ATP6V0C

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0016020 membrane	IBA GO_REF:0000033	ACCEPT	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). 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. Supporting Evidence: PMID:33065002 the membrane embedded, ring-shaped V o proton pump UniProt:P27449 Multi-pass membrane protein
GO:0006811 monoatomic ion transport	IEA GO_REF:0000043	ACCEPT	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. 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. Supporting Evidence: PMID:33065002 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
GO:0015078 proton transmembrane transporter activity	IEA GO_REF:0000120	ACCEPT	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. 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. Supporting Evidence: PMID:33065002 cycles of protonation and deprotonation of lipid-exposed glutamic acid residues for coupled proton transfer UniProt:P27449 E->A: Severely decreased proton transmembrane transport.
GO:0015986 proton motive force-driven ATP synthesis	IEA GO_REF:0000108	REMOVE	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. 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. Supporting Evidence: PMID:33065002 Vesicular- or vacuolar-type adenosine triphosphatases (V-ATPases) are ATP-driven proton pumps PMID:32001091 V-ATPases are membrane-embedded protein complexes that function as ATP hydrolysis-driven proton pumps
GO:0030665 clathrin-coated vesicle membrane	IEA GO_REF:0000044	ACCEPT	Summary: UniProt annotation indicates ATP6V0C localizes to clathrin-coated vesicle membranes, consistent with V-ATPase function in early endocytic compartments. 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. Supporting Evidence: UniProt:P27449 Cytoplasmic vesicle, clathrin-coated vesicle membrane
GO:0030672 synaptic vesicle membrane	IEA GO_REF:0000044	ACCEPT	Summary: ATP6V0C localizes to synaptic vesicle membranes where V-ATPase acidification is essential for neurotransmitter loading. Reason: Core localization for neuronal function. V-ATPase-mediated acidification of synaptic vesicles creates the electrochemical gradient required for vesicular neurotransmitter transporters. Supporting Evidence: UniProt:P27449 Cytoplasmic vesicle, secretory vesicle, synaptic vesicle membrane
GO:0031410 cytoplasmic vesicle	IEA GO_REF:0000043	ACCEPT	Summary: ATP6V0C localizes to various cytoplasmic vesicles including lysosomes, endosomes, synaptic vesicles, and secretory granules. 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. Supporting Evidence: PMID:33065002 acidification of intracellular vesicles, organelles, and the extracellular milieu
GO:0033177 proton-transporting two-sector ATPase complex, proton-transporting domain	IEA GO_REF:0000002	ACCEPT	Summary: ATP6V0C is a subunit of the V0 (proton-transporting) domain of the two-sector V-ATPase. 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. 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:0033179 proton-transporting V-type ATPase, V0 domain	IEA GO_REF:0000002	ACCEPT	Summary: ATP6V0C is a core component of the V0 domain, forming the c-ring that mediates proton translocation. 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. Supporting Evidence: PMID:33065002 a membrane-embedded Vo complex for proton transfer UniProt:P27449 The proton translocation complex V0 consists of the proton transport subunit a, a ring of proteolipid subunits c9c''
GO:0046961 proton-transporting ATPase activity, rotational mechanism	IEA GO_REF:0000002	ACCEPT	Summary: ATP6V0C is part of the V-ATPase which uses a rotational mechanism for proton transport. The c-ring rotates during the catalytic cycle. 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. Supporting Evidence: PMID:33065002 ATP hydrolysis by the cytoplasmic V 1 ATPase drives the rotation of the membrane embedded, ring-shaped V o proton pump
GO:0098588 bounding membrane of organelle	IEA GO_REF:0000117	ACCEPT	Summary: ATP6V0C localizes to the membranes of organelles including lysosomes and endosomes. 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. Supporting Evidence: PMID:33065002 acidification of intracellular vesicles, organelles, and the extracellular milieu
