tigA

id: Q00216
gene_symbol: tigA
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:5061
  label: Aspergillus niger
description: >-
  Protein disulfide-isomerase tigA (tunicamycin-inducible gene A polypeptide) is a member
  of the PDI family in Aspergillus niger. It contains two thioredoxin domains with redox-active
  CXXC motifs and a C-terminal ERp29-like domain. TigA has dual activities: it acts as a protein
  disulfide isomerase catalyzing the rearrangement of disulfide bonds (demonstrated by refolding
  of denatured/reduced RNase A), and exhibits chaperone activity (demonstrated by refolding of
  denatured prochymosin but not GAPDH, indicating substrate specificity). It is induced by
  tunicamycin treatment (ER stress) and resides in the ER lumen. It is not a trigger factor
  homolog; it is a bona fide PDI family member.
existing_annotations:
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IEA
  original_reference_id: GO_REF:0000118
  review:
    summary: >-
      TreeGrafter IEA annotation for protein folding. TigA is a PDI family member with
      demonstrated chaperone activity assisting protein folding (PMID:16234854). Consistent
      with IDA evidence for the same term.
    action: ACCEPT
    reason: >-
      TigA has experimentally demonstrated protein folding chaperone activity
      (refolding of denatured prochymosin; PMID:16234854) and PDI isomerase activity
      that assists protein folding. This IEA is consistent with experimental evidence.
    supported_by:
      - reference_id: PMID:16234854
        supporting_text: "TIGA also exhibited chaperone activity in the refolding of denatured prochymosin"
- term:
    id: GO:0003756
    label: protein disulfide isomerase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      Combined IEA annotation for PDI activity based on InterPro and EC number mapping.
      UniProt names this protein "Protein disulfide-isomerase tigA" with EC 5.3.4.1.
      Experimentally, TigA catalyzes refolding of denatured and reduced RNase A via
      disulfide isomerase activity (PMID:16234854).
    action: ACCEPT
    reason: >-
      This is a core molecular function of TigA. The protein belongs to the PDI family,
      has two thioredoxin domains with CXXC active sites, and experimentally demonstrates
      isomerase activity catalyzing RNase A refolding (PMID:16234854).
    supported_by:
      - reference_id: PMID:16234854
        supporting_text: "TIGA acted as an isomerase, catalyzing the refolding of denatured and reduced ribonuclease A."
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      Combined IEA annotation for ER localization based on InterPro (ERp29 domain) and
      PANTHER. TigA has a signal peptide and a C-terminal HDEL ER retention signal
      (positions 356-359), consistent with ER lumen residence.
    action: ACCEPT
    reason: >-
      TigA contains a signal peptide (residues 1-19) and C-terminal ER retention motif
      (HDEL). UniProt annotates subcellular location as ER lumen. This is consistent
      with its function as a PDI in the ER. The more specific term GO:0005788 (ER lumen)
      is also annotated.
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      IEA annotation for ER lumen based on UniProt subcellular location mapping. TigA
      has a signal peptide and C-terminal HDEL ER retention signal, placing it in the
      ER lumen.
    action: ACCEPT
    reason: >-
      Correct and more specific than GO:0005783. TigA is a soluble ER lumen protein
      with signal peptide and HDEL retention motif.
- term:
    id: GO:0016853
    label: isomerase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      IEA annotation for isomerase activity from UniProt keyword mapping. This is a
      broad parent of the more specific GO:0003756 (protein disulfide isomerase activity).
    action: ACCEPT
    reason: >-
      Correct but very broad. The more specific term GO:0003756 is also annotated.
      Acceptable as a broad IEA.
