id: P27449 gene_symbol: ATP6V0C product_type: PROTEIN taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- ATP6V0C encodes the 16 kDa proteolipid subunit c of the V0 domain of vacuolar H+-ATPase (V-ATPase). This small (155 amino acid) integral membrane protein with four transmembrane helices is a core structural component of the proton-conducting c-ring rotor. Nine copies of ATP6V0C assemble with one copy of ATP6V0B (subunit c'') to form the complete c-ring within the V0 membrane domain. The c-ring rotates during ATP hydrolysis by the V1 domain, enabling proton translocation across membranes via a conserved glutamate residue (E139) that serves as the proton-binding site. ATP6V0C-containing V-ATPases acidify lysosomes, endosomes, Golgi, synaptic vesicles, and secretory granules, and in specialized cells (osteoclasts, kidney intercalated cells) also function at the plasma membrane. ATP6V0C is the binding target of the V-ATPase inhibitor bafilomycin A1. Heterozygous pathogenic variants in ATP6V0C cause early-onset epilepsy with or without developmental delay (EPEO3, OMIM 620465). existing_annotations: # === IBA annotation === - term: id: GO:0016020 label: membrane evidence_type: IBA original_reference_id: GO_REF:0000033 review: summary: >- ATP6V0C is an integral membrane protein with four transmembrane helices that forms part of the V0 domain c-ring. The IBA annotation to 'membrane' is phylogenetically supported and consistent with structural data (PMID:33065002). action: ACCEPT reason: >- Core localization annotation. ATP6V0C is a multi-pass membrane protein that spans the lipid bilayer four times. This is a fundamental property of the protein as a proteolipid subunit. supported_by: - reference_id: PMID:33065002 supporting_text: the membrane embedded, ring-shaped V o proton pump - reference_id: UniProt:P27449 supporting_text: Multi-pass membrane protein # === IEA annotations === - term: id: GO:0006811 label: monoatomic ion transport evidence_type: IEA original_reference_id: GO_REF:0000043 review: summary: >- ATP6V0C functions in proton (H+) transport as part of the V-ATPase complex. The annotation to 'monoatomic ion transport' is correct but very general. action: ACCEPT reason: >- This is a valid but broad annotation. The more specific term 'proton transmembrane transport' (GO:1902600) is also annotated, so this general parent term is acceptable as IEA. supported_by: - reference_id: PMID:33065002 supporting_text: ATP hydrolysis by the cytoplasmic V 1 ATPase drives the rotation of the membrane embedded, ring-shaped V o proton pump to allow cycles of protonation and deprotonation - term: id: GO:0015078 label: proton transmembrane transporter activity evidence_type: IEA original_reference_id: GO_REF:0000120 review: summary: >- ATP6V0C is a proton-conducting pore-forming subunit of V-ATPase. The c-ring directly participates in proton translocation via the conserved E139 proton-binding site. action: ACCEPT reason: >- Core molecular function annotation. ATP6V0C contributes directly to the proton channel activity through its conserved glutamate residue (E139) that binds and releases protons during the rotary transport cycle. supported_by: - reference_id: PMID:33065002 supporting_text: cycles of protonation and deprotonation of lipid-exposed glutamic acid residues for coupled proton transfer - reference_id: UniProt:P27449 supporting_text: 'E->A: Severely decreased proton transmembrane transport.' - term: id: GO:0015986 label: proton motive force-driven ATP synthesis evidence_type: IEA original_reference_id: GO_REF:0000108 review: summary: >- This annotation is INCORRECT for ATP6V0C. V-ATPases are proton PUMPS that use ATP hydrolysis to drive proton transport, not ATP synthases that use proton gradients to synthesize ATP. This is a common confusion arising from structural similarity between V-ATPases and F-ATPases. action: REMOVE reason: >- V-ATPases function in the OPPOSITE direction to ATP synthases. V-ATPases hydrolyze ATP to pump protons, creating acidification. F-ATP synthases use proton gradients to synthesize ATP. While the two enzyme families are evolutionarily related and share structural features, their functions are distinct. ATP6V0C is exclusively a component of V-ATPases. supported_by: - reference_id: PMID:33065002 supporting_text: Vesicular- or vacuolar-type adenosine triphosphatases (V-ATPases) are ATP-driven proton pumps - reference_id: PMID:32001091 supporting_text: V-ATPases are membrane-embedded protein complexes that function as ATP hydrolysis-driven proton pumps - term: id: GO:0030665 label: clathrin-coated vesicle membrane evidence_type: IEA original_reference_id: GO_REF:0000044 review: summary: >- UniProt annotation indicates ATP6V0C localizes to clathrin-coated vesicle membranes, consistent with V-ATPase function in early endocytic compartments. action: ACCEPT reason: >- V-ATPases begin acidifying vesicles early in the endocytic pathway. Presence on clathrin-coated vesicles is consistent with the requirement for rapid acidification after vesicle internalization. supported_by: - reference_id: UniProt:P27449 supporting_text: Cytoplasmic vesicle, clathrin-coated vesicle membrane - term: id: GO:0030672 label: synaptic vesicle membrane evidence_type: IEA original_reference_id: GO_REF:0000044 review: summary: >- ATP6V0C localizes to synaptic vesicle membranes where V-ATPase acidification is essential for neurotransmitter loading. action: ACCEPT reason: >- Core localization for neuronal function. V-ATPase-mediated acidification of synaptic vesicles creates the electrochemical gradient required for vesicular neurotransmitter transporters. supported_by: - reference_id: UniProt:P27449 supporting_text: Cytoplasmic vesicle, secretory vesicle, synaptic vesicle membrane - term: id: GO:0031410 label: cytoplasmic vesicle evidence_type: IEA original_reference_id: GO_REF:0000043 review: summary: >- ATP6V0C localizes to various cytoplasmic vesicles including lysosomes, endosomes, synaptic vesicles, and secretory granules. action: ACCEPT reason: >- General localization annotation that is correct. More specific vesicle membrane annotations are also present. This parent term captures the overall vesicular distribution of V-ATPases. supported_by: - reference_id: PMID:33065002 supporting_text: acidification of intracellular vesicles, organelles, and the extracellular milieu - term: id: GO:0033177 label: proton-transporting two-sector ATPase complex, proton-transporting domain evidence_type: IEA original_reference_id: GO_REF:0000002 review: summary: >- ATP6V0C is a subunit of the V0 (proton-transporting) domain of the two-sector V-ATPase. action: ACCEPT reason: >- Core complex membership annotation. The V-ATPase is a two-sector enzyme with V1 (catalytic) and V0 (proton-transporting) domains. ATP6V0C is a structural component of the V0 domain. 