tagC

id: Q23868
gene_symbol: tagC
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:44689
  label: Dictyostelium discoideum
description: TagC is a large, prestalk-specific, multi-pass membrane protein of
  Dictyostelium discoideum with an unusual bifunctional architecture, combining an
  N-terminal subtilisin-like serine protease (peptidase S8) domain with a
  C-terminal ABC transporter B-family (multidrug-resistance-type) module
  comprising a transmembrane domain and an ATP-binding cassette. During
  culmination TagC is expressed exclusively in prestalk cells, where its protease
  domain becomes exposed on the cell surface in response to the intercellular
  signal GABA. There it cleaves AcbA (acyl-CoA-binding protein), which is released
  from neighboring prespore cells, to generate the spore differentiation factor
  SDF-2. SDF-2 then acts on the histidine kinase receptor DhkA to trigger rapid
  encapsulation of prespore cells into spores, coupling terminal cell
  differentiation to fruiting-body morphogenesis. Loss of TagC abolishes SDF-2
  production and causes a cell-autonomous defect in prestalk specialization.
existing_annotations:
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: TagC is a multi-pass membrane protein whose C-terminal ABC
      transporter module contains six predicted transmembrane helices. Membrane
      localization is correct, though the more specific plasma membrane is where
      the protease acts.
    action: ACCEPT
    reason: The phylogenetic inference of membrane localization is consistent with
      the six transmembrane helices annotated in the ABC transporter region and
      with the exposure of the protease domain on the surface of prestalk cells.
    supported_by:
    - reference_id: PMID:16672332
      supporting_text: GABA also induces exposure of the protease domain of TagC
        on the surface of prestalk cells where it can convert AcbA to SDF-2
- term:
    id: GO:0042626
    label: ATPase-coupled transmembrane transporter activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: TagC carries a complete, conserved ABC transporter B-family module
      (transmembrane domain plus an ATP-binding cassette with an intact Walker A
      motif), so an ATPase-coupled transporter activity is structurally plausible
      and phylogenetically inferred. However, no transport substrate or transport
      activity has been demonstrated experimentally; the only demonstrated
      function is the serine protease processing of AcbA. The transporter module
      is hypothesized to participate in export of the peptide signal.
    action: KEEP_AS_NON_CORE
    reason: The ABC transporter activity is inferred from homology to multidrug
      resistance exporters and is biologically plausible given the intact ABC
      module, but it remains untested for TagC and is not the demonstrated core
      function. The proposed role is export of the peptide signal generated by the
      protease domain.
    supported_by:
    - reference_id: PMID:7744252
      supporting_text: implying a mechanism of action that includes
    - reference_id: PMID:12456012
      supporting_text: Other members of the superfamily may serve specialized
        developmental roles by releasing intercellular signals at appropriate stages
        of development
- term:
    id: GO:0055085
    label: transmembrane transport
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Biological-process counterpart of the phylogenetically inferred ABC
      transporter activity. As with the molecular function, transmembrane
      transport is plausible from the intact ABC module but has not been
      demonstrated for TagC.
    action: KEEP_AS_NON_CORE
    reason: Inferred from the ABC transporter module by phylogeny; biologically
      plausible (possible export of the peptide signal) but untested and not the
      demonstrated core process.
    supported_by:
    - reference_id: PMID:12456012
      supporting_text: Dictyostelium appears to be equipped to rapidly export a
        wide variety of compounds
- term:
    id: GO:0004252
    label: serine-type endopeptidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: The N-terminal peptidase S8 (subtilisin-like) domain confers
      serine-type endopeptidase activity. This is the demonstrated core molecular
      function of TagC - it cleaves AcbA internally to release the SDF-2 peptide,
      and this activity is blocked by a serine protease inhibitor.
    action: ACCEPT
    reason: The InterPro2GO assignment of serine-type endopeptidase activity is
      confirmed by experimental evidence - TagC processes AcbA to SDF-2, this
      processing requires tagC, and it is abolished by a serine protease
      inhibitor. This is the more specific and appropriate MF term for the
      protease domain.
    supported_by:
    - reference_id: PMID:16672332
      supporting_text: GABA also induces exposure of the protease domain of TagC
        on the surface of prestalk cells where it can convert AcbA to SDF-2
    - reference_id: PMID:15897458
      supporting_text: Addition of the serine protease inhibitor tosyl
        phenylalanyl chloromethylketone to primed cells just before addition of
        AcbA blocked all production of SDF-2
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: The C-terminal ABC transporter nucleotide-binding domain contains a
      Walker A/P-loop motif (annotated ATP-binding site in UniProt), so ATP
      binding is a credible biochemical property. It supports the putative
      transporter activity rather than being a core function in itself.
