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