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
|
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
The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
ATP6V1C2 (Gene ID: ATP6V1C2, UniProt: Q8NEY4) encodes the V-type proton ATPase subunit C2 in Homo sapiens, a specialized isoform belonging to the V-ATPase C subunit family (jobstschwan2020wholeexomesequencing pages 4-10). This gene has been correctly identified and matches the protein description from UniProt as a component of the vacuolar H+-ATPase (V-ATPase) complex. ATP6V1C2 is distinct from its paralog ATP6V1C1, with ATP6V1C2 showing predominantly kidney-specific expression while ATP6V1C1 is more widely distributed (jobstschwan2020wholeexomesequencing pages 4-10, a2023thepathophysiologyof pages 11-14).
ATP6V1C2 encodes a structural component of the cytosolic V1 domain of the V-ATPase, a large multisubunit enzyme complex responsible for ATP-dependent proton transport across cellular membranes (eaton2021theh+atpase(vatpase) pages 1-5, wang2020structuresofa pages 1-3). The V-ATPase is evolutionarily related to the mitochondrial F-type ATP synthase but functions exclusively as an ATP-driven proton pump rather than an ATP synthase (eaton2021theh+atpase(vatpase) pages 1-5).
The complete V-ATPase complex consists of two main sectors: the peripheral V1 domain (located in the cytosol) responsible for ATP hydrolysis, and the integral membrane V0 domain that forms the transmembrane proton pore (wang2020structuresofa pages 1-3, abbas2020structureofvatpase pages 2-4). Recent cryo-electron microscopy structures of mammalian V-ATPases at near-atomic resolution (2.9-3.9 Å) have revealed that the V1 complex comprises subunits A3, B3, C, D, E3, F, G3, and H, while the V0 complex contains subunits a, c-ring, d, e, and accessory proteins (wang2020structuresofa pages 1-3, abbas2020structureofvatpase pages 2-4, wang2020structuresofa pages 3-5).
Within the V1 domain, subunit C (encoded by ATP6V1C2 in kidney tissue) is part of the bottom collar region that forms critical connections between the catalytic A3B3 head and the membrane-embedded V0 sector (wang2020structuresofa pages 3-5). The C subunit, along with subunit H and the N-terminal domain of the a subunit, creates a structural bridge that couples ATP hydrolysis in the V1 domain to proton translocation through the V0 domain (eaton2021theh+atpase(vatpase) pages 5-9, abbas2020structureofvatpase pages 2-4).
The V-ATPase operates as a rotary molecular motor. ATP hydrolysis in the A3B3 hexamer drives rotation of a central stalk (composed of D and F subunits) and the associated c-ring in the membrane (wang2020structuresofa pages 1-3, wang2020structuresofa pages 3-5). This rotation causes sequential protonation and deprotonation of conserved glutamic acid residues in the c-ring subunits, enabling proton transport across the membrane with an ATP:H+ stoichiometry of 3:10 (abbas2020structureofvatpase pages 2-4). The C subunit, as part of the peripheral stator apparatus, undergoes conformational changes during the catalytic cycle and is essential for maintaining the coupling between ATP hydrolysis and proton pumping (jobstschwan2020wholeexomesequencing pages 4-10, eaton2021theh+atpase(vatpase) pages 5-9).
ATP6V1C2 itself does not directly bind or transport substrates. However, as an integral component of the V-ATPase complex, it supports the enzyme's function of transporting protons (H+) across membranes, utilizing ATP as the energy source (eaton2021theh+atpase(vatpase) pages 1-5, abbas2020structureofvatpase pages 1-2). In the kidney, this proton transport activity is essential for urinary acidification (a2023thepathophysiologyof pages 5-8).
ATP6V1C2 protein localizes as part of V-ATPase complexes in specialized kidney cells. The V-ATPase holoenzyme (molecular weight ~830,000 Da) is found on both the apical plasma membrane and intracellular vesicles of type A intercalated cells in the renal collecting duct (a2023thepathophysiologyof pages 5-8, eaton2021theh+atpase(vatpase) pages 5-9). Early electron microscopy studies identified these V-ATPase molecules as "portasomes" - large electron-dense structures visible on proton-secreting membranes (eaton2021theh+atpase(vatpase) pages 5-9). The enzyme can form hexagonally arranged paracrystalline arrays on membranes at densities exceeding 10,000 molecules per square micron (eaton2021theh+atpase(vatpase) pages 5-9).
The presence of V-ATPase on both apical membranes and cytoplasmic vesicles is consistent with a recycling mechanism where V-ATPase-containing vesicles can fuse with the apical membrane to increase proton-secreting capacity in response to acidification demands (eaton2021theh+atpase(vatpase) pages 5-9).
ATP6V1C2 exhibits highly restricted tissue expression, being predominantly expressed in the kidney, particularly in intercalated cells of the renal collecting duct (jobstschwan2020wholeexomesequencing pages 4-10, a2023thepathophysiologyof pages 11-14). Single-cell RNA sequencing data from mouse kidney demonstrates that ATP6V1C2 is highly enriched in intercalated cells compared to other renal cell types (jobstschwan2020wholeexomesequencing pages 4-10, a2023thepathophysiologyof pages 11-14).
Type A (acid-secretory) intercalated cells are the primary site of ATP6V1C2 expression. These specialized epithelial cells in the collecting duct system are characterized by high expression of V-ATPase subunits, carbonic anhydrase II (CAII), and the anion exchanger AE1 (SLC4A1) (a2023thepathophysiologyof pages 5-8). Transcriptomic profiling across multiple organs has identified intercalated cells as part of a conserved "ionocyte family" of pH-regulating cells that express FOXI1 (the master transcription factor), along with ATP6V1B1, ATP6V1C2, and KRT7 (casellas2023transcriptomicprofilecomparison pages 1-2).