    action: KEEP_AS_NON_CORE
    reason: ATP binding is inferred from the conserved nucleotide-binding cassette
      of the ABC module and is consistent with the annotated Walker A motif, but
      it is a supporting biochemical capacity of the untested transporter module,
      not the demonstrated core function.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: TagC is displayed at the prestalk cell surface, where its protease
      domain is exposed and acts on extracellular AcbA. Plasma membrane
      localization is well supported and functionally meaningful.
    action: ACCEPT
    reason: The protease domain of TagC is exposed on the surface of prestalk
      cells, consistent with plasma membrane localization; this is the site where
      it converts AcbA to SDF-2.
    supported_by:
    - reference_id: PMID:16672332
      supporting_text: GABA also induces exposure of the protease domain of TagC
        on the surface of prestalk cells where it can convert AcbA to SDF-2
- term:
    id: GO:0006508
    label: proteolysis
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: General proteolysis is correct for TagC given its serine protease
      domain and its demonstrated cleavage of AcbA. The more specific protein
      processing term (also annotated) better captures the biology.
    action: ACCEPT
    reason: TagC is a functional protease that cleaves AcbA; proteolysis is a
      correct, if general, biological process annotation supported by the
      protease-inhibitor-sensitive processing of AcbA.
    supported_by:
    - reference_id: PMID:15897458
      supporting_text: Addition of the serine protease inhibitor tosyl
        phenylalanyl chloromethylketone to primed cells just before addition of
        AcbA blocked all production of SDF-2
- term:
    id: GO:0008236
    label: serine-type peptidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: Serine-type peptidase activity from the peptidase S8 domain is
      correct. The more specific serine-type endopeptidase activity term (also
      annotated) is preferable, but the parent term is not wrong.
    action: ACCEPT
    reason: Correct annotation of the protease domain; the demonstrated cleavage
      of AcbA and sensitivity to a serine protease inhibitor confirm serine-type
      peptidase activity.
    supported_by:
    - reference_id: PMID:15897458
      supporting_text: Addition of the serine protease inhibitor tosyl
        phenylalanyl chloromethylketone to primed cells just before addition of
        AcbA blocked all production of SDF-2
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Membrane localization from combined IEA methods, consistent with the
      multi-pass membrane topology of the ABC transporter region and with the
      cell-surface display of the protease domain.
    action: ACCEPT
    reason: TagC is a multi-pass membrane protein; membrane localization is
      correct and corroborated by exposure of the protease domain at the prestalk
      cell surface.
    supported_by:
    - reference_id: PMID:16672332
      supporting_text: GABA also induces exposure of the protease domain of TagC
        on the surface of prestalk cells where it can convert AcbA to SDF-2
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: ATP hydrolysis is inferred from the ABC nucleotide-binding domain. It
      is a plausible activity of the transporter module but has not been
      demonstrated for TagC and is not a core function.
    action: KEEP_AS_NON_CORE
    reason: Inferred from the conserved ABC ATPase cassette; plausible but untested
      for TagC, and it supports the putative transporter activity rather than
      representing the demonstrated core function.
- term:
    id: GO:0030154
    label: cell differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: TagC is required for prestalk specialization and, through SDF-2
      generation, for the terminal differentiation (encapsulation) of prespore
      cells into spores. Cell differentiation is a correct but downstream/broad
      developmental role rather than the molecular core function.
    action: KEEP_AS_NON_CORE
    reason: TagC contributes to cell differentiation indirectly, via its protease
      activity that generates the SDF-2 encapsulation signal; this is a genuine
      developmental role but is a downstream consequence of the core protease
      function.
    supported_by:
    - reference_id: PMID:15897458
      supporting_text: It appears that AcbA is released from prespore cells and
        proteolytically cleaved by prestalk cells to generate SDF-2, which then
        triggers rapid sporulation of prespore cells
- term:
    id: GO:0055085
    label: transmembrane transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: InterPro2GO transmembrane transport from the ABC transmembrane domain.