GO:1902600 proton transmembrane transport	IEA GO_REF:0000120	ACCEPT	Summary: ATP6V0C directly participates in proton transmembrane transport as part of the V-ATPase proton pump. 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. Supporting Evidence: PMID:33065002 coupled proton transfer PMID:36074901 the patient variants interfere with the interactions between the ATP6V0C and ATP6V0A subunits during ATP hydrolysis
GO:0005515 protein binding	IPI PMID:11543633 Cloning, mapping, and characterization of a human homologue ...	KEEP AS NON CORE	Summary: PMID:11543633 (Pan et al. 2001) reports interaction between ATP6V0C and LASS2 (CERS2), a ceramide synthase. This interaction is also documented in UniProt. 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. Supporting Evidence: UniProt:P27449 Interacts with LASS2 (PubMed:11543633) PMID:11543633 Cloning, mapping, and characterization of a human homologue of the yeast longevity assurance gene LAG1.
GO:0005515 protein binding	IPI PMID:1334459 The BPV-1 E5 protein, the 16 kDa membrane pore-forming prote...	ACCEPT	Summary: PMID:1334459 reports interaction with bovine papillomavirus E5 oncoprotein, a viral protein that binds the 16 kDa proteolipid of V-ATPase. 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. Supporting Evidence: UniProt:P27449 Interacts with the V0 complex V-ATPase subunit a4 ATP6V0A4 PMID:1334459 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.
GO:0005515 protein binding	IPI PMID:21988832 Toward an understanding of the protein interaction network o...	KEEP AS NON CORE	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. Reason: High-throughput interaction study. The annotation may reflect real interactions but 'protein binding' without specifying partners provides limited functional information. Supporting Evidence: PMID:21988832 establish a human liver protein interaction network (HLPN) composed of 3484 interactions among 2582 proteins
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	KEEP AS NON CORE	Summary: PMID:25416956 is a proteome-scale human interactome mapping study. High-throughput data. Reason: High-throughput interaction study. Without specific interaction partners, this provides limited insight into ATP6V0C function. Supporting Evidence: PMID:25416956 we describe a systematic map of
GO:0005515 protein binding	IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari...	KEEP AS NON CORE	Summary: PMID:31515488 studies genetic variant effects on protein interactions. High-throughput data. Reason: High-throughput study focused on variant effects on interactions. Generic 'protein binding' annotation provides limited functional insight. Supporting Evidence: PMID:31515488 Extensive disruption of protein interactions by genetic variants
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	KEEP AS NON CORE	Summary: PMID:32296183 is a reference map of human binary protein interactome. High-throughput data. Reason: High-throughput binary interactome mapping. Generic annotation without specific partners. Supporting Evidence: PMID:32296183 a human 'all-by-all' reference interactome map of human binary protein interactions
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	KEEP AS NON CORE	Summary: PMID:32814053 studies neurodegenerative disease protein interactomes. May identify disease-relevant interactions for ATP6V0C. Reason: Interactome mapping in context of neurodegeneration. Could be relevant given ATP6V0C mutations cause neurological disease, but generic annotation is not informative. Supporting Evidence: PMID:32814053 Here, we report on an interactome map that focuses on neurodegenerative disease
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	KEEP AS NON CORE	Summary: PMID:33961781 is a dual proteome-scale network study of human interactome remodeling. Reason: High-throughput interactome study. Generic annotation without specific functional context. Supporting Evidence: PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome
GO:0033176 proton-transporting V-type ATPase complex	IEA GO_REF:0000107	ACCEPT	Summary: ATP6V0C is a core subunit of the V-ATPase complex. This is well-established structurally. Reason: Core complex membership annotation. Nine copies of ATP6V0C form the c-ring of the V-ATPase. 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