While ATP6V1C2 shows kidney-predominant expression, its paralog ATP6V1C1 is more ubiquitously expressed across tissues (jobstschwan2020wholeexomesequencing pages 4-10). This tissue-specific isoform expression allows for specialized regulation of V-ATPase function in different cellular contexts.
The primary biological role of ATP6V1C2 is in maintaining systemic acid-base balance through renal acid excretion (a2023thepathophysiologyof pages 5-8, eaton2021theh+atpase(vatpase) pages 1-5). In type A intercalated cells, cytosolic carbonic anhydrase II catalyzes the conversion of CO2 and H2O into H+ and HCO3-. The H+ is secreted into the tubular lumen via apically located V-ATPases (containing ATP6V1C2), while HCO3- is transported into the blood by basolaterally located AE1 (a2023thepathophysiologyof pages 5-8).
This process accounts for approximately 30 mEq of acid excretion per day, completing the removal and buffering of non-volatile acids produced by normal metabolism (a2023thepathophysiologyof pages 5-8). The kidney must excrete approximately 1 mEq of acid per kg body weight per day (~70 mEq/day for a 70 kg person) to maintain acid-base homeostasis (a2023thepathophysiologyof pages 5-8).
Intercalated cells show remarkable plasticity in response to acid-base challenges. During chronic acidosis or acid loading, the relative number of type A intercalated cells increases, accompanied by upregulation of V-ATPase activity (a2023thepathophysiologyof pages 5-8). This adaptive response requires coordinated regulation by transcription factors including FOXI1, TFCP2L1, and NOTCH signaling pathways (a2023thepathophysiologyof pages 5-8).
V-ATPases serve as scaffolds for nutrient-sensing complexes. They physically interact with mTORC1 (mechanistic target of rapamycin complex 1) and AMPK (AMP-activated protein kinase) on lysosomal membranes, linking cellular pH homeostasis to metabolic regulation (eaton2021theh+atpase(vatpase) pages 1-5). While this signaling function has been best characterized for ubiquitously expressed V-ATPase isoforms, ATP6V1C2-containing complexes in kidney cells may participate in similar regulatory mechanisms.
The most compelling experimental evidence for ATP6V1C2 function comes from yeast complementation studies of a patient-derived mutation (jobstschwan2020wholeexomesequencing pages 10-15, jobstschwan2020wholeexomesequencing pages 4-10). Researchers modeled the human ATP6V1C2 p.Ile168Thr mutation in the yeast ortholog VMA5 (encoding the yeast V-ATPase C subunit) by introducing the corresponding p.Ile178Thr mutation into the genomic copy of VMA5.
Growth Assays: Three independent mutant yeast strains carrying the vma5 p.Ile178Thr mutation failed to grow on medium buffered to pH 7.5 with 60 mM CaCl2, conditions that are lethal to yeast lacking functional V-ATPase (jobstschwan2020wholeexomesequencing pages 4-10). This phenotype indicates a significant loss of V-ATPase function.
Biochemical Activity: Vacuolar vesicles isolated from mutant strains showed markedly reduced concanamycin A-sensitive V-ATPase activity compared to wild-type controls (jobstschwan2020wholeexomesequencing pages 10-15). This direct measurement of enzyme activity confirms that the mutation impairs proton-pumping function.
Protein Expression and Stability: Immunoblot analysis revealed that the mutant Vma5 protein was barely detectable in whole cell lysates, suggesting protein instability (jobstschwan2020wholeexomesequencing pages 10-15). However, low levels of mutant Vma5 could be detected in isolated vacuolar vesicles, indicating that some mutant protein can assemble into V-ATPase complexes at the vacuole. Associated V1 subunits A and B also showed reduced levels in mutant strains, while V0 subunit Vph1 (ortholog of mammalian a subunit) remained at normal levels (jobstschwan2020wholeexomesequencing pages 10-15). This pattern suggests that the mutation specifically impairs V1 complex assembly or stability without affecting V0 trafficking to the vacuole.
A homozygous missense variant c.503T>C (p.Ile168Thr) in ATP6V1C2 was identified in a patient from a consanguineous family presenting with hypokalemic metabolic acidosis, alkaline urine, and early kidney failure (jobstschwan2020wholeexomesequencing pages 4-10, a2023thepathophysiologyof pages 11-14). The clinical phenotype was consistent with distal renal tubular acidosis (dRTA), a disorder characterized by failure to acidify urine below pH 5.5 despite metabolic acidosis (a2023thepathophysiologyof pages 1-5, chang2025acasereport pages 1-2).
However, it is important to note that as of current literature reviews, this remains the only identified patient with ATP6V1C2 variants causing dRTA (a2023thepathophysiologyof pages 11-14). The 2023 comprehensive review on dRTA pathophysiology cautions that stronger supporting evidence is needed, as biallelic protein-changing variants in ATP6V1C2 are relatively common in the general population, and the identified variant is more common than would be expected for this rare disorder (a2023thepathophysiologyof pages 11-14). Additional patients with causative variants in ATP6V1C2 must be identified to definitively confirm its role as a dRTA gene (a2023thepathophysiologyof pages 11-14).
The disease-associated residue Ile168 in human ATP6V1C2 (Ile178 in yeast Vma5) shows evolutionary conservation as either isoleucine or the biochemically similar leucine from yeast to humans (jobstschwan2020wholeexomesequencing pages 4-10). This conservation across ~1 billion years of evolution strongly suggests functional importance.
Structural modeling places Ile168 within a hydrophobic knuckle region that slides against another hydrophobic surface of the C subunit during the ATP hydrolysis cycle (jobstschwan2020wholeexomesequencing pages 4-10). The V-ATPase cycles through three main rotational states, and the C subunit undergoes conformational changes during these transitions (wang2020structuresofa pages 1-3, wang2020structuresofa pages 3-5).
