tra-2

id: Q17307
gene_symbol: tra-2
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:6238
  label: Caenorhabditis briggsae
description: >-
  Cbr-TRA-2 is the Caenorhabditis briggsae ortholog of the sex-determining transformer
  protein TRA-2, a large multi-pass integral membrane protein that is a central,
  membrane-localized regulator of the nematode sex-determination pathway. It promotes
  female (oocyte) cell fates in XX animals by repressing the masculinizing FEM proteins:
  its intracellular domain binds and sequesters FEM-3 at the membrane, preventing FEM-3
  from inhibiting the terminal transcription factor TRA-1. In XO animals the secreted
  male-promoting signal HER-1 binds the TRA-2 extracellular domain and antagonizes this
  activity, so TRA-2 also behaves as a receptor for HER-1. The intracellular MX regulatory
  domain additionally binds the TRA-1 transcription factor directly, and proteolytic
  cleavage of TRA-2 (by the calpain-like protease TRA-3) generates a feminizing fragment.
  Through these activities TRA-2 governs both somatic sexual differentiation and the
  germline sperm/oocyte decision (including hermaphrodite spermatogenesis). The FEM-3-binding
  region of TRA-2 is hypervariable and coevolves rapidly with FEM-3, making tra-2 a key
  gene for comparative study of sex-determination pathway evolution between C. briggsae
  and C. elegans.
existing_annotations:
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      TRA-2 is an integral multi-pass membrane protein and the UniProt subcellular
      location is "Membrane; Multi-pass membrane protein". An IDA membrane annotation
      (GO:0016020) is independently supported. Plasma membrane is the biologically
      expected localization for a receptor that binds the secreted HER-1 ligand and
      sequesters FEM proteins at the cell surface; the IBA call is consistent with the
      family. Accepted as the cellular location where TRA-2 acts.
    action: ACCEPT
- term:
    id: GO:0004888
    label: transmembrane signaling receptor activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      TRA-2 functions as a membrane receptor for the secreted male-promoting signal
      HER-1; HER-1 binding to the TRA-2 extracellular domain modulates the masculinizing
      output of the pathway. This receptor activity is a core molecular function of TRA-2
      and is consistent across the TRA-2 family (IBA). Accepted and retained as a core
      molecular function.
    action: ACCEPT
- term:
    id: GO:0018992
    label: germ-line sex determination
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      TRA-2 controls the germline sperm/oocyte decision and hermaphrodite spermatogenesis;
      null mutants have masculinized germ lines producing only sperm (disruption phenotype).
      This is independently supported by an IMP annotation (PMID:11250902). A core
      biological process for tra-2. Accepted.
    action: ACCEPT
- term:
    id: GO:0004888
    label: transmembrane signaling receptor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro2GO (IPR032848, Ce-Tra-2) electronic annotation of the same receptor
      activity supported by the IBA call above. Consistent with TRA-2 acting as a
      receptor for HER-1. Accepted as a redundant but correct electronic annotation.
    action: ACCEPT
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Electronic mapping from the UniProt subcellular-location keyword "Membrane".
      Correct but more general than the supported localization; the IDA membrane and
      IBA plasma membrane annotations are more informative. Kept as a correct, if
      general, component annotation.
    action: ACCEPT
- term:
    id: GO:0040021
    label: hermaphrodite germ-line sex determination
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      More specific child of germ-line sex determination, appropriate for tra-2 given
      its required role in the hermaphrodite germline sperm/oocyte switch and
      hermaphrodite spermatogenesis (PMID:24098152 disruption phenotype; PMID:11250902
      MX-domain control of spermatogenesis). This specificity is well justified for the
      gene; accepted as a core process annotation.
    action: ACCEPT
- term:
    id: GO:0042001
    label: hermaphrodite somatic sex determination
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      TRA-2 promotes female somatic fates in XX animals; null mutants make incomplete
      (masculinized) male tails, indicating a somatic sex-determination role in addition
      to the germline role. The hermaphrodite-specific somatic term is appropriate.
      Accepted.
    action: ACCEPT
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IDA
  original_reference_id: PMID:10783162
  qualifier: located_in
  review:
    summary: >-
      Direct experimental (IDA) membrane localization. Sokol & Kuwabara show that the
      membrane protein TRA-2A is a substrate of the TRA-3 protease, working with the
      membrane-associated form of TRA-2. The membrane localization is central to TRA-2
      function (HER-1 reception, FEM sequestration). Accepted as experimentally
      supported localization.
    action: ACCEPT
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11250902
  qualifier: enables
  review:
    summary: >-
      IPI annotation (with UniProtKB:Q17308, Cbr-TRA-1) capturing the direct, MX-domain-dependent
      binding of TRA-2 to the TRA-1 transcription factor, demonstrated in C. briggsae as
      well as C. elegans. "protein binding" is uninformative on its own; the specific
      molecular function is better captured as protein-macromolecule adaptor/sequestration
      activity (see core_functions). The underlying interaction is real and experimentally
      supported, so the binding-partner information is retained, but the generic GO:0005515
      term is marked over-annotated per curation guidance to avoid bare "protein binding".