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 - term: id: GO:0033179 label: proton-transporting V-type ATPase, V0 domain evidence_type: IEA original_reference_id: GO_REF:0000002 review: summary: >- ATP6V0C is a core component of the V0 domain, forming the c-ring that mediates proton translocation. action: ACCEPT reason: >- Core complex membership annotation. Nine copies of ATP6V0C form the majority of the c-ring in the V0 domain. This is the most specific and accurate complex annotation for this protein. supported_by: - reference_id: PMID:33065002 supporting_text: a membrane-embedded Vo complex for proton transfer - reference_id: UniProt:P27449 supporting_text: The proton translocation complex V0 consists of the proton transport subunit a, a ring of proteolipid subunits c9c'' - term: id: GO:0046961 label: proton-transporting ATPase activity, rotational mechanism evidence_type: IEA original_reference_id: GO_REF:0000002 review: summary: >- ATP6V0C is part of the V-ATPase which uses a rotational mechanism for proton transport. The c-ring rotates during the catalytic cycle. action: ACCEPT reason: >- Core molecular function annotation. The V-ATPase uses a rotary mechanism where ATP hydrolysis drives rotation of the c-ring, enabling proton translocation. This is well-established biochemically and structurally. supported_by: - reference_id: PMID:33065002 supporting_text: ATP hydrolysis by the cytoplasmic V 1 ATPase drives the rotation of the membrane embedded, ring-shaped V o proton pump - term: id: GO:0098588 label: bounding membrane of organelle evidence_type: IEA original_reference_id: GO_REF:0000117 review: summary: >- ATP6V0C localizes to the membranes of organelles including lysosomes and endosomes. action: ACCEPT reason: >- General localization annotation that is correct. V-ATPases are present in the limiting membranes of various organelles where they establish and maintain luminal pH. supported_by: - reference_id: PMID:33065002 supporting_text: acidification of intracellular vesicles, organelles, and the extracellular milieu - term: id: GO:1902600 label: proton transmembrane transport evidence_type: IEA original_reference_id: GO_REF:0000120 review: summary: >- ATP6V0C directly participates in proton transmembrane transport as part of the V-ATPase proton pump. action: ACCEPT reason: >- Core biological process annotation. This is the primary function of ATP6V0C as part of the V-ATPase. The c-ring containing ATP6V0C is the proton-conducting element of the complex. supported_by: - reference_id: PMID:33065002 supporting_text: coupled proton transfer - reference_id: PMID:36074901 supporting_text: the patient variants interfere with the interactions between the ATP6V0C and ATP6V0A subunits during ATP hydrolysis # === IPI protein binding annotations === - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:11543633 review: summary: >- PMID:11543633 (Pan et al. 2001) reports interaction between ATP6V0C and LASS2 (CERS2), a ceramide synthase. This interaction is also documented in UniProt. action: KEEP_AS_NON_CORE reason: >- 'Protein binding' is too vague. The specific interaction partner (CERS2/LASS2) has been identified. However, the functional significance for V-ATPase function is unclear. Keeping as non-core since interaction with CERS2 may relate to ceramide metabolism regulation. supported_by: - reference_id: UniProt:P27449 supporting_text: Interacts with LASS2 (PubMed:11543633) - reference_id: PMID:11543633 supporting_text: Cloning, mapping, and characterization of a human homologue of the yeast longevity assurance gene LAG1. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:1334459 review: summary: >- PMID:1334459 reports interaction with bovine papillomavirus E5 oncoprotein, a viral protein that binds the 16 kDa proteolipid of V-ATPase. action: ACCEPT reason: >- This is a documented viral-host protein interaction. E5 binds ATP6V0C and is thought to inhibit V-ATPase function. While 'protein binding' is vague, this viral interaction has biological significance for viral pathogenesis. supported_by: - reference_id: UniProt:P27449 supporting_text: Interacts with the V0 complex V-ATPase subunit a4 ATP6V0A4 - reference_id: PMID:1334459 supporting_text: The BPV-1 E5 protein, the 16 kDa membrane pore-forming protein and the PDGF receptor exist in a complex that is dependent on hydrophobic transmembrane interactions. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:21988832 review: summary: >- PMID:21988832 is a large-scale liver protein interaction study. Without access to specific interaction partners identified for ATP6V0C, this annotation provides limited functional insight. action: KEEP_AS_NON_CORE reason: >- High-throughput interaction study. The annotation may reflect real interactions but 'protein binding' without specifying partners provides limited functional information. supported_by: - reference_id: PMID:21988832 supporting_text: establish a human liver protein interaction network (HLPN) composed of 3484 interactions among 2582 proteins - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25416956 review: summary: >- PMID:25416956 is a proteome-scale human interactome mapping study. High-throughput data. action: KEEP_AS_NON_CORE reason: >- High-throughput interaction study. Without specific interaction partners, this provides limited insight into ATP6V0C function. supported_by: - reference_id: PMID:25416956 supporting_text: we describe a systematic map of - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:31515488 review: summary: >- PMID:31515488 studies genetic variant effects on protein interactions. High-throughput data. action: KEEP_AS_NON_CORE reason: >- High-throughput study focused on variant effects on interactions. Generic 'protein binding' annotation provides limited functional insight. supported_by: - reference_id: PMID:31515488 supporting_text: Extensive disruption of protein interactions by genetic variants - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32296183 review: summary: >- PMID:32296183 is a reference map of human binary protein interactome. High-throughput data. action: KEEP_AS_NON_CORE reason: >- High-throughput binary interactome mapping. Generic annotation without specific partners. supported_by: - reference_id: PMID:32296183 supporting_text: a human 'all-by-all' reference interactome map of human binary protein interactions - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32814053 review: summary: >- PMID:32814053 studies neurodegenerative disease protein interactomes. May identify disease-relevant interactions for ATP6V0C. action: KEEP_AS_NON_CORE reason: >- Interactome mapping in context of neurodegeneration. Could be relevant given ATP6V0C mutations cause neurological disease, but generic annotation is not informative. supported_by: - reference_id: PMID:32814053 supporting_text: Here, we report on an interactome map that focuses on neurodegenerative disease - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33961781 review: summary: >- PMID:33961781 is a dual proteome-scale network study of human interactome remodeling. action: KEEP_AS_NON_CORE reason: >- High-throughput interactome study. Generic annotation without specific functional context. supported_by: - reference_id: PMID:33961781 supporting_text: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome # === More IEA annotations === - term: id: GO:0033176 label: proton-transporting V-type ATPase complex evidence_type: IEA original_reference_id: GO_REF:0000107 review: summary: >- ATP6V0C is a core subunit of the V-ATPase complex. This is well-established structurally. action: ACCEPT reason: >- Core complex membership annotation. Nine copies of ATP6V0C form the c-ring of the V-ATPase. 