Protein stability prediction using CUPSAT software suggested that the Ile168Thr substitution (replacing a non-polar hydrophobic residue with a polar one) would stabilize the protein in state 1 but destabilize states 2 and 3 (jobstschwan2020wholeexomesequencing pages 4-10). This differential stability could prevent the dynamic conformational changes required for normal V-ATPase catalytic function, effectively locking the enzyme in a less active configuration.
Recent high-resolution structures reveal that in human V-ATPase, subunit C1 (the isoform found in ubiquitously expressed V-ATPases) interacts with multiple components including the foot domain of peripheral stalk PS-2, the head domain of subunit H, and the N-terminal domain of the a subunit (wang2020structuresofa pages 3-5). While these structures used C1 rather than the kidney-specific C2 isoform, the high sequence similarity suggests ATP6V1C2 occupies an analogous structural position.
ATP6V1C2 is a candidate gene for autosomal recessive distal renal tubular acidosis (dRTA) (jobstschwan2020wholeexomesequencing pages 4-10, a2023thepathophysiologyof pages 11-14, a2023thepathophysiologyof pages 1-5). dRTA is characterized by:
The established genetic causes of dRTA include mutations in ATP6V0A4, ATP6V1B1 (both V-ATPase subunits), SLC4A1 (AE1), FOXI1 (transcription factor), and WDR72 (involved in V-ATPase trafficking) (a2023thepathophysiologyof pages 1-5, a2023thepathophysiologyof pages 5-8, a2023thepathophysiologyof pages 11-14). These known genes account for approximately 58-70% of familial dRTA cases (jobstschwan2020wholeexomesequencing pages 4-10), indicating that additional genes remain to be discovered.
ATP6V1C2 mutations represent a potential explanation for some of the remaining 20-25% of dRTA cases without identified genetic causes (a2023thepathophysiologyof pages 11-14). However, genetic confirmation through identification of additional affected families is needed before ATP6V1C2 can be definitively established as a dRTA disease gene.
| Annotation category | ATP6V1C2 functional annotation | Key evidence/citation |
|---|---|---|
| Gene symbol and protein name | ATP6V1C2 encodes V-type proton ATPase subunit C2 in Homo sapiens; it is a C-subunit isoform of the cytosolic V1 sector of the vacuolar H+-ATPase (V-ATPase). Literature distinguishes it from the paralog ATP6V1C1, with ATP6V1C2 described as predominantly kidney-enriched. | (jobstschwan2020wholeexomesequencing pages 4-10, a2023thepathophysiologyof pages 11-14) |
| Primary function and molecular mechanism | ATP6V1C2 is inferred to act as a structural/regulatory V1 subunit of V-ATPase rather than as a catalytic ATP-hydrolyzing site or membrane proton pore. In mammalian V-ATPase structures, the homologous C subunit is part of the bottom collar/peripheral stalk region that helps connect the catalytic A3B3 head to the membrane-embedded V0 sector, supporting coupling of ATP hydrolysis in V1 to proton translocation in V0. Jobst-Schwan et al. further place ATP6V1C2 in the kidney V-ATPase required for acid secretion. | (wang2020structuresofa pages 3-5, wang2020structuresofa pages 1-3, jobstschwan2020wholeexomesequencing pages 4-10) |
| Substrate specificity | ATP6V1C2 does not itself form the proton pore, but it functions within the V-ATPase complex whose transported substrate is H+ (protons). V-ATPase uses ATP hydrolysis in V1 to drive proton movement through V0 across organelle or plasma membranes. In kidney intercalated cells, this proton transport acidifies urine. | (eaton2021theh+atpase(vatpase) pages 1-5, abbas2020structureofvatpase pages 1-2, a2023thepathophysiologyof pages 5-8) |
| Subcellular localization | ATP6V1C2 is expected in the cytosolic V1 domain of V-ATPase complexes that localize in kidney intercalated cells to the apical plasma membrane and intracellular acidic vesicles associated with proton secretion/recycling. The broader V-ATPase in intercalated cells has been visualized on apical membranes and vesicles, consistent with a recycling proton-pump system. | (a2023thepathophysiologyof pages 5-8, eaton2021theh+atpase(vatpase) pages 5-9) |
| Tissue / cell-type expression | Evidence consistently supports kidney-predominant expression, especially in renal intercalated cells of the collecting duct. Jobst-Schwan et al. report ATP6V1C2 is predominantly expressed in kidney and highly expressed in renal intercalated cells; the Nature Reviews Nephrology review states single-cell transcriptomic data show it is highly enriched in intercalated cells. Cross-organ ionocyte analyses also identify ATP6V1C2 among ionocyte/intercalated-cell markers linked to pH regulation. | (jobstschwan2020wholeexomesequencing pages 4-10, a2023thepathophysiologyof pages 11-14, casellas2023transcriptomicprofilecomparison pages 1-2) |
| Biological pathways involved | Main pathway/process: renal acid-base homeostasis via V-ATPase-dependent proton secretion in type A intercalated cells of the collecting duct. More broadly, V-ATPases regulate intracellular/organelle acidification, membrane trafficking, signaling, and nutrient sensing, but ATP6V1C2-specific evidence is strongest for urinary acidification and distal nephron proton transport. | (a2023thepathophysiologyof pages 5-8, eaton2021theh+atpase(vatpase) pages 1-5, wang2020structuresofa pages 1-3) |
| Associated diseases | ATP6V1C2 is a candidate disease gene for recessive distal renal tubular acidosis (dRTA). A homozygous missense variant was reported in a patient with hypokalemic metabolic acidosis and alkaline urine, and the 2023 review notes that confirmation remains limited because only one patient had been identified and stronger human genetic evidence is still needed. Thus, current interpretation is plausible but not fully definitive disease association. | (jobstschwan2020wholeexomesequencing pages 4-10, a2023thepathophysiologyof pages 11-14, a2023thepathophysiologyof pages 1-5) |
| Experimental evidence from functional studies | The strongest direct evidence comes from yeast complementation/modeling of the human patient variant p.Ile168Thr using the orthologous yeast VMA5 p.Ile178Thr mutation. Mutant yeast failed to grow under alkaline/high-Ca2+ stress, indicating loss of V-ATPase function. Vacuolar vesicles from mutant strains showed markedly reduced concanamycin A-sensitive V-ATPase activity. Immunoblots showed reduced levels of mutant Vma5 and reduced associated V1 subunits A and B, supporting impaired protein stability/assembly and insufficient pump function. | (jobstschwan2020wholeexomesequencing pages 10-15, jobstschwan2020wholeexomesequencing pages 4-10) |
| Structural / evolutionary conservation | The disease-implicated residue Ile168 is reported as evolutionarily conserved as Ile/Leu from yeast to human. It lies in a hydrophobic knuckle that slides against another hydrophobic surface during the ATPase catalytic cycle, suggesting a role in required conformational dynamics. Structural prediction indicated the Ile168Thr change may stabilize one conformational state while destabilizing others, potentially blocking dynamic transitions needed for active V-ATPase function. | (jobstschwan2020wholeexomesequencing pages 4-10, jobstschwan2020wholeexomesequencing pages 10-15) |
Table: This table summarizes the current functional annotation of human ATP6V1C2, integrating gene identity, molecular role, localization, expression, pathways, disease links, and experimental evidence. It is useful as a compact evidence-based reference for interpreting ATP6V1C2 in renal acidification and distal renal tubular acidosis.