    action: MARK_AS_OVER_ANNOTATED
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12477393
  qualifier: enables
  review:
    summary: >-
      IPI annotation (with UniProtKB:Q8I8U6, Cbr-FEM-3) capturing the direct, species-specific
      binding of TRA-2 to FEM-3; this interaction sequesters FEM-3 and is the molecular
      basis of TRA-2 feminizing activity, and the FEM-3-binding region of TRA-2 is
      hypervariable and rapidly coevolving with FEM-3. The interaction is well supported,
      but the bare "protein binding" term is uninformative. The specific adaptor/sequestration
      function is captured in core_functions; the generic term is marked over-annotated.
    action: MARK_AS_OVER_ANNOTATED
- term:
    id: GO:0018992
    label: germ-line sex determination
  evidence_type: IMP
  original_reference_id: PMID:11250902
  qualifier: involved_in
  review:
    summary: >-
      Experimental (IMP) annotation. Genetic interactions between tra-1 and tra-2(mx)
      mutations, and the requirement of the MX domain for the onset of hermaphrodite
      spermatogenesis, establish tra-2 involvement in the germline sex-determination
      decision. A core biological process for tra-2, experimentally supported. Accepted.
    action: ACCEPT
- term:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  evidence_type: IPI
  original_reference_id: PMID:12477393
  qualifier: enables
  review:
    summary: >-
      Proposed new, more-informative molecular function replacing the bare "protein
      binding" IPI annotations. TRA-2's intracellular domain directly binds and
      sequesters FEM-3 at the membrane (PMID:12477393) and also binds TRA-1 via the MX
      domain (PMID:11250902), physically tethering pathway components; this adaptor/
      sequestration activity is the molecular basis of TRA-2 feminizing function. Added
      as a NEW annotation to capture the specific function.
    action: NEW
core_functions:
- molecular_function:
    id: GO:0004888
    label: transmembrane signaling receptor activity
  directly_involved_in:
  - id: GO:0007530
    label: sex determination
  description: >-
    TRA-2 is a large multi-pass integral membrane protein that acts as the cell-surface
    receptor for the secreted male-promoting signal HER-1. HER-1 binding to the TRA-2
    extracellular domain antagonizes TRA-2's feminizing activity, switching the
    sex-determination pathway toward the male fate in XO animals. This receptor activity
    is conserved across the TRA-2 family.
  supported_by:
  - reference_id: GO_REF:0000033
    supporting_text: >-
      IBA annotation from PANTHER phylogenetic analysis assigning transmembrane signaling
      receptor activity to the TRA-2 family (PANTHER:PTN002217563).
- molecular_function:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  directly_involved_in:
  - id: GO:0007530
    label: sex determination
  description: >-
    Through its intracellular domain TRA-2 directly binds and sequesters the masculinizing
    protein FEM-3 at the membrane, preventing FEM-3 from blocking the terminal transcription
    factor TRA-1; the same intracellular region (MX regulatory domain) also binds TRA-1
    directly. This membrane-tethering/sequestration activity links the FEM-3 and TRA-1
    components of the pathway and is the molecular basis of TRA-2 feminizing function.
    The FEM-3-binding region is hypervariable and coevolves rapidly with FEM-3.
  supported_by:
  - reference_id: PMID:12477393
    supporting_text: >-
      the FEM-3 protein interacts with TRA-2 in each species, but in a
      strictly species-specific manner
  - reference_id: PMID:11250902
    supporting_text: >-
      the TRA-1 transcription factor binds the
      intracellular domain of the TRA-2 membrane protein
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:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: PMID:10783162
  title: 'Proteolysis in Caenorhabditis elegans sex determination: cleavage of TRA-2A
    by TRA-3.'
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Abstract-only cache. Establishes that the membrane protein TRA-2A is a substrate
      of the TRA-3 calpain-like protease and that cleavage generates a feminizing
      fragment; supports the IDA membrane localization. Work is in C. elegans but
      directly informs the conserved Cbr-TRA-2 biology.
- id: PMID:11250902
  title: The TRA-1 transcription factor binds TRA-2 to regulate sexual fates in Caenorhabditis
    elegans.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract-only cache, but explicitly reports an MX-dependent Cb-TRA-1/Cb-TRA-2
      interaction in C. briggsae (no cross-species interaction), directly supporting the
      Cbr-specific TRA-1 binding and germline sex-determination (spermatogenesis) roles.
- id: PMID:12477393
  title: Rapid coevolution of the nematode sex-determining genes fem-3 and tra-2.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract-only cache. Directly addresses C. briggsae: FEM-3 interacts with TRA-2 in
      a strictly species-specific manner and the FEM-3-binding domain of TRA-2 is
      hypervariable and rapidly coevolving. Supports the FEM-3 sequestration/adaptor
      function and the comparative-evolution framing.