GO:0097401 synaptic vesicle lumen acidification	IEA GO_REF:0000107	ACCEPT	Summary: V-ATPase acidifies synaptic vesicle lumens, which is required for neurotransmitter loading. 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. Supporting Evidence: file:human/ATP6V0C/ATP6V0C-deep-research-openai.md synaptic vesicle acidification by V-ATPase is required to load various neurotransmitters into vesicles
GO:0000139 Golgi membrane	NAS PMID:32001091 Structure and Roles of V-type ATPases.	ACCEPT	Summary: PMID:32001091 is a review on V-ATPase structure and roles. V-ATPases localize to Golgi membranes for lumen acidification. 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. Supporting Evidence: PMID:32001091 V-ATPases are the primary source of organellar acidification in all eukaryotes
GO:0005765 lysosomal membrane	NAS PMID:32001091 Structure and Roles of V-type ATPases.	ACCEPT	Summary: V-ATPases are critical for lysosomal acidification. ATP6V0C localizes to lysosomal membranes. 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. Supporting Evidence: PMID:32001091 V-ATPases are membrane-embedded protein complexes that function as ATP hydrolysis-driven proton pumps PMID:17897319 17 polypeptides comprising or associated with the vacuolar adenosine triphosphatase
GO:0005886 plasma membrane	NAS PMID:32001091 Structure and Roles of V-type ATPases.	ACCEPT	Summary: V-ATPases localize to the plasma membrane in specialized cell types (osteoclasts, kidney intercalated cells, some cancer cells). 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. Supporting Evidence: PMID:33065002 Plasma membrane V-ATPases carry out extracellular acidification in specialized organs PMID:32001091 Epub 2020 Jan 28. Structure and Roles of V-type ATPases.
GO:0007035 vacuolar acidification	NAS PMID:32001091 Structure and Roles of V-type ATPases.	ACCEPT	Summary: V-ATPases are responsible for vacuolar/organellar acidification. Reason: Core biological process. V-ATPase-mediated acidification is essential for organelle function. In mammalian cells, 'vacuolar' encompasses lysosomes and related acidic compartments. Supporting Evidence: PMID:32001091 V-ATPases are membrane-embedded protein complexes that function as ATP hydrolysis-driven proton pumps
GO:0007042 lysosomal lumen acidification	NAS PMID:32001091 Structure and Roles of V-type ATPases.	ACCEPT	Summary: V-ATPases acidify the lysosomal lumen to maintain optimal pH for hydrolases. Reason: Core biological process. Lysosomal acidification is essential for degradative function. ATP6V0C knockdown impairs lysosomal acidification and autophagic flux. Supporting Evidence: PMID:32001091 making them essential for many fundamental cellular processes
GO:0007042 lysosomal lumen acidification	NAS PMID:33065002 Structures of a Complete Human V-ATPase Reveal Mechanisms of...	ACCEPT	Summary: PMID:33065002 is the structural study of human V-ATPase. Confirms V-ATPase role in lysosomal acidification. Reason: Same function as above, different reference. PMID:33065002 provides structural basis for V-ATPase proton pumping that underlies lysosomal acidification. Supporting Evidence: PMID:33065002 acidification of intracellular vesicles, organelles, and the extracellular milieu
GO:0010008 endosome membrane	NAS PMID:32001091 Structure and Roles of V-type ATPases.	ACCEPT	Summary: V-ATPases localize to endosome membranes for endosomal acidification. Reason: Core localization. Endosomal acidification is required for receptor-ligand uncoupling, endocytic trafficking, and cargo sorting. Supporting Evidence: PMID:33065002 essential in establishing and maintaining the pH homeostasis of endosomes and lysosomes PMID:32001091 Epub 2020 Jan 28. Structure and Roles of V-type ATPases.
GO:0016020 membrane	IDA PMID:33065002 Structures of a Complete Human V-ATPase Reveal Mechanisms of...	ACCEPT	Summary: PMID:33065002 provides cryo-EM structures of human V-ATPase showing ATP6V0C in the membrane-embedded V0 domain. Reason: Direct structural evidence for membrane localization. The cryo-EM structures show ATP6V0C as an integral membrane protein with four transmembrane helices. Supporting Evidence: PMID:33065002 a membrane-embedded Vo complex for proton transfer