ATP6V1C2 encodes a kidney-specific V-ATPase subunit essential for urinary acidification. The protein functions as a structural component of the V1 cytosolic domain, helping to couple ATP hydrolysis to proton transport. It is predominantly expressed in type A intercalated cells of the renal collecting duct, where it participates in the critical physiological process of renal acid excretion and systemic pH homeostasis.
Loss-of-function mutations impair V-ATPase activity and cause a clinical phenotype consistent with distal renal tubular acidosis, though additional human genetic evidence is needed for definitive confirmation. Experimental yeast studies, structural modeling, and evolutionary conservation all support ATP6V1C2's essential role in maintaining proper V-ATPase function for renal acid-base regulation.
References:
- Jobst-Schwan et al. (2020). Whole exome sequencing identified ATP6V1C2 as a novel candidate gene for recessive distal renal tubular acidosis. Kidney International, 97(3):567-579. doi:10.1016/j.kint.2019.09.026
- Wagner et al. (2023). The pathophysiology of distal renal tubular acidosis. Nature Reviews Nephrology, 19(6):384-400. doi:10.1038/s41581-023-00699-9
- Abbas et al. (2020). Structure of V-ATPase from the mammalian brain. Science, 367(6483):1240-1246. doi:10.1126/science.aaz2924
- Wang et al. (2020). Structures of a Complete Human V-ATPase Reveal Mechanisms of Its Assembly. Molecular Cell, 80(3):501-511. doi:10.1016/j.molcel.2020.09.029
- Eaton et al. (2021). The H+-ATPase (V-ATPase): from proton pump to signaling complex in health and disease. American Journal of Physiology-Cell Physiology, 320(3):C392-C414. doi:10.1152/ajpcell.00442.2020
- Casellas et al. (2023). Transcriptomic profile comparison reveals conservation of ionocytes across multiple organs. Scientific Reports, 13(1):3516. doi:10.1038/s41598-023-30603-1
References
(jobstschwan2020wholeexomesequencing pages 4-10): Tilman Jobst-Schwan, Verena Klämbt, Maureen Tarsio, John F. Heneghan, Amar J. Majmundar, Shirlee Shril, Florian Buerger, Isabel Ottlewski, Boris E. Shmukler, Rezan Topaloglu, Seema Hashmi, Farkhanda Hafeez, Francesco Emma, Marcella Greco, Guido F. Laube, Hanan M. Fathy, Martin Pohl, Jutta Gellermann, Danko Milosevic, Michelle A. Baum, Shrikant Mane, Richard P. Lifton, Patricia M. Kane, Seth L. Alper, and Friedhelm Hildebrandt. Whole exome sequencing identified atp6v1c2 as a novel candidate gene for recessive distal renal tubular acidosis. Kidney International, 97:567-579, Mar 2020. URL: https://doi.org/10.1016/j.kint.2019.09.026, doi:10.1016/j.kint.2019.09.026. This article has 67 citations and is from a highest quality peer-reviewed journal.
(a2023thepathophysiologyof pages 11-14): Carsten A Wagner, Robert Unwin, Sergio C Lopez-Garcia, Robert Kleta, Detlef Bockenhauer, and Stephen Walsh. The pathophysiology of distal renal tubular acidosis. Nature Reviews Nephrology, 19:384-400, Apr 2023. URL: https://doi.org/10.1038/s41581-023-00699-9, doi:10.1038/s41581-023-00699-9. This article has 83 citations and is from a domain leading peer-reviewed journal.
(eaton2021theh+atpase(vatpase) pages 1-5): Amity F. Eaton, Maria Merkulova, and Dennis Brown. The h+-atpase (v-atpase): from proton pump to signaling complex in health and disease. Mar 2021. URL: https://doi.org/10.1152/ajpcell.00442.2020, doi:10.1152/ajpcell.00442.2020. This article has 188 citations.
(wang2020structuresofa pages 1-3): Longfei Wang, Di Wu, Carol V. Robinson, Hao Wu, and Tian-Min Fu. Structures of a complete human v-atpase reveal mechanisms of its assembly. Molecular Cell, 80:501-511.e3, Nov 2020. URL: https://doi.org/10.1016/j.molcel.2020.09.029, doi:10.1016/j.molcel.2020.09.029. This article has 184 citations and is from a highest quality peer-reviewed journal.