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 - term: id: GO:0097401 label: synaptic vesicle lumen acidification evidence_type: IEA original_reference_id: GO_REF:0000107 review: summary: >- V-ATPase acidifies synaptic vesicle lumens, which is required for neurotransmitter loading. action: ACCEPT reason: >- Important neuronal function. V-ATPase-mediated acidification creates the proton gradient needed by vesicular neurotransmitter transporters. ATP6V0C mutations cause epilepsy, supporting the importance of this function. supported_by: - reference_id: file:human/ATP6V0C/ATP6V0C-deep-research-openai.md supporting_text: synaptic vesicle acidification by V-ATPase is required to load various neurotransmitters into vesicles # === NAS annotations from PMID:32001091 (V-ATPase review) === - term: id: GO:0000139 label: Golgi membrane evidence_type: NAS original_reference_id: PMID:32001091 review: summary: >- PMID:32001091 is a review on V-ATPase structure and roles. V-ATPases localize to Golgi membranes for lumen acidification. action: ACCEPT reason: >- V-ATPases are present on Golgi membranes where they contribute to Golgi lumen acidification. This is consistent with the established role of V-ATPases in organelle acidification. supported_by: - reference_id: PMID:32001091 supporting_text: V-ATPases are the primary source of organellar acidification in all eukaryotes - term: id: GO:0005765 label: lysosomal membrane evidence_type: NAS original_reference_id: PMID:32001091 review: summary: >- V-ATPases are critical for lysosomal acidification. ATP6V0C localizes to lysosomal membranes. action: ACCEPT reason: >- Core localization. Lysosomes require V-ATPase for maintaining acidic pH (~4.5-5) needed for hydrolase activity. This is a primary function of V-ATPases. supported_by: - reference_id: PMID:32001091 supporting_text: V-ATPases are membrane-embedded protein complexes that function as ATP hydrolysis-driven proton pumps - reference_id: PMID:17897319 supporting_text: 17 polypeptides comprising or associated with the vacuolar adenosine triphosphatase - term: id: GO:0005886 label: plasma membrane evidence_type: NAS original_reference_id: PMID:32001091 review: summary: >- V-ATPases localize to the plasma membrane in specialized cell types (osteoclasts, kidney intercalated cells, some cancer cells). action: ACCEPT reason: >- V-ATPases are targeted to the plasma membrane in specialized cells where extracellular acidification is required (bone resorption, urinary acid secretion). While not ubiquitous, this is an important physiological location. supported_by: - reference_id: PMID:33065002 supporting_text: Plasma membrane V-ATPases carry out extracellular acidification in specialized organs - reference_id: PMID:32001091 supporting_text: Epub 2020 Jan 28. Structure and Roles of V-type ATPases. - term: id: GO:0007035 label: vacuolar acidification evidence_type: NAS original_reference_id: PMID:32001091 review: summary: >- V-ATPases are responsible for vacuolar/organellar acidification. action: ACCEPT reason: >- Core biological process. V-ATPase-mediated acidification is essential for organelle function. In mammalian cells, 'vacuolar' encompasses lysosomes and related acidic compartments. supported_by: - reference_id: PMID:32001091 supporting_text: V-ATPases are membrane-embedded protein complexes that function as ATP hydrolysis-driven proton pumps - term: id: GO:0007042 label: lysosomal lumen acidification evidence_type: NAS original_reference_id: PMID:32001091 review: summary: >- V-ATPases acidify the lysosomal lumen to maintain optimal pH for hydrolases. action: ACCEPT reason: >- Core biological process. Lysosomal acidification is essential for degradative function. ATP6V0C knockdown impairs lysosomal acidification and autophagic flux. supported_by: - reference_id: PMID:32001091 supporting_text: making them essential for many fundamental cellular processes - term: id: GO:0007042 label: lysosomal lumen acidification evidence_type: NAS original_reference_id: PMID:33065002 review: summary: >- PMID:33065002 is the structural study of human V-ATPase. Confirms V-ATPase role in lysosomal acidification. action: ACCEPT reason: >- Same function as above, different reference. PMID:33065002 provides structural basis for V-ATPase proton pumping that underlies lysosomal acidification. supported_by: - reference_id: PMID:33065002 supporting_text: acidification of intracellular vesicles, organelles, and the extracellular milieu - term: id: GO:0010008 label: endosome membrane evidence_type: NAS original_reference_id: PMID:32001091 review: summary: >- V-ATPases localize to endosome membranes for endosomal acidification. action: ACCEPT reason: >- Core localization. Endosomal acidification is required for receptor-ligand uncoupling, endocytic trafficking, and cargo sorting. supported_by: - reference_id: PMID:33065002 supporting_text: essential in establishing and maintaining the pH homeostasis of endosomes and lysosomes - reference_id: PMID:32001091 supporting_text: Epub 2020 Jan 28. Structure and Roles of V-type ATPases. - term: id: GO:0016020 label: membrane evidence_type: IDA original_reference_id: PMID:33065002 review: summary: >- PMID:33065002 provides cryo-EM structures of human V-ATPase showing ATP6V0C in the membrane-embedded V0 domain. action: ACCEPT reason: >- Direct structural evidence for membrane localization. The cryo-EM structures show ATP6V0C as an integral membrane protein with four transmembrane helices. supported_by: - reference_id: PMID:33065002 supporting_text: a membrane-embedded Vo complex for proton transfer - term: id: GO:0033176 label: proton-transporting V-type ATPase complex evidence_type: NAS original_reference_id: PMID:33065002 review: summary: >- PMID:33065002 provides structural evidence for ATP6V0C as a V-ATPase component. action: ACCEPT reason: >- Core complex annotation. The cryo-EM structures directly visualize nine copies of ATP6V0C in the V-ATPase c-ring. supported_by: - reference_id: PMID:33065002 supporting_text: Aided by mass spectrometry, we build all known protein subunits - term: id: GO:0048388 label: endosomal lumen acidification evidence_type: NAS original_reference_id: PMID:32001091 review: summary: >- V-ATPases acidify endosomal lumens during the endocytic pathway. action: ACCEPT reason: >- Core biological process. Endosomal acidification is required for receptor recycling, cargo processing, and endosome maturation. supported_by: - reference_id: PMID:33065002 supporting_text: establishing and maintaining the pH homeostasis of endosomes - reference_id: PMID:32001091 supporting_text: Epub 2020 Jan 28. Structure and Roles of V-type ATPases. - term: id: GO:0051452 label: intracellular pH reduction evidence_type: NAS original_reference_id: PMID:32001091 review: summary: >- V-ATPases reduce (acidify) the pH of intracellular compartments. action: ACCEPT reason: >- Core biological process describing the outcome of V-ATPase proton pumping activity. supported_by: - reference_id: PMID:33065002 supporting_text: As ATP hydrolysis-driven proton pumps that acidify intracellular vesicles - reference_id: PMID:32001091 supporting_text: Epub 2020 Jan 28. Structure and Roles of V-type ATPases. - term: id: GO:0061795 label: Golgi lumen acidification evidence_type: NAS original_reference_id: PMID:32001091 review: summary: >- V-ATPases contribute to Golgi lumen acidification. action: ACCEPT reason: >- Valid biological process. Golgi acidification is important for protein processing, glycosylation, and sorting in the secretory pathway. supported_by: - reference_id: file:human/ATP6V0C/ATP6V0C-deep-research-openai.md supporting_text: the low pH in Golgi and secretory granules facilitates proper protein processing - reference_id: PMID:32001091 supporting_text: Epub 2020 Jan 28. Structure and Roles of V-type ATPases. - term: id: GO:1902600 label: proton transmembrane transport evidence_type: NAS original_reference_id: PMID:33065002 review: summary: >- PMID:33065002 provides structural basis for V-ATPase proton transport mechanism. action: ACCEPT reason: >- Core biological process. This is the primary function of ATP6V0C as part of the V-ATPase. supported_by: - reference_id: PMID:33065002 supporting_text: coupled proton transfer # === ISS annotation === - term: id: GO:0000220 label: vacuolar proton-transporting V-type ATPase, V0 domain evidence_type: ISS original_reference_id: GO_REF:0000024 review: summary: >- ATP6V0C is a core component of the V0 domain based on sequence similarity to characterized orthologs (e.g., yeast). action: ACCEPT reason: >- Core complex membership. ATP6V0C shares 72% identity with yeast ortholog and cryo-EM structures confirm its position in the human V0 domain. supported_by: - reference_id: file:human/ATP6V0C/ATP6V0C-deep-research-openai.md supporting_text: the human c subunit shares ~72% amino acid identity with its yeast ortholog # === Proteostasis PN projection re-review === - term: id: GO:0046610 label: lysosomal proton-transporting V-type ATPase, V0 domain evidence_type: TAS original_reference_id: PMID:33065002 qualifier: part_of review: summary: >- The Proteostasis PN projection maps the V0 lysosomal V-ATPase proton pump component leaf to GO:0046610. This is a conservative and supported lysosome-specific refinement of the existing V0-domain and lysosomal membrane annotations for ATP6V0C. action: NEW reason: >- ATP6V0C is a c-ring proteolipid in the V0 proton-translocation domain, and V-ATPase is established at lysosomal membranes where it acidifies the lysosomal lumen. The PN context should be captured as lysosomal V0-domain complex membership, not as a broad new autophagy-initiation or mTORC1-process annotation for ATP6V0C itself. additional_reference_ids: - PMID:33065002 - UniProt:P27449 - file:human/ATP6V0C/ATP6V0C-deep-research-falcon.md - file:human/ATP6V0C/ATP6V0C-notes.md supported_by: - reference_id: PMID:33065002 supporting_text: a membrane-embedded Vo complex for proton transfer - reference_id: PMID:33065002 supporting_text: establishing and maintaining the pH homeostasis of endosomes and lysosomes - reference_id: UniProt:P27449 supporting_text: The proton translocation complex V0 consists of the proton transport subunit a, a ring of proteolipid subunits c9c'' - reference_id: file:human/ATP6V0C/ATP6V0C-deep-research-falcon.md supporting_text: V‑ATPases are broadly present on intracellular organelles (endosomes, lysosomes, secretory vesicles, Golgi/ER intermediates), where they acidify lumens # === TAS Reactome annotations - Lysosomal membrane === - term: id: GO:0005765 label: lysosomal membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-9639286 review: summary: >- Reactome pathway for RRAGC,D GTP/GDP exchange. V-ATPase on lysosomal membrane participates in mTORC1 regulation through Rag GTPase signaling. action: ACCEPT reason: >- V-ATPase-Ragulator complex on lysosomal membrane is involved in amino acid sensing and mTORC1 regulation. This is a well-documented secondary function of lysosomal V-ATPases. supported_by: - reference_id: file:human/ATP6V0C/ATP6V0C-deep-research-falcon.md supporting_text: V‑ATPase is a central hub at lysosomes linking acidification to mTORC1 nutrient sensing/signaling - term: id: GO:0005765 label: lysosomal membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-9640167 review: summary: >- Reactome pathway for RRAGA,B GDP/GTP exchange. Related to mTORC1 signaling. action: ACCEPT reason: >- Lysosomal membrane localization required for V-ATPase role in mTORC1 regulation. supported_by: - reference_id: PMID:33065002 supporting_text: V-ATPases have also been shown to directly associate with and regulate signaling complexes in the Notch, Wnt, and mTOR pathways - term: id: GO:0005765 label: lysosomal membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-9640168 review: summary: >- Reactome pathway for V-ATPase:Ragulator:Rag complex dissociation with SLC38A9. action: ACCEPT reason: >- Lysosomal membrane localization for V-ATPase participation in amino acid sensing. supported_by: - reference_id: file:human/ATP6V0C/ATP6V0C-deep-research-falcon.md supporting_text: V‑ATPase is a central hub at lysosomes linking acidification to mTORC1 nutrient sensing/signaling - term: id: GO:0005765 label: lysosomal membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-9640175 review: summary: >- Reactome pathway for V-ATPase:Ragulator:Rag binding to SLC38A9:Arginine. action: ACCEPT reason: >- Part of amino acid sensing machinery at lysosomal membrane. supported_by: - reference_id: file:human/ATP6V0C/ATP6V0C-deep-research-falcon.md supporting_text: V‑ATPase is a central hub at lysosomes linking acidification to mTORC1 nutrient sensing/signaling - term: id: GO:0005765 label: lysosomal membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-9640195 review: summary: >- Reactome pathway for RRAGA,B GTP hydrolysis. action: ACCEPT reason: >- Lysosomal localization for mTORC1 regulatory function. supported_by: - reference_id: PMID:33065002 supporting_text: V-ATPases have also been shown to directly associate with and regulate signaling complexes - term: id: GO:0005765 label: lysosomal membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-9645598 review: summary: >- Reactome pathway for RRAGC,D GTP hydrolysis. action: ACCEPT reason: >- Lysosomal membrane localization for mTORC1 signaling. supported_by: - reference_id: PMID:33065002 supporting_text: acidification of intracellular vesicles, organelles, and the extracellular milieu - term: id: GO:0005765 label: lysosomal membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-9645608 review: summary: >- Reactome pathway for V-ATPase:Ragulator:Rag binding to mTORC1. action: ACCEPT reason: >- V-ATPase participates in mTORC1 recruitment to lysosomal membrane. supported_by: - reference_id: file:human/ATP6V0C/ATP6V0C-deep-research-falcon.md supporting_text: V‑ATPase is a central hub at lysosomes linking acidification to mTORC1 nutrient sensing/signaling - term: id: GO:0005765 label: lysosomal membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-9646468 review: summary: >- Reactome pathway for mTORC1 binding to RHEB:GTP. action: ACCEPT reason: >- Lysosomal V-ATPase involved in mTORC1 activation pathway. supported_by: - reference_id: PMID:33065002 supporting_text: V-ATPases have also been shown to directly associate with and regulate signaling complexes in the Notch, Wnt, and mTOR pathways - term: id: GO:0005765 label: lysosomal membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-9858913 review: summary: >- Reactome pathway for MITF-M-dependent ATP6V0C gene expression. action: ACCEPT reason: >- MITF is a transcription factor regulating lysosomal biogenesis genes including ATP6V0C. This supports lysosomal localization and function. supported_by: - reference_id: UniProt:P27449 supporting_text: Reactome; R-HSA-9857377; Regulation of MITF-M-dependent genes involved in lysosome biogenesis and autophagy # === TAS Reactome annotations - Plasma membrane and granules === - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-6798739 review: summary: >- Reactome pathway for exocytosis of azurophil granule membrane proteins. V-ATPase components are present on neutrophil granule membranes and reach plasma membrane upon degranulation. action: ACCEPT reason: >- During neutrophil degranulation, granule membranes fuse with plasma membrane, delivering V-ATPase. This is a specialized immune cell function. supported_by: - reference_id: UniProt:P27449 supporting_text: Reactome; R-HSA-6798695; Neutrophil degranulation - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-6798747 review: summary: >- Reactome pathway for exocytosis of tertiary granule membrane proteins. action: ACCEPT reason: >- V-ATPase on tertiary granule membranes reaches plasma membrane during degranulation. supported_by: - reference_id: UniProt:P27449 supporting_text: Reactome; R-HSA-6798695; Neutrophil degranulation - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-6800426 review: summary: >- Reactome pathway for exocytosis of ficolin-rich granule membrane proteins. action: ACCEPT reason: >- V-ATPase delivery to plasma membrane via granule exocytosis in neutrophils. supported_by: - reference_id: UniProt:P27449 supporting_text: Reactome; R-HSA-6798695; Neutrophil degranulation - term: id: GO:0035577 label: azurophil granule membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-6798739 review: summary: >- V-ATPase is present on azurophil (primary) granule membranes in neutrophils. action: ACCEPT reason: >- V-ATPases acidify granule contents in immune cells. Azurophil granules contain antimicrobial proteins that require acidic pH for processing/activation. supported_by: - reference_id: file:human/ATP6V0C/ATP6V0C-deep-research-openai.md supporting_text: In immune cells like neutrophils and macrophages, V-ATPases help acidify phagosomes and granules - term: id: GO:0070821 label: tertiary granule membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-6798747 review: summary: >- V-ATPase is present on tertiary granule membranes in neutrophils. action: ACCEPT reason: >- V-ATPases present on various neutrophil granule types for granule acidification. supported_by: - reference_id: UniProt:P27449 supporting_text: Reactome; R-HSA-6798695; Neutrophil degranulation - term: id: GO:0101003 label: ficolin-1-rich granule membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-6800426 review: summary: >- V-ATPase is present on ficolin-1-rich granule membranes. action: ACCEPT reason: >- V-ATPase localization to various neutrophil granule types. supported_by: - reference_id: UniProt:P27449 supporting_text: Reactome; R-HSA-6798695; Neutrophil degranulation # === NAS annotation for autophagy regulation === - term: id: GO:0016241 label: regulation of macroautophagy evidence_type: NAS original_reference_id: PMID:22982048 review: summary: >- PMID:22982048 studies lipofuscin formation and autophagy. V-ATPase function is required for autophagy completion (autophagosome-lysosome fusion and degradation). action: KEEP_AS_NON_CORE reason: >- V-ATPase function is required for autophagy because lysosomal acidification is needed for autophagosome-lysosome fusion and cargo degradation. In the PN context this remains a downstream consequence of the core lysosomal acidification role, not evidence that ATP6V0C directly regulates autophagy initiation. supported_by: - reference_id: file:human/ATP6V0C/ATP6V0C-deep-research-falcon.md supporting_text: V‑ATPase‑driven acidification is essential for lysosomal hydrolase activity and endocytic/autophagic cargo degradation - reference_id: PMID:22982048 supporting_text: macroautophagy is responsible for the uptake of lipofuscin into the lysosomes # === HDA annotations === - term: id: GO:0005925 label: focal adhesion evidence_type: HDA original_reference_id: PMID:21423176 review: summary: >- PMID:21423176 is a proteomics study of focal adhesions that identified ATP6V0C. Focal adhesion localization may be a minor or transient localization. action: MARK_AS_OVER_ANNOTATED reason: >- High-throughput proteomics identification. Focal adhesion is not a primary localization for V-ATPase subunits and may represent contamination or very minor localization. The core localizations are on organelle membranes (lysosomes, endosomes, etc.). supported_by: - reference_id: PMID:21423176 supporting_text: We identified 905 focal adhesion proteins, 459 of which changed in abundance with myosin II inhibition - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:20093472 review: summary: >- PMID:20093472 (Cruciat et al. 2010) shows interaction between V-ATPase and prorenin receptor (PRR/ATP6AP2) in the context of Wnt signaling. action: ACCEPT reason: >- This represents interaction within the V-ATPase complex. ATP6AP2 (PRR) is a V-ATPase accessory subunit. While 'protein binding' is vague, this is a functionally relevant interaction for V-ATPase-mediated Wnt signaling. supported_by: - reference_id: PMID:20093472 supporting_text: PRR functions in a renin-independent manner as an adaptor between Wnt receptors and