GO:0033176 proton-transporting V-type ATPase complex	NAS PMID:33065002 Structures of a Complete Human V-ATPase Reveal Mechanisms of...	ACCEPT	Summary: PMID:33065002 provides structural evidence for ATP6V0C as a V-ATPase component. Reason: Core complex annotation. The cryo-EM structures directly visualize nine copies of ATP6V0C in the V-ATPase c-ring. Supporting Evidence: PMID:33065002 Aided by mass spectrometry, we build all known protein subunits
GO:0048388 endosomal lumen acidification	NAS PMID:32001091 Structure and Roles of V-type ATPases.	ACCEPT	Summary: V-ATPases acidify endosomal lumens during the endocytic pathway. Reason: Core biological process. Endosomal acidification is required for receptor recycling, cargo processing, and endosome maturation. Supporting Evidence: PMID:33065002 establishing and maintaining the pH homeostasis of endosomes PMID:32001091 Epub 2020 Jan 28. Structure and Roles of V-type ATPases.
GO:0051452 intracellular pH reduction	NAS PMID:32001091 Structure and Roles of V-type ATPases.	ACCEPT	Summary: V-ATPases reduce (acidify) the pH of intracellular compartments. Reason: Core biological process describing the outcome of V-ATPase proton pumping activity. Supporting Evidence: PMID:33065002 As ATP hydrolysis-driven proton pumps that acidify intracellular vesicles PMID:32001091 Epub 2020 Jan 28. Structure and Roles of V-type ATPases.
GO:0061795 Golgi lumen acidification	NAS PMID:32001091 Structure and Roles of V-type ATPases.	ACCEPT	Summary: V-ATPases contribute to Golgi lumen acidification. Reason: Valid biological process. Golgi acidification is important for protein processing, glycosylation, and sorting in the secretory pathway. Supporting Evidence: file:human/ATP6V0C/ATP6V0C-deep-research-openai.md the low pH in Golgi and secretory granules facilitates proper protein processing PMID:32001091 Epub 2020 Jan 28. Structure and Roles of V-type ATPases.
GO:1902600 proton transmembrane transport	NAS PMID:33065002 Structures of a Complete Human V-ATPase Reveal Mechanisms of...	ACCEPT	Summary: PMID:33065002 provides structural basis for V-ATPase proton transport mechanism. Reason: Core biological process. This is the primary function of ATP6V0C as part of the V-ATPase. Supporting Evidence: PMID:33065002 coupled proton transfer
GO:0000220 vacuolar proton-transporting V-type ATPase, V0 domain	ISS GO_REF:0000024	ACCEPT	Summary: ATP6V0C is a core component of the V0 domain based on sequence similarity to characterized orthologs (e.g., yeast). Reason: Core complex membership. ATP6V0C shares 72% identity with yeast ortholog and cryo-EM structures confirm its position in the human V0 domain. Supporting Evidence: file:human/ATP6V0C/ATP6V0C-deep-research-openai.md the human c subunit shares ~72% amino acid identity with its yeast ortholog
GO:0046610 lysosomal proton-transporting V-type ATPase, V0 domain	TAS PMID:33065002 Structures of a Complete Human V-ATPase Reveal Mechanisms of...	NEW	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. 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. Supporting Evidence: PMID:33065002 a membrane-embedded Vo complex for proton transfer PMID:33065002 establishing and maintaining the pH homeostasis of endosomes and lysosomes UniProt:P27449 The proton translocation complex V0 consists of the proton transport subunit a, a ring of proteolipid subunits c9c'' file:human/ATP6V0C/ATP6V0C-deep-research-falcon.md V‑ATPases are broadly present on intracellular organelles (endosomes, lysosomes, secretory vesicles, Golgi/ER intermediates), where they acidify lumens
GO:0005765 lysosomal membrane	TAS Reactome:R-HSA-9639286	ACCEPT	Summary: Reactome pathway for RRAGC,D GTP/GDP exchange. V-ATPase on lysosomal membrane participates in mTORC1 regulation through Rag GTPase signaling. 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. Supporting Evidence: file:human/ATP6V0C/ATP6V0C-deep-research-falcon.md V‑ATPase is a central hub at lysosomes linking acidification to mTORC1 nutrient sensing/signaling