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IDA
  original_reference_id: PMID:16234854
  review:
    summary: >-
      IDA annotation for protein folding from Liang et al. (2005). The study demonstrated
      that TigA assists protein folding through two mechanisms: PDI isomerase activity
      (refolding denatured/reduced RNase A) and chaperone activity (refolding denatured
      prochymosin). The chaperone activity showed substrate specificity, working on
      prochymosin but not on GAPDH (PMID:16234854).
    action: ACCEPT
    reason: >-
      Direct experimental evidence for protein folding activity through both isomerase
      and chaperone mechanisms. This is a core biological process for TigA.
    supported_by:
      - reference_id: PMID:16234854
        supporting_text: "TIGA acted as an isomerase, catalyzing the refolding of denatured and reduced ribonuclease A. TIGA also exhibited chaperone activity in the refolding of denatured prochymosin"
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IDA
  original_reference_id: PMID:16234854
  review:
    summary: >-
      IDA annotation for unfolded protein binding. TigA is a PDI family member with
      demonstrated chaperone activity -- it binds unfolded/denatured prochymosin and
      assists its refolding (PMID:16234854). This binding is part of its genuine
      chaperone function, not merely incidental interaction. GO:0051082 is proposed
      for obsoletion. The appropriate replacement is GO:0044183 (protein folding chaperone),
      which captures the functional role of TigA's binding to unfolded substrates.
    action: MODIFY
    reason: >-
      GO:0051082 is proposed for obsoletion. TigA genuinely binds unfolded proteins
      as part of its chaperone function (PMID:16234854), assisting their refolding.
      This is a true protein folding chaperone activity. The appropriate replacement
      term is GO:0044183 (protein folding chaperone), which accurately describes the
      functional context of TigA's interaction with unfolded substrates. TigA is not
      ATP-dependent, so the non-ATP-dependent parent term is appropriate.
    proposed_replacement_terms:
      - id: GO:0044183
        label: protein folding chaperone
    supported_by:
      - reference_id: PMID:16234854
        supporting_text: "TIGA also exhibited chaperone activity in the refolding of denatured prochymosin but not in the refolding of glyceraldehyde 3-phosphate dehydrogenase (GAPDH), indicating that it had substrate specificity with respect to chaperone activity."
references:
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  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: GO_REF:0000118
  title: TreeGrafter-generated GO annotations
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:9256071
  title: Isolation and characterisation of a novel stress-inducible PDI-family gene
    from Aspergillus niger.
  findings: []
- id: PMID:16234854
  title: Functional analysis of tunicamycin-inducible gene A polypeptide from Aspergillus
    niger.
  findings:
  - statement: TigA has PDI isomerase activity (refolding RNase A)
    supporting_text: "TIGA acted as an isomerase, catalyzing the refolding of denatured and reduced ribonuclease A."
  - statement: TigA has chaperone activity (refolding prochymosin but not GAPDH)
    supporting_text: "TIGA also exhibited chaperone activity in the refolding of denatured prochymosin but not in the refolding of glyceraldehyde 3-phosphate dehydrogenase (GAPDH), indicating that it had substrate specificity with respect to chaperone activity."
  - statement: N-terminal thioredoxin motif is more active than C-terminal
    supporting_text: "The N-terminal trx-motif was more active than the C-terminal trx-motif"
  - statement: First cysteine in each CXXC motif is necessary for isomerase activity
    supporting_text: "the first cysteine in each trx-motif was necessary for isomerase activity."
core_functions:
- description: >-
    Protein disulfide isomerase that catalyzes the rearrangement of disulfide bonds
    in substrate proteins, assisting their folding in the ER lumen.
  molecular_function:
    id: GO:0003756
    label: protein disulfide isomerase activity
  directly_involved_in:
  - id: GO:0006457
    label: protein folding
  locations:
  - id: GO:0005788
    label: endoplasmic reticulum lumen
- description: >-
    Protein folding chaperone with substrate-specific activity. Assists refolding of
    denatured prochymosin through a chaperone mechanism independent of its PDI activity.
  molecular_function:
    id: GO:0044183
    label: protein folding chaperone
  directly_involved_in:
  - id: GO:0006457
    label: protein folding
  locations:
  - id: GO:0005788
    label: endoplasmic reticulum lumen