the vacuolar H+-adenosine triphosphatase (V-ATPase) complex - term: id: GO:0030177 label: positive regulation of Wnt signaling pathway evidence_type: IMP original_reference_id: PMID:20093472 review: summary: >- PMID:20093472 demonstrates V-ATPase requirement for Wnt signaling. V-ATPase-mediated acidification is required for Wnt signal transduction. action: KEEP_AS_NON_CORE reason: >- This is a well-documented secondary function of V-ATPase. V-ATPase-mediated acidification in signaling endosomes is required for Wnt/beta-catenin pathway activation. However, this is not a core function of ATP6V0C - it is a downstream consequence of the acidification function in specific cellular contexts. supported_by: - reference_id: PMID:20093472 supporting_text: PRR and V-ATPase were required to mediate Wnt signaling - reference_id: PMID:33065002 supporting_text: V-ATPases have also been shown to directly associate with and regulate signaling complexes in the Notch, Wnt, and mTOR pathways - term: id: GO:0070062 label: extracellular exosome evidence_type: HDA original_reference_id: PMID:19056867 review: summary: >- PMID:19056867 is a proteomics study of urinary exosomes that identified ATP6V0C. action: KEEP_AS_NON_CORE reason: >- High-throughput proteomics data. V-ATPase subunits have been found in exosomes, consistent with their membrane localization and vesicular trafficking. However, this is not a primary functional localization. supported_by: - reference_id: PMID:19056867 supporting_text: used LC-MS/MS to profile the proteome of human urinary exosomes - term: id: GO:0005765 label: lysosomal membrane evidence_type: HDA original_reference_id: PMID:17897319 review: summary: >- PMID:17897319 is a proteomics study of lysosomal membrane proteins that identified V-ATPase subunits including ATP6V0C. action: ACCEPT reason: >- Direct proteomics identification in lysosomal membrane fractions. Consistent with the core function of V-ATPase in lysosomal acidification. supported_by: - reference_id: PMID:17897319 supporting_text: These included 17 polypeptides comprising or associated with the vacuolar adenosine triphosphatase - term: id: GO:0031625 label: ubiquitin protein ligase binding evidence_type: IPI original_reference_id: PMID:18298843 review: summary: >- PMID:18298843 demonstrates interaction between ATP6V0C and RNF182, an E3 ubiquitin ligase that targets ATP6V0C for degradation. action: ACCEPT reason: >- This represents a specific protein-protein interaction with regulatory function. RNF182-mediated ubiquitination of ATP6V0C leads to its degradation. This interaction is relevant for V-ATPase turnover and may be dysregulated in Alzheimer's disease. supported_by: - reference_id: UniProt:P27449 supporting_text: Interacts with RNF182; this interaction leads to ubiquitination and degradation via the proteasome pathway - reference_id: PMID:18298843 supporting_text: A novel brain-enriched E3 ubiquitin ligase RNF182 is up regulated in the brains of Alzheimer's patients and targets ATP6V0C for degradation. # === TAS annotations for phagocytic and endosome membranes === - term: id: GO:0030670 label: phagocytic vesicle membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-1222516 review: summary: >- Reactome pathway for phagosomal pH reduction. V-ATPase acidifies phagosomes for microbial killing. action: ACCEPT reason: >- V-ATPases are recruited to phagosomes to acidify the lumen, which is critical for antimicrobial defense. This is an important immune cell function. supported_by: - reference_id: UniProt:P27449 supporting_text: Reactome; R-HSA-1222556; ROS and RNS production in phagocytes - term: id: GO:0010008 label: endosome membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-5252133 review: summary: >- Reactome pathway for ATP6AP1 binding to V-ATPase. ATP6AP1 is an accessory subunit that helps assemble V-ATPase on endosomal membranes. action: ACCEPT reason: >- V-ATPases localize to endosomal membranes for endosome acidification, which is essential for receptor-ligand dissociation and cargo sorting. supported_by: - reference_id: PMID:33065002 supporting_text: We define ATP6AP1 as a structural hub for Vo complex assembly because it connects to multiple Vo subunits - term: id: GO:0010008 label: endosome membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-74723 review: summary: >- Reactome pathway for endosome acidification. action: ACCEPT reason: >- Core V-ATPase function in endosome acidification. supported_by: - reference_id: PMID:33065002 supporting_text: essential in establishing and maintaining the pH homeostasis of endosomes and lysosomes - term: id: GO:0010008 label: endosome membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-917841 review: summary: >- Reactome pathway for acidification of transferrin:transferrin receptor containing endosome. action: ACCEPT reason: >- V-ATPase acidifies endosomes during iron uptake via transferrin pathway. supported_by: - reference_id: UniProt:P27449 supporting_text: Reactome; R-HSA-917977; Transferrin endocytosis and recycling # === TAS annotations for ATPase activity === - term: id: GO:0046933 label: proton-transporting ATP synthase activity, rotational mechanism evidence_type: TAS original_reference_id: PMID:1709739 review: summary: >- PMID:1709739 is the original cloning paper for ATP6V0C. The annotation to 'ATP synthase activity' is INCORRECT - V-ATPases are proton PUMPS not ATP synthases. action: REMOVE reason: >- This is a mis-annotation. V-ATPases HYDROLYZE ATP to PUMP protons (acidification). F-ATP synthases use proton gradients to SYNTHESIZE ATP. While structurally related, these are functionally opposite. ATP6V0C is exclusively a V-ATPase subunit. supported_by: - reference_id: PMID:33065002 supporting_text: Vesicular- or vacuolar-type adenosine triphosphatases (V-ATPases) are ATP-driven proton pumps - reference_id: PMID:32001091 supporting_text: V-ATPases are membrane-embedded protein complexes that function as ATP hydrolysis-driven proton pumps - reference_id: PMID:1709739 supporting_text: CpG island in the region of an autosomal dominant polycystic kidney disease locus defines the 5' end of a gene encoding a putative proton channel. - term: id: GO:0046961 label: proton-transporting ATPase activity, rotational mechanism evidence_type: TAS original_reference_id: PMID:1709739 review: summary: >- PMID:1709739 describes ATP6V0C as part of the proton-transporting V-ATPase with rotational mechanism. action: ACCEPT reason: >- Core molecular function. V-ATPases use a rotational mechanism where ATP hydrolysis drives rotation of the c-ring for proton pumping. This is the correct term for V-ATPase activity. supported_by: - reference_id: PMID:1709739 supporting_text: The deduced amino acid sequence has 93% similarity to the 16-kDa proteolipid component that is believed to be part of the proton channel of the vacuolar H(+)-ATPase - reference_id: PMID:33065002 supporting_text: ATP hydrolysis