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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0016020 membrane | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: PMID:16672332 GABA also induces exposure of the protease domain of TagC on the surface of prestalk cells where it can convert AcbA to SDF-2 |
| GO:0042626 ATPase-coupled transmembrane transporter activity | IBA GO_REF:0000033 | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:7744252 implying a mechanism of action that includes PMID:12456012 Other members of the superfamily may serve specialized developmental roles by releasing intercellular signals at appropriate stages of development |
| GO:0055085 transmembrane transport | IBA GO_REF:0000033 | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:12456012 Dictyostelium appears to be equipped to rapidly export a wide variety of compounds |
| GO:0004252 serine-type endopeptidase activity | IEA GO_REF:0000002 | ACCEPT | 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. 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. Supporting Evidence: PMID:16672332 GABA also induces exposure of the protease domain of TagC on the surface of prestalk cells where it can convert AcbA to SDF-2 PMID:15897458 Addition of the serine protease inhibitor tosyl phenylalanyl chloromethylketone to primed cells just before addition of AcbA blocked all production of SDF-2 |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | KEEP AS NON CORE | 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. 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. |
| GO:0005886 plasma membrane | IEA GO_REF:0000117 | ACCEPT | 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. 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. Supporting Evidence: PMID:16672332 GABA also induces exposure of the protease domain of TagC on the surface of prestalk cells where it can convert AcbA to SDF-2 |
| GO:0006508 proteolysis | IEA GO_REF:0000002 | ACCEPT | 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. 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. Supporting Evidence: PMID:15897458 Addition of the serine protease inhibitor tosyl phenylalanyl chloromethylketone to primed cells just before addition of AcbA blocked all production of SDF-2 |
| GO:0008236 serine-type peptidase activity | IEA GO_REF:0000002 | ACCEPT | 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. Reason: Correct annotation of the protease domain; the demonstrated cleavage of AcbA and sensitivity to a serine protease inhibitor confirm serine-type peptidase activity. Supporting Evidence: PMID:15897458 Addition of the serine protease inhibitor tosyl phenylalanyl chloromethylketone to primed cells just before addition of AcbA blocked all production of SDF-2 |
| GO:0016020 membrane | IEA GO_REF:0000120 | ACCEPT | 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. 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. Supporting Evidence: PMID:16672332 GABA also induces exposure of the protease domain of TagC on the surface of prestalk cells where it can convert AcbA to SDF-2 |
| GO:0016887 ATP hydrolysis activity | IEA GO_REF:0000002 | KEEP AS NON CORE | 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. 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. |
| GO:0030154 cell differentiation | IEA GO_REF:0000117 | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:15897458 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 |
| GO:0055085 transmembrane transport | IEA GO_REF:0000002 | KEEP AS NON CORE | 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. Reason: Inferred from the ABC transmembrane domain; biologically plausible but untested for TagC, and not the demonstrated core process. Supporting Evidence: PMID:12456012 Dictyostelium appears to be equipped to rapidly export a wide variety of compounds |
| GO:0140359 ABC-type transporter activity | IEA GO_REF:0000002 | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:7744252 implying a mechanism of action that includes |
| GO:0005886 plasma membrane | TAS PMID:12456012 Evolutionary analyses of ABC transporters of Dictyostelium d... | ACCEPT | 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. 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. Supporting Evidence: PMID:16672332 GABA also induces exposure of the protease domain of TagC on the surface of prestalk cells where it can convert AcbA to SDF-2 |
| GO:0016485 protein processing | IMP PMID:15897458 Peptide signaling during terminal differentiation of Dictyos... | ACCEPT | 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. 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. Supporting Evidence: PMID:15897458 primed KP cells carrying a null mutation in tagC were unable to process exogenously added AcbA into SDF-2 activity PMID:16672332 GABA also induces exposure of the protease domain of TagC on the surface of prestalk cells where it can convert AcbA to SDF-2 |
| GO:0008236 serine-type peptidase activity | IMP PMID:15897458 Peptide signaling during terminal differentiation of Dictyos... | ACCEPT | 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. 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. Supporting Evidence: PMID:15897458 Addition of the serine protease inhibitor tosyl phenylalanyl chloromethylketone to primed cells just before addition of AcbA blocked all production of SDF-2 PMID:15897458 primed KP cells carrying a null mutation in tagC were unable to process exogenously added AcbA into SDF-2 activity |
| GO:0030154 cell differentiation | IMP PMID:7744252 A multidrug resistance transporter/serine protease gene is r... | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:7744252 prestalk cells induce encapsulation of prespore cells |
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