(abbas2020structureofvatpase pages 2-4): Yazan M. Abbas, Di Wu, Stephanie A. Bueler, Carol V. Robinson, and John L. Rubinstein. Structure of v-atpase from the mammalian brain. Mar 2020. URL: https://doi.org/10.1126/science.aaz2924, doi:10.1126/science.aaz2924. This article has 278 citations and is from a highest quality peer-reviewed journal.
(wang2020structuresofa pages 3-5): Longfei Wang, Di Wu, Carol V. Robinson, Hao Wu, and Tian-Min Fu. Structures of a complete human v-atpase reveal mechanisms of its assembly. Molecular Cell, 80:501-511.e3, Nov 2020. URL: https://doi.org/10.1016/j.molcel.2020.09.029, doi:10.1016/j.molcel.2020.09.029. This article has 184 citations and is from a highest quality peer-reviewed journal.
(eaton2021theh+atpase(vatpase) pages 5-9): Amity F. Eaton, Maria Merkulova, and Dennis Brown. The h+-atpase (v-atpase): from proton pump to signaling complex in health and disease. Mar 2021. URL: https://doi.org/10.1152/ajpcell.00442.2020, doi:10.1152/ajpcell.00442.2020. This article has 188 citations.
(abbas2020structureofvatpase pages 1-2): Yazan M. Abbas, Di Wu, Stephanie A. Bueler, Carol V. Robinson, and John L. Rubinstein. Structure of v-atpase from the mammalian brain. Mar 2020. URL: https://doi.org/10.1126/science.aaz2924, doi:10.1126/science.aaz2924. This article has 278 citations and is from a highest quality peer-reviewed journal.
(a2023thepathophysiologyof pages 5-8): Carsten A Wagner, Robert Unwin, Sergio C Lopez-Garcia, Robert Kleta, Detlef Bockenhauer, and Stephen Walsh. The pathophysiology of distal renal tubular acidosis. Nature Reviews Nephrology, 19:384-400, Apr 2023. URL: https://doi.org/10.1038/s41581-023-00699-9, doi:10.1038/s41581-023-00699-9. This article has 83 citations and is from a domain leading peer-reviewed journal.
(casellas2023transcriptomicprofilecomparison pages 1-2): Carla Pou Casellas, Cayetano Pleguezuelos-Manzano, Maarten B. Rookmaaker, Marianne C. Verhaar, and Hans Clevers. Transcriptomic profile comparison reveals conservation of ionocytes across multiple organs. Scientific Reports, Mar 2023. URL: https://doi.org/10.1038/s41598-023-30603-1, doi:10.1038/s41598-023-30603-1. This article has 24 citations and is from a peer-reviewed journal.
(jobstschwan2020wholeexomesequencing pages 10-15): Tilman Jobst-Schwan, Verena Klämbt, Maureen Tarsio, John F. Heneghan, Amar J. Majmundar, Shirlee Shril, Florian Buerger, Isabel Ottlewski, Boris E. Shmukler, Rezan Topaloglu, Seema Hashmi, Farkhanda Hafeez, Francesco Emma, Marcella Greco, Guido F. Laube, Hanan M. Fathy, Martin Pohl, Jutta Gellermann, Danko Milosevic, Michelle A. Baum, Shrikant Mane, Richard P. Lifton, Patricia M. Kane, Seth L. Alper, and Friedhelm Hildebrandt. Whole exome sequencing identified atp6v1c2 as a novel candidate gene for recessive distal renal tubular acidosis. Kidney International, 97:567-579, Mar 2020. URL: https://doi.org/10.1016/j.kint.2019.09.026, doi:10.1016/j.kint.2019.09.026. This article has 67 citations and is from a highest quality peer-reviewed journal.
(a2023thepathophysiologyof pages 1-5): Carsten A Wagner, Robert Unwin, Sergio C Lopez-Garcia, Robert Kleta, Detlef Bockenhauer, and Stephen Walsh. The pathophysiology of distal renal tubular acidosis. Nature Reviews Nephrology, 19:384-400, Apr 2023. URL: https://doi.org/10.1038/s41581-023-00699-9, doi:10.1038/s41581-023-00699-9. This article has 83 citations and is from a domain leading peer-reviewed journal.
(chang2025acasereport pages 1-2): Chenyang Chang, Hao Chen, Min Wang, Jingshan Chen, Yaomin Zou, Shaowen Hu, Kaiyuan Luo, Xingyu Rao, and Huifang Zhu. A case report and literature review of primary distal renal tubular acidosis resulting from a mutation in atp6v0a4. Frontiers in Pediatrics, Nov 2025. URL: https://doi.org/10.3389/fped.2025.1685798, doi:10.3389/fped.2025.1685798. This article has 0 citations.
UniProt: Q8NEY4 (VATC2_HUMAN), 427 AA. Gene HGNC:18264, chromosome 2.
Falcon deep research has now completed (file:human/ATP6V1C2/ATP6V1C2-deep-research-falcon.md,
18 citations). It corroborates the C2 (tissue-restricted C-subunit paralog) biology
above and sharpens the expression/role picture; no change to annotation calls.
Net: no change to calls — C2 is the tissue-restricted (renal intercalated cell)
regulatory C-subunit paralog supporting V-ATPase assembly and acid secretion.