      Same status as the IBA transmembrane transport annotation - plausible from
      the ABC module but not experimentally demonstrated for TagC.
    action: KEEP_AS_NON_CORE
    reason: Inferred from the ABC transmembrane domain; biologically plausible but
      untested for TagC, and not the demonstrated core process.
    supported_by:
    - reference_id: PMID:12456012
      supporting_text: Dictyostelium appears to be equipped to rapidly export a
        wide variety of compounds
- term:
    id: GO:0140359
    label: ABC-type transporter activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: ABC-type transporter activity from the ABC transmembrane domain. TagC
      has a complete ABCB-family module, so the annotation is structurally
      justified, but no transport activity has been demonstrated; the demonstrated
      function is the protease.
    action: KEEP_AS_NON_CORE
    reason: Inferred from the intact ABCB-family module; plausible (possible export
      of the peptide signal) but untested for TagC and not the demonstrated core
      function.
    supported_by:
    - reference_id: PMID:7744252
      supporting_text: implying a mechanism of action that includes
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: PMID:12456012
  qualifier: is_active_in
  review:
    summary: Traceable statement from the ABC transporter survey placing TagC-type
      ABCB proteins at the plasma membrane. Consistent with the cell-surface
      exposure of the TagC protease domain, this localization is where TagC acts on
      extracellular AcbA.
    action: ACCEPT
    reason: Plasma membrane is the functional site of TagC, where the protease
      domain is exposed on the prestalk cell surface to convert AcbA to SDF-2.
    supported_by:
    - reference_id: PMID:16672332
      supporting_text: GABA also induces exposure of the protease domain of TagC
        on the surface of prestalk cells where it can convert AcbA to SDF-2
- term:
    id: GO:0016485
    label: protein processing
  evidence_type: IMP
  original_reference_id: PMID:15897458
  qualifier: involved_in
  review:
    summary: Strong loss-of-function evidence establishes that TagC is required to
      process AcbA into the SDF-2 peptide. tagC-null cells cannot convert
      exogenous AcbA into SDF-2 activity. This is a core biological process for
      TagC.
    action: ACCEPT
    reason: Anjard and Loomis 2005 showed by mutant phenotype that primed
      tagC-null cells cannot process AcbA into SDF-2, directly demonstrating that
      TagC performs the protein-processing step that releases the SDF-2 signal.
    supported_by:
    - reference_id: PMID:15897458
      supporting_text: primed KP cells carrying a null mutation in tagC were
        unable to process exogenously added AcbA into SDF-2 activity
    - reference_id: PMID:16672332
      supporting_text: GABA also induces exposure of the protease domain of TagC
        on the surface of prestalk cells where it can convert AcbA to SDF-2
- term:
    id: GO:0008236
    label: serine-type peptidase activity
  evidence_type: IMP
  original_reference_id: PMID:15897458
  qualifier: enables
  review:
    summary: Mutant-phenotype evidence for the protease activity of TagC -
      processing of AcbA to SDF-2 requires tagC and is blocked by a serine
      protease inhibitor, demonstrating serine-type peptidase activity. This is
      the core molecular function.
    action: ACCEPT
    reason: The IMP evidence is solid - AcbA processing to SDF-2 depends on tagC
      and is abolished by the serine protease inhibitor tosyl phenylalanyl
      chloromethylketone, confirming TagC serine-type peptidase activity.
    supported_by:
    - reference_id: PMID:15897458
      supporting_text: Addition of the serine protease inhibitor tosyl
        phenylalanyl chloromethylketone to primed cells just before addition of
        AcbA blocked all production of SDF-2
    - reference_id: PMID:15897458
      supporting_text: primed KP cells carrying a null mutation in tagC were
        unable to process exogenously added AcbA into SDF-2 activity
- term:
    id: GO:0030154
    label: cell differentiation
  evidence_type: IMP
  original_reference_id: PMID:7744252
  qualifier: acts_upstream_of_or_within
  review:
    summary: The tag-gene locus (tagB/tagC) is required for prestalk
      specialization, and prestalk cells in turn induce encapsulation of prespore
      cells during culmination. TagC contributes to cell differentiation, but as a
      developmental role acting upstream via signal generation rather than as its
      molecular core function.
    action: KEEP_AS_NON_CORE
    reason: Genetic evidence places TagC in the pathway controlling prestalk
      specialization and spore encapsulation. This is a genuine developmental role
      but is a downstream/upstream-of consequence of the core protease function,
      not the molecular activity itself.
    supported_by:
    - reference_id: PMID:7744252
      supporting_text: prestalk cells induce encapsulation of prespore cells
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:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning
    models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:12456012
  title: Evolutionary analyses of ABC transporters of Dictyostelium discoideum.
  findings:
  - statement: Some Dictyostelium ABC superfamily members serve specialized
      developmental roles by releasing intercellular signals at appropriate
      developmental stages.
    supporting_text: Other members of the superfamily may serve specialized
      developmental roles by releasing intercellular signals at appropriate stages
      of development
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PMC full text confirmed; an evolutionary survey classifying TagC
      within the ABCB family. Supports the transporter-module context but does not
      experimentally establish transport activity for TagC.
