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.
| 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. |
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Download this section (compressed HTML)Q: 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?
Q: 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?
Q: Under what physiological conditions does V1-V0 disassembly occur in human cells, and what happens to the released free C1 subunit?
Q: Are there disease-causing mutations in ATP6V1C1 (analogous to the dominant mutations in ATP6V1B2 that cause DDOD/ZLS2)?
Q: Is there functional redundancy between ATP6V1C1 (ubiquitous) and ATP6V1C2 (testis) in any tissue type?
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
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