GO:0005765 lysosomal membrane	TAS Reactome:R-HSA-9640167	ACCEPT	Summary: Reactome pathway for RRAGA,B GDP/GTP exchange. Related to mTORC1 signaling. Reason: Lysosomal membrane localization required for V-ATPase role in mTORC1 regulation. Supporting Evidence: PMID:33065002 V-ATPases have also been shown to directly associate with and regulate signaling complexes in the Notch, Wnt, and mTOR pathways
GO:0005765 lysosomal membrane	TAS Reactome:R-HSA-9640168	ACCEPT	Summary: Reactome pathway for V-ATPase:Ragulator:Rag complex dissociation with SLC38A9. Reason: Lysosomal membrane localization for V-ATPase participation in amino acid sensing. Supporting Evidence: file:human/ATP6V0C/ATP6V0C-deep-research-falcon.md V‑ATPase is a central hub at lysosomes linking acidification to mTORC1 nutrient sensing/signaling
GO:0005765 lysosomal membrane	TAS Reactome:R-HSA-9640175	ACCEPT	Summary: Reactome pathway for V-ATPase:Ragulator:Rag binding to SLC38A9:Arginine. Reason: Part of amino acid sensing machinery at lysosomal membrane. Supporting Evidence: file:human/ATP6V0C/ATP6V0C-deep-research-falcon.md V‑ATPase is a central hub at lysosomes linking acidification to mTORC1 nutrient sensing/signaling
GO:0005765 lysosomal membrane	TAS Reactome:R-HSA-9640195	ACCEPT	Summary: Reactome pathway for RRAGA,B GTP hydrolysis. Reason: Lysosomal localization for mTORC1 regulatory function. Supporting Evidence: PMID:33065002 V-ATPases have also been shown to directly associate with and regulate signaling complexes
GO:0005765 lysosomal membrane	TAS Reactome:R-HSA-9645598	ACCEPT	Summary: Reactome pathway for RRAGC,D GTP hydrolysis. Reason: Lysosomal membrane localization for mTORC1 signaling. Supporting Evidence: PMID:33065002 acidification of intracellular vesicles, organelles, and the extracellular milieu
GO:0005765 lysosomal membrane	TAS Reactome:R-HSA-9645608	ACCEPT	Summary: Reactome pathway for V-ATPase:Ragulator:Rag binding to mTORC1. Reason: V-ATPase participates in mTORC1 recruitment to lysosomal membrane. Supporting Evidence: file:human/ATP6V0C/ATP6V0C-deep-research-falcon.md V‑ATPase is a central hub at lysosomes linking acidification to mTORC1 nutrient sensing/signaling
GO:0005765 lysosomal membrane	TAS Reactome:R-HSA-9646468	ACCEPT	Summary: Reactome pathway for mTORC1 binding to RHEB:GTP. Reason: Lysosomal V-ATPase involved in mTORC1 activation pathway. Supporting Evidence: PMID:33065002 V-ATPases have also been shown to directly associate with and regulate signaling complexes in the Notch, Wnt, and mTOR pathways
GO:0005765 lysosomal membrane	TAS Reactome:R-HSA-9858913	ACCEPT	Summary: Reactome pathway for MITF-M-dependent ATP6V0C gene expression. Reason: MITF is a transcription factor regulating lysosomal biogenesis genes including ATP6V0C. This supports lysosomal localization and function. Supporting Evidence: UniProt:P27449 Reactome; R-HSA-9857377; Regulation of MITF-M-dependent genes involved in lysosome biogenesis and autophagy
GO:0005886 plasma membrane	TAS Reactome:R-HSA-6798739	ACCEPT	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. Reason: During neutrophil degranulation, granule membranes fuse with plasma membrane, delivering V-ATPase. This is a specialized immune cell function. Supporting Evidence: UniProt:P27449 Reactome; R-HSA-6798695; Neutrophil degranulation
GO:0005886 plasma membrane	TAS Reactome:R-HSA-6798747	ACCEPT	Summary: Reactome pathway for exocytosis of tertiary granule membrane proteins. Reason: V-ATPase on tertiary granule membranes reaches plasma membrane during degranulation. Supporting Evidence: UniProt:P27449 Reactome; R-HSA-6798695; Neutrophil degranulation
GO:0005886 plasma membrane	TAS Reactome:R-HSA-6800426	ACCEPT	Summary: Reactome pathway for exocytosis of ficolin-rich granule membrane proteins. Reason: V-ATPase delivery to plasma membrane via granule exocytosis in neutrophils. Supporting Evidence: UniProt:P27449 Reactome; R-HSA-6798695; Neutrophil degranulation
GO:0035577 azurophil granule membrane	TAS Reactome:R-HSA-6798739	ACCEPT	Summary: V-ATPase is present on azurophil (primary) granule membranes in neutrophils. Reason: V-ATPases acidify granule contents in immune cells. Azurophil granules contain antimicrobial proteins that require acidic pH for processing/activation. Supporting Evidence: file:human/ATP6V0C/ATP6V0C-deep-research-openai.md In immune cells like neutrophils and macrophages, V-ATPases help acidify phagosomes and granules