*-deep-research*.md file found in this gene directory.This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.
id: Q8NEY4
gene_symbol: ATP6V1C2
product_type: PROTEIN
status: COMPLETE
taxon:
id: NCBITaxon:9606
label: Homo sapiens
description: '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.'
alternative_products:
- name: '1'
id: Q8NEY4-1
- name: '2'
id: Q8NEY4-2
sequence_note: VSP_024883
existing_annotations:
- term:
id: GO:0046961
label: proton-transporting ATPase activity, rotational mechanism
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: enables
review:
summary: 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.
action: ACCEPT
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.
supported_by:
- reference_id: file:human/ATP6V1C2/ATP6V1C2-uniprot.txt
supporting_text: Subunit C is necessary for the assembly of the catalytic sector
of the enzyme and is likely to have a specific function in its catalytic activity
reference_section_type: DATABASE_ENTRY
- term:
id: GO:0015078
label: proton transmembrane transporter activity
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: enables
review:
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.
action: MARK_AS_OVER_ANNOTATED
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.
supported_by:
- reference_id: file:human/ATP6V1C2/ATP6V1C2-uniprot.txt
supporting_text: a multisubunit enzyme composed of a peripheral complex (V1)
that hydrolyzes ATP and a membrane integral complex (V0) that translocates
protons
reference_section_type: DATABASE_ENTRY
- term:
id: GO:0033180
label: proton-transporting V-type ATPase, V1 domain
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: part_of
review:
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.
action: ACCEPT
reason: Definitionally correct; subunit C2 is a component of the V1 domain as
established for the C-subunit family.
supported_by:
- reference_id: file:human/ATP6V1C2/ATP6V1C2-uniprot.txt
supporting_text: 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
reference_section_type: DATABASE_ENTRY
- term:
id: GO:0046961
label: proton-transporting ATPase activity, rotational mechanism
evidence_type: IEA
original_reference_id: GO_REF:0000120
qualifier: enables
review:
summary: Duplicate of the IBA annotation for the same molecular function, here
from a combined automated IEA pipeline. The function is correct for the V-ATPase
to which C2 contributes.
action: ACCEPT
reason: Core molecular function of the V-ATPase; consistent with the IBA annotation
(GO_REF:0000033) for the identical term GO:0046961.
supported_by:
- reference_id: file:human/ATP6V1C2/ATP6V1C2-uniprot.txt
supporting_text: Subunit C is necessary for the assembly of the catalytic sector
of the enzyme and is likely to have a specific function in its catalytic activity
reference_section_type: DATABASE_ENTRY
- term:
id: GO:1902600
label: proton transmembrane transport
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: involved_in
review:
summary: Proton transmembrane transport is the core biological process of 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.
action: ACCEPT
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.
supported_by:
- reference_id: file:human/ATP6V1C2/ATP6V1C2-uniprot.txt
supporting_text: V-ATPase is responsible for acidifying and maintaining the
pH of intracellular compartments
reference_section_type: DATABASE_ENTRY
- term:
id: GO:0042802
label: identical protein binding
evidence_type: IPI
original_reference_id: PMID:21356312
qualifier: enables
review:
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.
action: MARK_AS_OVER_ANNOTATED
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.
supported_by:
- reference_id: PMID:21356312
supporting_text: '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'
reference_section_type: ABSTRACT
- term:
id: GO:0016241
label: regulation of macroautophagy
evidence_type: NAS
original_reference_id: PMID:22982048
qualifier: involved_in
review:
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.
action: MARK_AS_OVER_ANNOTATED
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.
supported_by:
- reference_id: PMID:22982048
supporting_text: both the autophagosomes and the lysosomal system are not mandatory
for the formation of lipofuscin
reference_section_type: ABSTRACT
- term:
id: GO:0030177
label: positive regulation of Wnt signaling pathway
evidence_type: IMP
original_reference_id: PMID:20093472
qualifier: involved_in
review:
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.
action: KEEP_AS_NON_CORE
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.
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.
Moreover, PRR and V-ATPase were required to mediate Wnt signaling
reference_section_type: ABSTRACT
- term:
id: GO:0070062
label: extracellular exosome
evidence_type: HDA
original_reference_id: PMID:19056867
qualifier: located_in
review:
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.
action: MARK_AS_OVER_ANNOTATED
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.
supported_by:
- reference_id: PMID:19056867
supporting_text: we used LC-MS/MS to profile the proteome of human urinary exosomes.
Overall, the analysis identified 1132 proteins unambiguously
reference_section_type: ABSTRACT
- term:
id: GO:0005765
label: lysosomal membrane
evidence_type: HDA
original_reference_id: PMID:17897319
qualifier: located_in
review:
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.
action: ACCEPT
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.
supported_by:
- reference_id: PMID:17897319
supporting_text: In membranes purified from placental lysosomes, we identified
58 proteins, known to reside at least partially in the lysosomal membrane.
These included 17 polypeptides comprising or associated with the vacuolar
adenosine triphosphatase.
reference_section_type: ABSTRACT
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-1222516
qualifier: located_in
review:
summary: Cytosol localization reflects the regulated disassembly of V1 from V0;
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.
action: KEEP_AS_NON_CORE
reason: Valid but non-core; cytosolic subunit C represents the disassembled/free
V1 state rather than the primary functional membrane location.
supported_by:
- reference_id: Reactome:R-HSA-1222516
supporting_text: Intraphagosomal pH is lowered to 5 by V-ATPase
reference_section_type: OTHER
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5252133
qualifier: located_in
review:
summary: Duplicate cytosol annotation from a different Reactome reaction (ATP6AP1
binds V-ATPase). Same reasoning applies regarding the free cytosolic V1 pool.
action: KEEP_AS_NON_CORE
reason: Valid; cytosolic subunit C reflects the V1-V0 disassembly state. Redundant
Reactome TAS annotation.
supported_by:
- reference_id: Reactome:R-HSA-5252133
supporting_text: ATP6AP1 binds V-ATPase
reference_section_type: OTHER
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-74723
qualifier: located_in
review:
summary: Duplicate cytosol annotation from the Reactome endosome acidification
reaction.
action: KEEP_AS_NON_CORE
reason: Same as other cytosol TAS annotations; valid but non-core.
