ATP6V1C2 encodes the C2 subunit of the V1 peripheral domain of the vacuolar-type H+-ATPase (V-ATPase), one of two human paralogs of subunit C (the other being ATP6V1C1). The V-ATPase is a multisubunit rotary proton pump in which a peripheral V1 complex hydrolyzes ATP to drive proton translocation through the membrane-embedded V0 complex, acidifying intracellular compartments (endosomes, lysosomes, Golgi, secretory vesicles) and, in some specialized cells, the extracellular space. Subunit C is present in a single copy per V1 complex and sits at the interface between the catalytic V1 head and the peripheral stator stalk, where it is required for assembly of the catalytic V1 sector. Subunit C is a key regulator of reversible V1-V0 assembly and disassembly: it dissociates from both V1 and V0 when the holoenzyme disassembles and re-binds during reassembly, making it a regulatory hub for controlling V-ATPase activity. ATP6V1C2 is a tissue-restricted isoform, originally reported as kidney- and placenta-enriched and broadly expressed in lung/kidney epithelia, in contrast to the ubiquitously expressed ATP6V1C1. It does not itself hydrolyze ATP or translocate protons but participates in the rotary catalytic mechanism as a structural and regulatory component of the V1 domain.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0046961 proton-transporting ATPase activity, rotational mechanism | IBA GO_REF:0000033 | ACCEPT | Summary: Proton-transporting ATPase activity via the rotational mechanism is the core molecular function of the V-ATPase to which subunit C2 contributes as a single-copy component of the V1 catalytic sector. The IBA phylogenetic inference is consistent with the established function of the C-subunit family. Reason: Core molecular function of the V-ATPase; subunit C is required for assembly and function of the catalytic V1 sector and participates in the rotary catalytic mechanism as part of V1. Supporting Evidence: file:human/ATP6V1C2/ATP6V1C2-uniprot.txt Subunit C is necessary for the assembly of the catalytic sector of the enzyme and is likely to have a specific function in its catalytic activity |
| GO:0015078 proton transmembrane transporter activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: Proton transmembrane transporter activity is a broader transporter term transferred by InterPro domain mapping. The V-ATPase translocates protons, but the C subunit itself is not the proton-conducting transporter, and this term is less specific than GO:0046961. Reason: Broad InterPro IEA transfer; subunit C is a regulatory/structural V1 subunit and is not itself the proton transporter. The more specific rotational-mechanism term (GO:0046961) is preferred for representing the complex's function. Supporting Evidence: file:human/ATP6V1C2/ATP6V1C2-uniprot.txt a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons |
| GO:0033180 proton-transporting V-type ATPase, V1 domain | IEA GO_REF:0000002 | ACCEPT | Summary: ATP6V1C2 is a subunit of the V1 domain by definition; subunit C is present in a single copy per V1 complex. The InterPro IEA membership term is correct. Reason: Definitionally correct; subunit C2 is a component of the V1 domain as established for the C-subunit family. Supporting Evidence: file:human/ATP6V1C2/ATP6V1C2-uniprot.txt The V1 complex consists of three catalytic AB heterodimers that form a heterohexamer, three peripheral stalks each consisting of EG heterodimers, one central rotor including subunits D and F, and the regulatory subunits C and H |
| GO:0046961 proton-transporting ATPase activity, rotational mechanism | IEA GO_REF:0000120 | ACCEPT | Summary: Duplicate of the IBA annotation for the same molecular function, here from a combined automated IEA pipeline. The function is correct for the V-ATPase to which C2 contributes. Reason: Core molecular function of the V-ATPase; consistent with the IBA annotation (GO_REF:0000033) for the identical term GO:0046961. Supporting Evidence: file:human/ATP6V1C2/ATP6V1C2-uniprot.txt Subunit C is necessary for the assembly of the catalytic sector of the enzyme and is likely to have a specific function in its catalytic activity |
| GO:1902600 proton transmembrane transport | IEA GO_REF:0000002 | ACCEPT | Summary: Proton transmembrane transport is the core biological process of the V-ATPase. Subunit C2 is required for V1 assembly and thus contributes to proton transport; the InterPro IEA annotation is consistent with the established function. Reason: Core biological process of the V-ATPase; subunit C is required for assembly of the catalytic V1 sector and therefore for proton transport by the holoenzyme. Supporting Evidence: file:human/ATP6V1C2/ATP6V1C2-uniprot.txt V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments |
