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