supported_by:
- reference_id: Reactome:R-HSA-74723
supporting_text: Endosome acidification
reference_section_type: OTHER
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-917841
qualifier: located_in
review:
summary: Duplicate cytosol annotation from the Reactome transferrin-endosome acidification
reaction.
action: KEEP_AS_NON_CORE
reason: Same as other cytosol TAS annotations; valid but non-core.
supported_by:
- reference_id: Reactome:R-HSA-917841
supporting_text: Acidification of Tf:TfR1 containing endosome
reference_section_type: OTHER
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9639286
qualifier: located_in
review:
summary: Duplicate cytosol annotation from a Reactome mTORC1 amino-acid-sensing
reaction.
action: KEEP_AS_NON_CORE
reason: Same as other cytosol TAS annotations; valid but non-core.
supported_by:
- reference_id: Reactome:R-HSA-9639286
supporting_text: RRAGC,D exchanges GTP for GDP
reference_section_type: OTHER
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9640167
qualifier: located_in
review:
summary: Duplicate cytosol annotation from a Reactome mTORC1 reaction (RRAGA,B
GDP/GTP exchange).
action: KEEP_AS_NON_CORE
reason: Same as other cytosol TAS annotations; valid but non-core.
supported_by:
- reference_id: Reactome:R-HSA-9640167
supporting_text: RRAGA,B exchanges GDP for GTP
reference_section_type: OTHER
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9640168
qualifier: located_in
review:
summary: Duplicate cytosol annotation from a Reactome v-ATPase:Ragulator:SLC38A9
dissociation reaction.
action: KEEP_AS_NON_CORE
reason: Same as other cytosol TAS annotations; valid but non-core.
supported_by:
- reference_id: Reactome:R-HSA-9640168
supporting_text: v-ATPase:Ragulator:RRAGA,B:GTP:RRAGC,D:GDP:SLC38A9:Arginine
dissociates yielding v-ATPase:Ragulator:RRAGA,B:GTP:RRAGC,D:GDP and SLC38A9:Arginine
reference_section_type: OTHER
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9640175
qualifier: located_in
review:
summary: Duplicate cytosol annotation from a Reactome v-ATPase:Ragulator:SLC38A9
binding reaction.
action: KEEP_AS_NON_CORE
reason: Same as other cytosol TAS annotations; valid but non-core.
supported_by:
- reference_id: Reactome:R-HSA-9640175
supporting_text: v-ATPase:Ragulator:RagA,B:GDP:RagC,D:GDP binds SLC38A9:Arginine
reference_section_type: OTHER
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9640195
qualifier: located_in
review:
summary: Duplicate cytosol annotation from a Reactome mTORC1 reaction (RRAGA,B
GTP hydrolysis).
action: KEEP_AS_NON_CORE
reason: Same as other cytosol TAS annotations; valid but non-core.
supported_by:
- reference_id: Reactome:R-HSA-9640195
supporting_text: RRAGA,B hydrolyzes GTP
reference_section_type: OTHER
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9645598
qualifier: located_in
review:
summary: Duplicate cytosol annotation from a Reactome mTORC1 reaction (RRAGC,D
GTP hydrolysis).
action: KEEP_AS_NON_CORE
reason: Same as other cytosol TAS annotations; valid but non-core.
supported_by:
- reference_id: Reactome:R-HSA-9645598
supporting_text: RRAGC,D hydrolyzes GTP
reference_section_type: OTHER
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9645608
qualifier: located_in
review:
summary: Duplicate cytosol annotation from a Reactome v-ATPase:Ragulator binds
mTORC1 reaction.
action: KEEP_AS_NON_CORE
reason: Same as other cytosol TAS annotations; valid but non-core.
supported_by:
- reference_id: Reactome:R-HSA-9645608
supporting_text: v-ATPase:Ragulator:RRAGA,B:GTP:RRAGC,D:GDP binds mTORC1
reference_section_type: OTHER
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9646468
qualifier: located_in
review:
summary: Duplicate cytosol annotation from a Reactome mTORC1:RHEB reaction.
action: KEEP_AS_NON_CORE
reason: Same as other cytosol TAS annotations; valid but non-core.
supported_by:
- reference_id: Reactome:R-HSA-9646468
supporting_text: mTORC1 binds RHEB:GTP
reference_section_type: OTHER
references:
- id: GO_REF:0000002
title: Gene Ontology annotation through association of InterPro records with GO
terms
findings: []
- id: GO_REF:0000033
title: Annotation inferences using phylogenetic trees
findings: []
- id: GO_REF:0000120
title: Combined Automated Annotation using Multiple IEA Methods
findings: []
- id: PMID:12384298
title: Molecular cloning and characterization of novel tissue-specific isoforms
of the human vacuolar H(+)-ATPase C, G and d subunits, and their evaluation in
autosomal recessive distal renal tubular acidosis.
findings:
- statement: ATP6V1C2 was cloned as a novel tissue-specific isoform of the human
V-ATPase C subunit; reported as kidney- and placenta-enriched.
supporting_text: Molecular cloning and characterization of novel tissue-specific
isoforms of the human vacuolar H(+)-ATPase C, G and d subunits
reference_section_type: TITLE
- id: PMID:17897319
title: Integral and associated lysosomal membrane proteins.
findings:
- statement: ATP6V1C2 was detected among V-ATPase polypeptides in purified placental
lysosomal membrane fractions.
supporting_text: In membranes purified from placental lysosomes, we identified
58 proteins, known to reside at least partially in the lysosomal membrane. These
included 17 polypeptides comprising or associated with the vacuolar adenosine
triphosphatase.
reference_section_type: ABSTRACT
- id: PMID:19056867
title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
findings:
- statement: ATP6V1C2 detected in a bulk urinary-exosome proteome (1132 proteins);
likely reflects endolysosomal/MVB membrane content rather than a primary exosomal
function.
supporting_text: we used LC-MS/MS to profile the proteome of human urinary exosomes.