| GO:0042802 identical protein binding | IPI PMID:21356312 Expression, purification and characterization of isoforms of... | MARK AS OVER ANNOTATED | Summary: The cited paper expressed and purified human V-ATPase peripheral stalk subunit isoforms, including C2, using an E. coli cell-free system to study isoform-specific interactions. The abstract does not demonstrate C2 self-association (homodimerization); moreover, subunit C is present in a single copy per V1 complex, so an identical-protein-binding (self) interaction is not part of its known biology. This is an uninformative binding term. Reason: The supporting publication characterizes expression and purification of isoforms but does not establish C2 self-association; 'identical protein binding' is uninformative and inconsistent with the single-copy stoichiometry of subunit C in V1. Supporting Evidence: PMID:21356312 we expressed and purified the isoforms of human V-ATPase peripheral stalk subunits using Escherichia coli cell-free protein synthesis system: E1, E2, G1, G2, G3, C1, C2, H and N-terminal soluble part of a1 and a2 isoforms |
| GO:0016241 regulation of macroautophagy | NAS PMID:22982048 Lipofuscin is formed independently of macroautophagy and lys... | MARK AS OVER ANNOTATED | Summary: The cited paper studies lipofuscin formation and lysosomal/autophagy activity in senescent fibroblasts and does not study ATP6V1C2 directly. Any link to regulation of macroautophagy is indirect, via the general requirement of V-ATPase-dependent lysosomal acidification for autophagic degradation. Reason: Regulation of macroautophagy is an indirect downstream consequence of lysosomal acidification; the NAS annotation rests on a paper that does not examine ATP6V1C2 and does not establish a direct or specific role for this subunit in autophagy regulation. Supporting Evidence: PMID:22982048 both the autophagosomes and the lysosomal system are not mandatory for the formation of lipofuscin |
| 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: This study showed that the prorenin receptor (ATP6AP2/PRR) acts as an adaptor between Wnt receptors and the V-ATPase, and that PRR and V-ATPase activity (acidification) are required for Wnt/beta-catenin signaling. The role reflects a general requirement for V-ATPase-mediated acidification rather than a subunit-specific function of ATP6V1C2. Reason: A genuine but pathway-level/downstream role inherited from the general requirement for V-ATPase acidification in Wnt signaling; not a core or C2-specific function. The work studied the V-ATPase complex and PRR, not ATP6V1C2 specifically. 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. Moreover, PRR and V-ATPase were required to mediate Wnt signaling |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | MARK AS OVER ANNOTATED | Summary: ATP6V1C2 was detected in a large-scale mass-spectrometry proteome of human urinary exosomes (1132 proteins identified). This high-throughput catalog hit likely reflects the V-ATPase residing on endolysosomal/multivesicular-body membranes that give rise to exosomes, rather than a primary exosomal function. Reason: HDA detection in a bulk urinary-exosome proteome is not evidence of a true exosomal residence or function for this V-ATPase subunit; such hits commonly reflect endolysosomal/MVB membrane content captured during exosome isolation. Supporting Evidence: PMID:19056867 we used LC-MS/MS to profile the proteome of human urinary exosomes. Overall, the analysis identified 1132 proteins unambiguously |
| GO:0005765 lysosomal membrane | HDA PMID:17897319 Integral and associated lysosomal membrane proteins. | ACCEPT | Summary: ATP6V1C2 was detected by proteomics in purified placental lysosomal membrane fractions, among 17 polypeptides comprising or associated with the vacuolar ATPase. This is consistent with assembled V-ATPase residing on the lysosomal membrane, where V1 subunits are peripherally associated. Reason: Lysosomal/endolysosomal membrane is the primary functional location of assembled V-ATPase in most cell types; proteomic detection in placental lysosomal membranes supports this localization for subunit C2. Supporting Evidence: PMID:17897319 In membranes purified from placental lysosomes, we identified 58 proteins, known to reside at least partially in the lysosomal membrane. These included 17 polypeptides comprising or associated with the vacuolar adenosine triphosphatase. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1222516 | KEEP AS NON CORE | Summary: Cytosol localization reflects the regulated disassembly of V1 from V0; free subunit C is released into the cytosol when the holoenzyme disassembles. This Reactome annotation (intraphagosomal pH lowering) places the V-ATPase machinery in the cytosol. Reason: Valid but non-core; cytosolic subunit C represents the disassembled/free V1 state rather than the primary functional membrane location. Supporting Evidence: Reactome:R-HSA-1222516 Intraphagosomal pH is lowered to 5 by V-ATPase |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5252133 | KEEP AS NON CORE | Summary: Duplicate cytosol annotation from a different Reactome reaction (ATP6AP1 binds V-ATPase). Same reasoning applies regarding the free cytosolic V1 pool. Reason: Valid; cytosolic subunit C reflects the V1-V0 disassembly state. Redundant Reactome TAS annotation. Supporting Evidence: Reactome:R-HSA-5252133 ATP6AP1 binds V-ATPase |