GO:0070821 tertiary granule membrane	TAS Reactome:R-HSA-6798747	ACCEPT	Summary: V-ATPase is present on tertiary granule membranes in neutrophils. Reason: V-ATPases present on various neutrophil granule types for granule acidification. Supporting Evidence: UniProt:P27449 Reactome; R-HSA-6798695; Neutrophil degranulation
GO:0101003 ficolin-1-rich granule membrane	TAS Reactome:R-HSA-6800426	ACCEPT	Summary: V-ATPase is present on ficolin-1-rich granule membranes. Reason: V-ATPase localization to various neutrophil granule types. Supporting Evidence: UniProt:P27449 Reactome; R-HSA-6798695; Neutrophil degranulation
GO:0016241 regulation of macroautophagy	NAS PMID:22982048 Lipofuscin is formed independently of macroautophagy and lys...	KEEP AS NON CORE	Summary: PMID:22982048 studies lipofuscin formation and autophagy. V-ATPase function is required for autophagy completion (autophagosome-lysosome fusion and degradation). 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. Supporting Evidence: file:human/ATP6V0C/ATP6V0C-deep-research-falcon.md V‑ATPase‑driven acidification is essential for lysosomal hydrolase activity and endocytic/autophagic cargo degradation PMID:22982048 macroautophagy is responsible for the uptake of lipofuscin into the lysosomes
GO:0005925 focal adhesion	HDA PMID:21423176 Analysis of the myosin-II-responsive focal adhesion proteome...	MARK AS OVER ANNOTATED	Summary: PMID:21423176 is a proteomics study of focal adhesions that identified ATP6V0C. Focal adhesion localization may be a minor or transient localization. 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.). Supporting Evidence: PMID:21423176 We identified 905 focal adhesion proteins, 459 of which changed in abundance with myosin II inhibition
GO:0005515 protein binding	IPI PMID:20093472 Requirement of prorenin receptor and vacuolar H+-ATPase-medi...	ACCEPT	Summary: PMID:20093472 (Cruciat et al. 2010) shows interaction between V-ATPase and prorenin receptor (PRR/ATP6AP2) in the context of Wnt signaling. 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. Supporting Evidence: PMID:20093472 PRR functions in a renin-independent manner as an adaptor between Wnt receptors and the vacuolar H+-adenosine triphosphatase (V-ATPase) complex
GO:0030177 positive regulation of Wnt signaling pathway	IMP PMID:20093472 Requirement of prorenin receptor and vacuolar H+-ATPase-medi...	KEEP AS NON CORE	Summary: PMID:20093472 demonstrates V-ATPase requirement for Wnt signaling. V-ATPase-mediated acidification is required for Wnt signal transduction. 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. Supporting Evidence: PMID:20093472 PRR and V-ATPase were required to mediate Wnt signaling PMID:33065002 V-ATPases have also been shown to directly associate with and regulate signaling complexes in the Notch, Wnt, and mTOR pathways
GO:0070062 extracellular exosome	HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos...	KEEP AS NON CORE	Summary: PMID:19056867 is a proteomics study of urinary exosomes that identified ATP6V0C. 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. Supporting Evidence: PMID:19056867 used LC-MS/MS to profile the proteome of human urinary exosomes
GO:0005765 lysosomal membrane	HDA PMID:17897319 Integral and associated lysosomal membrane proteins.	ACCEPT	Summary: PMID:17897319 is a proteomics study of lysosomal membrane proteins that identified V-ATPase subunits including ATP6V0C. Reason: Direct proteomics identification in lysosomal membrane fractions. Consistent with the core function of V-ATPase in lysosomal acidification. Supporting Evidence: PMID:17897319 These included 17 polypeptides comprising or associated with the vacuolar adenosine triphosphatase