Overall, the analysis identified 1132 proteins unambiguously
reference_section_type: ABSTRACT
- id: PMID:20093472
title: Requirement of prorenin receptor and vacuolar H+-ATPase-mediated acidification
for Wnt signaling.
findings:
- statement: PRR (ATP6AP2) acts as an adaptor between Wnt receptors and the V-ATPase;
PRR and V-ATPase acidification are required for Wnt signaling. The role is a
general V-ATPase requirement, not C2-specific.
supporting_text: 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
reference_section_type: ABSTRACT
- id: PMID:21356312
title: Expression, purification and characterization of isoforms of peripheral stalk
subunits of human V-ATPase.
findings:
- statement: Human V-ATPase peripheral stalk subunit isoforms, including C2, were
expressed and purified in a cell-free system; no C2 self-association is demonstrated.
supporting_text: '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'
reference_section_type: ABSTRACT
- id: PMID:22982048
title: Lipofuscin is formed independently of macroautophagy and lysosomal activity
in stress-induced prematurely senescent human fibroblasts.
findings:
- statement: The lipofuscin study does not examine ATP6V1C2; the macroautophagy
link is indirect via V-ATPase-dependent lysosomal acidification.
supporting_text: both the autophagosomes and the lysosomal system are not mandatory
for the formation of lipofuscin
reference_section_type: ABSTRACT
- id: Reactome:R-HSA-1222516
title: Intraphagosomal pH is lowered to 5 by V-ATPase
findings: []
- id: Reactome:R-HSA-5252133
title: ATP6AP1 binds V-ATPase
findings: []
- id: Reactome:R-HSA-74723
title: Endosome acidification
findings: []
- id: Reactome:R-HSA-917841
title: Acidification of Tf:TfR1 containing endosome
findings: []
- id: Reactome:R-HSA-9639286
title: RRAGC,D exchanges GTP for GDP
findings: []
- id: Reactome:R-HSA-9640167
title: RRAGA,B exchanges GDP for GTP
findings: []
- id: Reactome:R-HSA-9640168
title: v-ATPase:Ragulator:RRAGA,B:GTP:RRAGC,D:GDP:SLC38A9:Arginine dissociates yielding
v-ATPase:Ragulator:RRAGA,B:GTP:RRAGC,D:GDP and SLC38A9:Arginine
findings: []
- id: Reactome:R-HSA-9640175
title: v-ATPase:Ragulator:RagA,B:GDP:RagC,D:GDP binds SLC38A9:Arginine
findings: []
- id: Reactome:R-HSA-9640195
title: RRAGA,B hydrolyzes GTP
findings: []
- id: Reactome:R-HSA-9645598
title: RRAGC,D hydrolyzes GTP
findings: []
- id: Reactome:R-HSA-9645608
title: v-ATPase:Ragulator:RRAGA,B:GTP:RRAGC,D:GDP binds mTORC1
findings: []
- id: Reactome:R-HSA-9646468
title: mTORC1 binds RHEB:GTP
findings: []
- id: file:human/ATP6V1C2/ATP6V1C2-uniprot.txt
title: UniProtKB entry for ATP6V1C2 (Q8NEY4)
findings:
- statement: Subunit C is necessary for assembly of the catalytic V1 sector and
likely has a specific function in V-ATPase catalytic activity.
supporting_text: Subunit C is necessary for the assembly of the catalytic sector
of the enzyme and is likely to have a specific function in its catalytic activity
reference_section_type: DATABASE_ENTRY
- statement: ATP6V1C2 expression is kidney- and placenta-enriched.
supporting_text: Kidney and placenta.
reference_section_type: DATABASE_ENTRY
core_functions:
- description: ATP6V1C2 is a tissue-restricted C subunit of the V1 domain of the vacuolar-type
H+-ATPase. As a single-copy subunit at the interface of the V1 catalytic head
and the peripheral stator stalk, it is required for assembly of the catalytic
V1 sector and contributes to the proton-transporting ATPase activity of the holoenzyme,
which acidifies intracellular compartments.
contributes_to_molecular_function:
id: GO:0046961
label: proton-transporting ATPase activity, rotational mechanism
directly_involved_in:
- id: GO:1902600
label: proton transmembrane transport
locations:
- id: GO:0005765
label: lysosomal membrane
in_complex:
id: GO:0033180
label: proton-transporting V-type ATPase, V1 domain
- description: Subunit C acts as a regulator of reversible V1-V0 assembly and disassembly.
It dissociates from both V1 and V0 upon disassembly and re-binds during reassembly,
providing a regulatory mechanism for controlling V-ATPase activity in response
to cellular signals.
contributes_to_molecular_function:
id: GO:0046961
label: proton-transporting ATPase activity, rotational mechanism
in_complex:
id: GO:0033180
label: proton-transporting V-type ATPase, V1 domain
proposed_new_terms: []
suggested_questions:
- question: 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?
- question: 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?
- question: Are there phenotypes or disease associations specific to ATP6V1C2 (e.g.,
in kidney acid-base handling) that distinguish it from ATP6V1C1?
suggested_experiments:
- hypothesis: ATP6V1C2 governs isoform-specific V1-V0 assembly/disassembly dynamics
distinct from ATP6V1C1.
description: 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.
experiment_type: BIOCHEMISTRY
- hypothesis: ATP6V1C2 is the functionally predominant C subunit in specific kidney/lung
epithelial cells and cannot be fully replaced by ATP6V1C1 there.
description: Generate ATP6V1C2 knockout in relevant epithelial cell models and assess
lysosomal/compartment acidification, V-ATPase assembly, and whether ectopic ATP6V1C1
rescues the phenotype.
experiment_type: CELL_BIOLOGY