- id: PMID:15897458
  title: Peptide signaling during terminal differentiation of Dictyostelium.
  findings:
  - statement: Production of SDF-2 depends on the prestalk gene tagC, which encodes
      an ABC transporter fused to a serine protease.
    supporting_text: Production of SDF-2 depends on expression of the prestalk
      gene, tagC , which encodes a member of the ABC transporter family fused to a
      serine protease
  - statement: tagC-null cells cannot process exogenously added AcbA into SDF-2,
      demonstrating that TagC performs the AcbA-processing step.
    supporting_text: primed KP cells carrying a null mutation in tagC were unable
      to process exogenously added AcbA into SDF-2 activity
  - statement: AcbA processing to SDF-2 is blocked by a serine protease inhibitor,
      indicating a serine protease activity.
    supporting_text: Addition of the serine protease inhibitor tosyl phenylalanyl
      chloromethylketone to primed cells just before addition of AcbA blocked all
      production of SDF-2
  - statement: AcbA released from prespore cells is proteolytically cleaved by
      prestalk cells to generate SDF-2, triggering rapid sporulation.
    supporting_text: It appears that AcbA is released from prespore cells and
      proteolytically cleaved by prestalk cells to generate SDF-2, which then
      triggers rapid sporulation of prespore cells
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PMC full text confirmed. Primary functional evidence that TagC is
      the serine protease that processes AcbA to SDF-2; underpins the core protease
      and protein-processing annotations.
- id: PMID:16672332
  title: GABA induces terminal differentiation of Dictyostelium through a GABAB
    receptor.
  findings:
  - statement: GABA induces exposure of the TagC protease domain on the surface of
      prestalk cells, where it converts AcbA to SDF-2.
    supporting_text: GABA also induces exposure of the protease domain of TagC on
      the surface of prestalk cells where it can convert AcbA to SDF-2
  - statement: Prespore cells rapidly encapsulate into spores in response to the
      SDF-2 signal generated by TagC.
    supporting_text: they rapidly encapsulate in response to the signalling peptide
      SDF-2
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Abstract-only cache, but the abstract explicitly localizes the
      TagC protease domain to the prestalk cell surface and states it converts AcbA
      to SDF-2; supports plasma membrane localization and the protease function.
- id: PMID:7744252
  title: A multidrug resistance transporter/serine protease gene is required for
    prestalk specialization in Dictyostelium.
  findings:
  - statement: The tag genes encode MDR-transporter/serine-protease proteins whose
      mechanism is inferred to include proteolysis and export of peptide signals.
    supporting_text: implying a mechanism of action that includes
  - statement: Prestalk cells induce encapsulation of prespore cells during
      culmination.
    supporting_text: prestalk cells induce encapsulation of prespore cells
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Abstract-only cache; the paper primarily characterizes the
      paralog tagB but establishes the tag-gene paradigm (protease plus MDR
      transporter) and the prestalk-specialization/encapsulation role that the
      dictyBase IMP annotation transfers to tagC. Full text (not cached) presumably
      covers tagC; per policy the experimental annotation is retained.
core_functions:
- description: TagC is a subtilisin-like serine endopeptidase that, when its
    protease domain is displayed on the prestalk cell surface, cleaves the
    prespore-derived protein AcbA to release the diffusible spore differentiation
    factor SDF-2, thereby processing a pro-signal into its active peptide form.
  molecular_function:
    id: GO:0004252
    label: serine-type endopeptidase activity
  directly_involved_in:
  - id: GO:0016485
    label: protein processing
  locations:
  - id: GO:0005886
    label: plasma membrane
  supported_by:
  - reference_id: PMID:15897458
    supporting_text: primed KP cells carrying a null mutation in tagC were unable
      to process exogenously added AcbA into SDF-2 activity
  - reference_id: PMID:16672332
    supporting_text: GABA also induces exposure of the protease domain of TagC on
      the surface of prestalk cells where it can convert AcbA to SDF-2
- description: TagC possesses a complete, conserved ABC transporter B-family
    (multidrug-resistance-type) module - a multi-pass transmembrane domain plus an
    ATP-binding cassette - that is proposed to couple ATP binding and hydrolysis to
    transmembrane transport, potentially mediating export of the peptide signal.
    This activity is inferred from the intact domain architecture and has not yet
    been experimentally demonstrated for TagC.
  molecular_function:
    id: GO:0042626
    label: ATPase-coupled transmembrane transporter activity
  directly_involved_in:
  - id: GO:0055085
    label: transmembrane transport
  locations:
  - id: GO:0016020
    label: membrane
  supported_by:
  - reference_id: PMID:7744252
    supporting_text: implying a mechanism of action that includes
  - reference_id: PMID:12456012
    supporting_text: Other members of the superfamily may serve specialized
      developmental roles by releasing intercellular signals at appropriate stages
      of development