GO:0031625 ubiquitin protein ligase binding	IPI PMID:18298843 A novel brain-enriched E3 ubiquitin ligase RNF182 is up regu...	ACCEPT	Summary: PMID:18298843 demonstrates interaction between ATP6V0C and RNF182, an E3 ubiquitin ligase that targets ATP6V0C for degradation. 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. Supporting Evidence: UniProt:P27449 Interacts with RNF182; this interaction leads to ubiquitination and degradation via the proteasome pathway PMID:18298843 A novel brain-enriched E3 ubiquitin ligase RNF182 is up regulated in the brains of Alzheimer's patients and targets ATP6V0C for degradation.
GO:0030670 phagocytic vesicle membrane	TAS Reactome:R-HSA-1222516	ACCEPT	Summary: Reactome pathway for phagosomal pH reduction. V-ATPase acidifies phagosomes for microbial killing. Reason: V-ATPases are recruited to phagosomes to acidify the lumen, which is critical for antimicrobial defense. This is an important immune cell function. Supporting Evidence: UniProt:P27449 Reactome; R-HSA-1222556; ROS and RNS production in phagocytes
GO:0010008 endosome membrane	TAS Reactome:R-HSA-5252133	ACCEPT	Summary: Reactome pathway for ATP6AP1 binding to V-ATPase. ATP6AP1 is an accessory subunit that helps assemble V-ATPase on endosomal membranes. Reason: V-ATPases localize to endosomal membranes for endosome acidification, which is essential for receptor-ligand dissociation and cargo sorting. Supporting Evidence: PMID:33065002 We define ATP6AP1 as a structural hub for Vo complex assembly because it connects to multiple Vo subunits
GO:0010008 endosome membrane	TAS Reactome:R-HSA-74723	ACCEPT	Summary: Reactome pathway for endosome acidification. Reason: Core V-ATPase function in endosome acidification. Supporting Evidence: PMID:33065002 essential in establishing and maintaining the pH homeostasis of endosomes and lysosomes
GO:0010008 endosome membrane	TAS Reactome:R-HSA-917841	ACCEPT	Summary: Reactome pathway for acidification of transferrin:transferrin receptor containing endosome. Reason: V-ATPase acidifies endosomes during iron uptake via transferrin pathway. Supporting Evidence: UniProt:P27449 Reactome; R-HSA-917977; Transferrin endocytosis and recycling
GO:0046933 proton-transporting ATP synthase activity, rotational mechanism	TAS PMID:1709739 CpG island in the region of an autosomal dominant polycystic...	REMOVE	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. 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. Supporting Evidence: PMID:33065002 Vesicular- or vacuolar-type adenosine triphosphatases (V-ATPases) are ATP-driven proton pumps PMID:32001091 V-ATPases are membrane-embedded protein complexes that function as ATP hydrolysis-driven proton pumps PMID:1709739 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.
GO:0046961 proton-transporting ATPase activity, rotational mechanism	TAS PMID:1709739 CpG island in the region of an autosomal dominant polycystic...	ACCEPT	Summary: PMID:1709739 describes ATP6V0C as part of the proton-transporting V-ATPase with rotational mechanism. 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. Supporting Evidence: PMID:1709739 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 PMID:33065002 ATP hydrolysis by the cytoplasmic V 1 ATPase drives the rotation of the membrane embedded, ring-shaped V o proton pump
GO:0016020 membrane	TAS PMID:1709739 CpG island in the region of an autosomal dominant polycystic...	ACCEPT	Summary: PMID:1709739 describes ATP6V0C as having four transmembrane domains, establishing membrane localization. Reason: Core localization annotation based on original cloning and characterization paper. Supporting Evidence: PMID:1709739 a 155-amino acid peptide having four putative transmembrane domains
GO:1902600 proton transmembrane transport	TAS PMID:1709739 CpG island in the region of an autosomal dominant polycystic...	ACCEPT	Summary: PMID:1709739 identifies ATP6V0C as a component of the proton channel of V-ATPase. Reason: Core biological process annotation. This is the primary function of ATP6V0C. Supporting Evidence: PMID:1709739 believed to be part of the proton channel of the vacuolar H(+)-ATPase

Gene Description

Existing Annotations Review

Core Functions

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.

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.

References

Deep Research

Cyberian

Falcon

OpenAI

Perplexity

📚 Additional Documentation

Notes

Pn Notes

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