1C2 is expressed
      specifically in testes.
    supporting_text: Molecular cloning and characterization of novel tissue-specific
      isoforms of the human vacuolar H(+)-ATPase C, G and d subunits, and their evaluation
      in autosomal recessive distal renal tubular acidosis.
    reference_section_type: TITLE
- id: PMID:16415858
  title: V-ATPase interacts with ARNO and Arf6 in early endosomes and regulates the
    protein degradative pathway.
  findings:
  - statement: Arf6 interacts with the V0 c-subunit and ARNO with the a2-isoform
      of V-ATPase; the V1 C subunit is not the direct binding partner.
    supporting_text: Arf6 interacts with the c-subunit, and ARNO with the a2-isoform
      of V-ATPase
    reference_section_type: ABSTRACT
- id: PMID:17897319
  title: Integral and associated lysosomal membrane proteins.
  findings:
  - statement: ATP6V1C1 was detected among 17 polypeptides comprising or associated
      with the vacuolar adenosine triphosphatase in lysosomal membrane fractions.
    supporting_text: In membranes purified from placental lysosomes, we identified
      58 proteins, known to reside at least partially in the lysosomal membrane.
      These included 17 polypeptides comprising or associated with the vacuolar adenosine
      triphosphatase.
    reference_section_type: ABSTRACT
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  findings:
  - statement: ATP6V1C1 detected in urinary exosomes by large-scale MS/MS proteomics;
      likely contamination from lysosomes.
    supporting_text: Normal human urine contains large numbers of exosomes, which
      are 40- to 100-nm vesicles that originate as the internal vesicles in multivesicular
      bodies from every renal epithelial cell type facing the urinary space.
    reference_section_type: ABSTRACT
- id: PMID:22982048
  title: Lipofuscin is formed independently of macroautophagy and lysosomal activity
    in stress-induced prematurely senescent human fibroblasts.
  findings:
  - statement: The lipofuscin paper does not study ATP6V1C1 directly; regulation
      of macroautophagy is an indirect consequence of lysosomal acidification.
    supporting_text: both the autophagosomes and the lysosomal system are not mandatory
      for the formation of lipofuscin
    reference_section_type: ABSTRACT
- id: PMID:33065002
  title: Structures of a Complete Human V-ATPase Reveal Mechanisms of Its Assembly.
  findings:
  - statement: 'The V1 complex contains subunit C in a single copy: The V 1 ATPase
      is composed of three copies of subunits A, B, E, and G, and one copy of subunit
      C, D, F, and H.'
    supporting_text: 'The V 1 ATPase is composed of three copies of subunits A, B,
      E, and G, and one copy of subunit C, D, F, and H'
    reference_section_type: INTRODUCTION
  - statement: V-ATPase subunit C is necessary for assembly of the V1 catalytic sector.
    supporting_text: Subunit C is necessary for the assembly of the catalytic sector
      of the enzyme and is likely to have a specific function in its catalytic activity
    reference_section_type: OTHER
- 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: []
- id: Reactome:R-HSA-9858912
  title: MITF-M-dependent ATP6V1C1 gene expression
  findings: []
- id: file:human/ATP6V1C1/ATP6V1C1-uniprot.txt
  title: UniProtKB entry for ATP6V1C1 (P21283)
  findings:
  - statement: ATP6V1C1 subunit C is necessary for V1 assembly and has a specific
      function in catalytic activity.
    supporting_text: Subunit C is necessary for the assembly of the catalytic sector
      of the enzyme and is likely to have a specific function in its catalytic activity
    reference_section_type: DATABASE_ENTRY
  - statement: ATP6V1C1 is ubiquitously expressed.
    supporting_text: Ubiquitous.
    reference_section_type: DATABASE_ENTRY

core_functions:
- description: ATP6V1C1 is the ubiquitously expressed C1 regulatory subunit of the
    V1 domain of the vacuolar-type H+-ATPase. As a single-copy subunit of the V1
    complex, C1 is necessary for assembly of the catalytic V1 sector and is required
    for V-ATPase function. The assembled V-ATPase complex acidifies lysosomes, endosomes,
    and other intracellular compartments using its proton-transporting ATPase activity
    via a rotational mechanism.
  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
  in_complex:
    id: GO:0000221
    label: vacuolar proton-transporting V-type ATPase, V1 domain

suggested_questions:
- question: Does the C1 subunit have a direct catalytic role (e.g., direct contact
    with ATP or the rotating central stalk) or is its function purely structural/regulatory
    for V1 assembly?
- question: What is the structural basis for the requirement of subunit C in V1 assembly?
    Are there specific protein-protein contacts in the cryo-EM structure that explain
    why C is assembly-essential?
- question: Under what physiological conditions does V1-V0 disassembly occur in human
    cells, and what happens to the released free C1 subunit?
- question: Are there disease-causing mutations in ATP6V1C1 (analogous to the dominant
    mutations in ATP6V1B2 that cause DDOD/ZLS2)?
- question: Is there functional redundancy between ATP6V1C1 (ubiquitous) and ATP6V1C2
    (testis) in any tissue type?

suggested_experiments:
- hypothesis: Subunit C1 directly contacts the EG peripheral stalk subunits and the
    a-subunit of V0 during V1-V0 assembly.
  description: Use site-specific crosslinking mass spectrometry combined with cryo-EM
    to map direct contacts of C1 within the assembled V-ATPase and during V1-V0 assembly
    intermediates.
  experiment_type: STRUCTURAL_BIOLOGY
- hypothesis: Loss of ATP6V1C1 impairs lysosomal acidification and mTORC1 signaling
    in human cells.
  description: Generate ATP6V1C1 knockout human cell lines using CRISPR-Cas9 and
    measure lysosomal pH by ratiometric fluorescent probes and mTORC1 activity by
    S6K1 phosphorylation.
  experiment_type: CELL_BIOLOGY
- hypothesis: ATP6V1C2 can compensate for loss of ATP6V1C1 in non-testicular cell
    types.
  description: Express ATP6V1C2 ectopically in ATP6V1C1-knockout cells and assess
    rescue of lysosomal acidification and V-ATPase assembly by blue native PAGE and
    lysosomal pH measurements.
  experiment_type: CELL_BIOLOGY

ATP6V1C1

Gene Description

Existing Annotations Review

Core Functions

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Comprehensive Research Report on ATP6V1C1 (V-type proton ATPase subunit C1, UniProt: P21283) in Homo sapiens

1. Gene/Protein Identity and Verification

2. Structural Features and Molecular Function

3. Subcellular Localization

4. Key Biological Processes and Pathways

5. Disease Associations and Recent Research

Mendelian/Monogenic Disease

Autoimmunity/Immune Tolerance

Cancer and Other Pathologies

Renal and Bone Disorders

6. Recent Developments and Expert Analysis (2023–2024 Focus)

7. References

📚 Additional Documentation

Notes

ATP6V1C1 Research Notes

Gene overview

Core function — V-ATPase regulatory C subunit

Tissue specificity

Discovery and cloning

Interaction with ARF6/ARNO

Subcellular localizations

Annotation quality notes

Falcon deep research synthesis (2026-06-21)

Pn Notes

ATP6V1C1 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