by the cytoplasmic V 1 ATPase drives the rotation of the membrane embedded, ring-shaped V o proton pump - term: id: GO:0016020 label: membrane evidence_type: TAS original_reference_id: PMID:1709739 review: summary: >- PMID:1709739 describes ATP6V0C as having four transmembrane domains, establishing membrane localization. action: ACCEPT reason: >- Core localization annotation based on original cloning and characterization paper. supported_by: - reference_id: PMID:1709739 supporting_text: a 155-amino acid peptide having four putative transmembrane domains - term: id: GO:1902600 label: proton transmembrane transport evidence_type: TAS original_reference_id: PMID:1709739 review: summary: >- PMID:1709739 identifies ATP6V0C as a component of the proton channel of V-ATPase. action: ACCEPT reason: >- Core biological process annotation. This is the primary function of ATP6V0C. supported_by: - reference_id: PMID:1709739 supporting_text: believed to be part of the proton channel of the vacuolar H(+)-ATPase 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:0000043 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping 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:0000108 title: Automatic assignment of GO terms using logical inference, based on on inter-ontology links. 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:11543633 title: Cloning, mapping, and characterization of a human homologue of the yeast longevity assurance gene LAG1. findings: - statement: Identified interaction between ATP6V0C and LASS2/CERS2 supporting_text: the LASS2 protein interacts with several membrane-associated receptors or transporters - id: PMID:1334459 title: The BPV-1 E5 protein, the 16 kDa membrane pore-forming protein and the PDGF receptor exist in a complex that is dependent on hydrophobic transmembrane interactions. findings: - statement: Viral E5 protein interacts with ATP6V0C (16 kDa proteolipid) supporting_text: 16 kDa membrane pore-forming protein - id: PMID:1709739 title: CpG island in the region of an autosomal dominant polycystic kidney disease locus defines the 5' end of a gene encoding a putative proton channel. findings: - statement: Original cloning of human ATP6V0C supporting_text: a 155-amino acid peptide having four putative transmembrane domains - statement: Identified as 155 amino acid protein with four transmembrane domains supporting_text: a 155-amino acid peptide having four putative transmembrane domains - statement: Homologous to vacuolar H+-ATPase 16 kDa proteolipid supporting_text: 93% similarity to the 16-kDa proteolipid component - id: PMID:17897319 title: Integral and associated lysosomal membrane proteins. findings: - statement: Proteomics identification of V-ATPase subunits in lysosomal membrane fractions supporting_text: 17 polypeptides comprising or associated with the vacuolar adenosine triphosphatase - id: PMID:18298843 title: A novel brain-enriched E3 ubiquitin ligase RNF182 is up regulated in the brains of Alzheimer's patients and targets ATP6V0C for degradation. findings: - statement: RNF182 interacts with ATP6V0C supporting_text: an interaction between RNF182 and ATP6V0C - statement: RNF182 targets ATP6V0C for ubiquitin-proteasome degradation supporting_text: RNF182 targeted ATP6V0C for degradation by the ubiquitin-proteosome pathway - statement: Potential relevance to Alzheimer's disease supporting_text: up regulated in the brains of Alzheimer's patients - id: PMID:19056867 title: Large-scale proteomics and phosphoproteomics of urinary exosomes. findings: - statement: ATP6V0C identified in urinary exosome proteome supporting_text: used LC-MS/MS to profile the proteome of human urinary exosomes - id: PMID:20093472 title: Requirement of prorenin receptor and vacuolar H+-ATPase-mediated acidification for Wnt signaling. findings: - statement: V-ATPase required for Wnt/beta-catenin signaling supporting_text: PRR and V-ATPase were required to mediate Wnt signaling - statement: PRR/ATP6AP2 functions as adaptor between Wnt receptors and V-ATPase supporting_text: PRR functions in a renin-independent manner as an adaptor between Wnt receptors and the vacuolar H+-adenosine triphosphatase - id: PMID:21423176 title: Analysis of the myosin-II-responsive focal adhesion proteome reveals a role for β-Pix in negative regulation of focal adhesion maturation. findings: - statement: ATP6V0C identified in focal adhesion proteome (likely minor localization) supporting_text: We identified 905 focal adhesion proteins - id: PMID:21988832 title: Toward an understanding of the protein interaction network of the human liver. findings: - statement: Large-scale interactome study supporting_text: establish a human liver protein interaction network (HLPN) composed of 3484 interactions among 2582 proteins - id: PMID:22982048 title: Lipofuscin is formed independently of macroautophagy and lysosomal activity in stress-induced prematurely senescent human fibroblasts. findings: - statement: V-ATPase required for autophagy completion supporting_text: macroautophagy is responsible for the uptake of lipofuscin into the lysosomes - id: PMID:25416956 title: A proteome-scale map of the human interactome network. findings: - statement: Large-scale interactome mapping supporting_text: we describe a systematic map of - id: PMID:31515488 title: Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations. findings: - statement: Study of genetic variant effects on protein interactions supporting_text: Extensive disruption of protein interactions by genetic variants - id: PMID:32001091 title: Structure and Roles of V-type ATPases. findings: - statement: Comprehensive review of V-ATPase structure and function supporting_text: V-ATPases are membrane-embedded protein complexes that function as ATP hydrolysis-driven proton pumps - statement: V-ATPases essential for organellar acidification supporting_text: V-ATPases are the primary source of organellar acidification in all eukaryotes - statement: Multiple V-ATPase isoforms with differential localization supporting_text: several subunits of mammalian V-ATPase have multiple isoforms that are differentially localized - id: PMID:32296183 title: A reference map of the human binary protein interactome. findings: - statement: Large-scale binary interactome mapping supporting_text: a human 'all-by-all' reference interactome map of human binary protein interactions - id: PMID:32814053 title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. findings: - statement: Interactome study in neurodegeneration context supporting_text: Here, we report on an interactome map that focuses on neurodegenerative disease - id: PMID:33065002 title: Structures of a Complete Human V-ATPase Reveal Mechanisms of Its Assembly. findings: - statement: Cryo-EM structures of human V-ATPase at up to 2.9 A resolution supporting_text: we report cryoelectron microscopy structures of human V-ATPase in three rotational states at up