| GO:0005829 cytosol | TAS Reactome:R-HSA-74723 | KEEP AS NON CORE | Summary: Duplicate cytosol annotation from the Reactome endosome acidification reaction. Reason: Same as other cytosol TAS annotations; valid but non-core. Supporting Evidence: Reactome:R-HSA-74723 Endosome acidification |
| GO:0005829 cytosol | TAS Reactome:R-HSA-917841 | KEEP AS NON CORE | Summary: Duplicate cytosol annotation from the Reactome transferrin-endosome acidification reaction. Reason: Same as other cytosol TAS annotations; valid but non-core. Supporting Evidence: Reactome:R-HSA-917841 Acidification of Tf:TfR1 containing endosome |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9639286 | KEEP AS NON CORE | Summary: Duplicate cytosol annotation from a Reactome mTORC1 amino-acid-sensing reaction. Reason: Same as other cytosol TAS annotations; valid but non-core. Supporting Evidence: Reactome:R-HSA-9639286 RRAGC,D exchanges GTP for GDP |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9640167 | KEEP AS NON CORE | Summary: Duplicate cytosol annotation from a Reactome mTORC1 reaction (RRAGA,B GDP/GTP exchange). Reason: Same as other cytosol TAS annotations; valid but non-core. Supporting Evidence: Reactome:R-HSA-9640167 RRAGA,B exchanges GDP for GTP |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9640168 | KEEP AS NON CORE | Summary: Duplicate cytosol annotation from a Reactome v-ATPase:Ragulator:SLC38A9 dissociation reaction. Reason: Same as other cytosol TAS annotations; valid but non-core. Supporting Evidence: Reactome:R-HSA-9640168 v-ATPase:Ragulator:RRAGA,B:GTP:RRAGC,D:GDP:SLC38A9:Arginine dissociates yielding v-ATPase:Ragulator:RRAGA,B:GTP:RRAGC,D:GDP and SLC38A9:Arginine |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9640175 | KEEP AS NON CORE | Summary: Duplicate cytosol annotation from a Reactome v-ATPase:Ragulator:SLC38A9 binding reaction. Reason: Same as other cytosol TAS annotations; valid but non-core. Supporting Evidence: Reactome:R-HSA-9640175 v-ATPase:Ragulator:RagA,B:GDP:RagC,D:GDP binds SLC38A9:Arginine |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9640195 | KEEP AS NON CORE | Summary: Duplicate cytosol annotation from a Reactome mTORC1 reaction (RRAGA,B GTP hydrolysis). Reason: Same as other cytosol TAS annotations; valid but non-core. Supporting Evidence: Reactome:R-HSA-9640195 RRAGA,B hydrolyzes GTP |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9645598 | KEEP AS NON CORE | Summary: Duplicate cytosol annotation from a Reactome mTORC1 reaction (RRAGC,D GTP hydrolysis). Reason: Same as other cytosol TAS annotations; valid but non-core. Supporting Evidence: Reactome:R-HSA-9645598 RRAGC,D hydrolyzes GTP |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9645608 | KEEP AS NON CORE | Summary: Duplicate cytosol annotation from a Reactome v-ATPase:Ragulator binds mTORC1 reaction. Reason: Same as other cytosol TAS annotations; valid but non-core. Supporting Evidence: Reactome:R-HSA-9645608 v-ATPase:Ragulator:RRAGA,B:GTP:RRAGC,D:GDP binds mTORC1 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9646468 | KEEP AS NON CORE | Summary: Duplicate cytosol annotation from a Reactome mTORC1:RHEB reaction. Reason: Same as other cytosol TAS annotations; valid but non-core. Supporting Evidence: Reactome:R-HSA-9646468 mTORC1 binds RHEB:GTP |
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Download this section (compressed HTML)Q: Does ATP6V1C2 confer isoform-specific regulatory properties (e.g., different V1-V0 assembly/disassembly kinetics or signal responsiveness) relative to the ubiquitous ATP6V1C1, consistent with its restricted tissue expression?
Q: In which human tissues and cell types is ATP6V1C2 the predominant C subunit, and does it pair preferentially with particular a-subunit (ATP6V0A) variants in assembled V-ATPase complexes?
Q: Are there phenotypes or disease associations specific to ATP6V1C2 (e.g., in kidney acid-base handling) that distinguish it from ATP6V1C1?
Experiment: Reconstitute V-ATPase containing either C1 or C2 and measure assembly/disassembly kinetics and ATP-driven proton pumping in response to glucose deprivation or other signals, using blue native PAGE, fluorescent pH probes, and crosslinking mass spectrometry.
Hypothesis: ATP6V1C2 governs isoform-specific V1-V0 assembly/disassembly dynamics distinct from ATP6V1C1.
Type: BIOCHEMISTRY
Experiment: Generate ATP6V1C2 knockout in relevant epithelial cell models and assess lysosomal/compartment acidification, V-ATPase assembly, and whether ectopic ATP6V1C1 rescues the phenotype.
Hypothesis: ATP6V1C2 is the functionally predominant C subunit in specific kidney/lung epithelial cells and cannot be fully replaced by ATP6V1C1 there.
Type: CELL_BIOLOGY
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