to 2.9-Å resolution - statement: Nine copies of ATP6V0C (subunit c) form c-ring with one copy of ATP6V0B (c'') supporting_text: a membrane-embedded Vo complex for proton transfer - statement: ATP6AP1 serves as assembly hub connecting V0 subunits supporting_text: We define ATP6AP1 as a structural hub for Vo complex assembly because it connects to multiple Vo subunits - statement: Identified glycolipids and phospholipids in V0 complex supporting_text: identify glycolipids and phospholipids in the Vo complex - id: PMID:33961781 title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. findings: - statement: Cell-specific interactome remodeling study supporting_text: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome - id: PMID:36074901 title: ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy. findings: - statement: Pathogenic variants in ATP6V0C cause EPEO3 (epilepsy with developmental delay) supporting_text: ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder - statement: E139 is essential for proton translocation supporting_text: the patient variants interfere with the interactions between the ATP6V0C and ATP6V0A subunits - statement: Multiple variants characterized for effects on V-ATPase function supporting_text: variants impair V-ATPase function - id: file:human/ATP6V0C/ATP6V0C-deep-research-openai.md title: Deep research summary of ATP6V0C function and localization findings: - statement: Comprehensive literature review of ATP6V0C function - statement: Synaptic vesicle acidification required for neurotransmitter loading - statement: V-ATPase-Ragulator complex essential for mTORC1 activation - id: file:human/ATP6V0C/ATP6V0C-deep-research-falcon.md title: Falcon deep research summary of ATP6V0C function and PN-relevant V-ATPase biology findings: - statement: Falcon summarizes ATP6V0C as the V0 c proteolipid/c-ring component of human V-ATPase. supporting_text: ATP6V0C encodes the c proteolipid subunit of the membrane Vo sector of the V‑type H+‑ATPase (V‑ATPase) in Homo sapiens - statement: Falcon supports lysosomal acidification and autophagic cargo degradation as downstream outcomes of V-ATPase acidification. supporting_text: V‑ATPase‑driven acidification is essential for lysosomal hydrolase activity and endocytic/autophagic cargo degradation - id: file:human/ATP6V0C/ATP6V0C-notes.md title: ATP6V0C curation notes, including Proteostasis PN re-review findings: - statement: The PN projection supports adding GO:0046610 as a lysosome-specific V0-domain component annotation and does not support broad new autophagy or mTORC1 process annotations. - id: file:human/ATP6V0C/ATP6V0C-deep-research-cyberian.md title: Cyberian deep research on ATP6V0C function findings: [] # Reactome pathway references - id: Reactome:R-HSA-9639286 title: RRAGC,D GTP/GDP exchange findings: - statement: mTORC1 regulation pathway involving V-ATPase on lysosomal membrane - id: Reactome:R-HSA-9640167 title: RRAGA,B GDP/GTP exchange findings: - statement: mTORC1 signaling pathway on lysosomal membrane - id: Reactome:R-HSA-9640168 title: V-ATPase Ragulator Rag complex dissociation with SLC38A9 findings: - statement: Amino acid sensing pathway involving V-ATPase - id: Reactome:R-HSA-9640175 title: V-ATPase Ragulator Rag binding to SLC38A9 Arginine findings: - statement: Amino acid sensing machinery at lysosomal membrane - id: Reactome:R-HSA-9640195 title: RRAGA,B GTP hydrolysis findings: - statement: mTORC1 regulatory function at lysosomal membrane - id: Reactome:R-HSA-9645598 title: RRAGC,D GTP hydrolysis findings: - statement: mTORC1 signaling pathway - id: Reactome:R-HSA-9645608 title: V-ATPase Ragulator Rag binding to mTORC1 findings: - statement: mTORC1 recruitment to lysosomal membrane - id: Reactome:R-HSA-9646468 title: mTORC1 binding to RHEB GTP findings: - statement: mTORC1 activation pathway - id: Reactome:R-HSA-9858913 title: MITF-M-dependent ATP6V0C gene expression findings: - statement: Transcriptional regulation of ATP6V0C for lysosomal biogenesis - id: Reactome:R-HSA-6798739 title: Exocytosis of azurophil granule membrane proteins findings: - statement: V-ATPase delivery to plasma membrane during neutrophil degranulation - id: Reactome:R-HSA-6798747 title: Exocytosis of tertiary granule membrane proteins findings: - statement: V-ATPase on tertiary granule membranes - id: Reactome:R-HSA-6800426 title: Exocytosis of ficolin-rich granule membrane proteins findings: - statement: V-ATPase on ficolin-rich granule membranes - id: Reactome:R-HSA-1222516 title: Phagosomal pH reduction findings: - statement: V-ATPase acidification of phagosomes for antimicrobial defense - id: Reactome:R-HSA-5252133 title: ATP6AP1 binding to V-ATPase findings: - statement: V-ATPase assembly on endosomal membranes - id: Reactome:R-HSA-74723 title: Endosome acidification findings: - statement: Core V-ATPase function in endosome acidification - id: Reactome:R-HSA-917841 title: Acidification of transferrin transferrin receptor containing endosome findings: - statement: V-ATPase acidifies endosomes during iron uptake core_functions: - description: >- ATP6V0C is a core structural component of the V-ATPase V0 domain. Nine copies of ATP6V0C assemble with one copy of ATP6V0B to form the c-ring that rotates during proton translocation. The conserved glutamate residue E139 serves as the proton-binding site essential for proton transport. molecular_function: id: GO:0046961 label: proton-transporting ATPase activity, rotational mechanism directly_involved_in: - id: GO:1902600 label: proton transmembrane transport in_complex: id: GO:0033176 label: proton-transporting V-type ATPase complex supported_by: - reference_id: PMID:33065002 supporting_text: Here, we report cryoelectron microscopy structures of human V-ATPase in three rotational states at up to 2.9-Å resolution - reference_id: UniProt:P27449 supporting_text: 'E->A: Severely decreased proton transmembrane transport.' - description: >- As part of the V-ATPase complex, ATP6V0C is essential for acidifying intracellular compartments including lysosomes, endosomes, Golgi, and synaptic vesicles. Acidification is required for hydrolase activity, receptor-ligand dissociation, neurotransmitter loading, and protein processing. molecular_function: id: GO:0015078 label: proton transmembrane transporter activity directly_involved_in: - id: GO:0007042 label: lysosomal lumen acidification - id: GO:0048388 label: endosomal lumen acidification - id: GO:0097401 label: synaptic vesicle lumen acidification locations: - id: GO:0005765 label: lysosomal membrane - id: GO:0010008 label: endosome membrane - id: GO:0030672 label: synaptic vesicle membrane supported_by: - reference_id: PMID:32001091 supporting_text: V-ATPases are the primary source of organellar acidification in all eukaryotes - reference_id: PMID:33065002 supporting_text: acidification of intracellular vesicles, organelles, and the extracellular milieu status: COMPLETE