id: Q8WNR9
gene_symbol: CSTA
product_type: PROTEIN
status: DRAFT
taxon:
  id: NCBITaxon:9685
  label: Felis catus
description: >-
  Cystatin-A (stefin A) of the domestic cat, the allergen Fel d 3. A member of the
  cystatin (type 1 stefin) family, it is a small, single-domain, intracellular
  cysteine-protease inhibitor that reversibly and tightly binds the active site of
  papain-like (C1) cysteine proteases such as cathepsins, thereby negatively
  regulating proteolysis. Predominantly cytosolic, stefin A is also a structural
  precursor of the keratinocyte cornified envelope, crosslinked into the cornified
  layer during epidermal differentiation. It is a minor cat allergen that binds IgE.
existing_annotations:
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Stefin A is a cytosolic (intracellular) protease inhibitor; cytosolic localization is its principal functional compartment.
    action: ACCEPT
    reason: Consistent with the documented intracellular/cytoplasmic localization of cystatin A.
    supported_by:
    - reference_id: file:FELCA/CSTA/CSTA-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0004869
    label: cysteine-type endopeptidase inhibitor activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      The defining molecular function of cystatin A: reversible, tight-binding
      inhibition of papain-like cysteine endopeptidases (e.g. cathepsins B, H, L).
    action: ACCEPT
    reason: Core, family-defining function strongly supported by phylogeny and the curated UniProt function.
    supported_by:
    - reference_id: file:FELCA/CSTA/CSTA-uniprot.txt
      supporting_text: This is an intracellular thiol proteinase inhibitor.
- term:
    id: GO:0004866
    label: endopeptidase inhibitor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: Generic parent of the specific cysteine-type endopeptidase inhibitor activity already annotated.
    action: MARK_AS_OVER_ANNOTATED
    reason: Redundant broad parent; the specific cysteine-type term (GO:0004869) is the informative annotation.
- term:
    id: GO:0004869
    label: cysteine-type endopeptidase inhibitor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Electronic duplicate of the core cysteine-protease inhibitor activity.
    action: ACCEPT
    reason: Consistent with the family-defining inhibitory function.
    supported_by:
    - reference_id: file:FELCA/CSTA/CSTA-uniprot.txt
      supporting_text: This is an intracellular thiol proteinase inhibitor.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: UniProt records cytoplasmic localization for stefin A.
    action: ACCEPT
    reason: Directly supported by the curated subcellular location.
    supported_by:
    - reference_id: file:FELCA/CSTA/CSTA-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000118
  qualifier: located_in
  review:
    summary: Electronic cytosol annotation, consistent with the intracellular localization.
    action: ACCEPT
    reason: Consistent with documented cytoplasmic/cytosolic localization.
- term:
    id: GO:0001533
    label: cornified envelope
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: >-
      Stefin A is a well-known component/precursor of the keratinocyte cornified
      envelope, crosslinked into the cornified layer during epidermal differentiation.
    action: ACCEPT
    reason: Consistent with the established role of cystatin A in the cornified envelope of skin.
- term:
    id: GO:0002020
    label: protease binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: >-
      Cystatin A binds the target protease active site; protease binding is the
      mechanistic basis of its inhibitory activity rather than a separate function.
    action: KEEP_AS_NON_CORE
    reason: Mechanistically part of the inhibitor activity; retained as supporting/non-core.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: >-
      Stefin A is principally intracellular; it appears extracellularly in the skin/
      cornified layer and as an environmental allergen, but the extracellular region
      is not its primary functional compartment.
    action: KEEP_AS_NON_CORE
    reason: Secondary localization; the core functional compartment is the cytosol.
- term:
    id: GO:0030216
    label: keratinocyte differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Consistent with stefin A's contribution to epidermal/keratinocyte differentiation via the cornified envelope.
    action: KEEP_AS_NON_CORE
    reason: Plausible developmental role tied to the cornified-envelope function; electronic, non-core.
- term:
    id: GO:0045861
    label: negative regulation of proteolysis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: The direct biological-process consequence of cysteine-protease inhibition by stefin A.
    action: ACCEPT
    reason: Directly follows from the core inhibitor activity.
    supported_by:
    - reference_id: file:FELCA/CSTA/CSTA-uniprot.txt
      supporting_text: This is an intracellular thiol proteinase inhibitor.
- term:
    id: GO:0098609
    label: cell-cell adhesion
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Electronically transferred cell-cell adhesion association; not a
      well-established function of cystatin A and tangential to its protease-inhibitor
      and cornified-envelope roles.
    action: KEEP_AS_NON_CORE
    reason: Weakly supported electronic annotation; retained as non-core pending evidence.
- term:
    id: GO:1904090
    label: peptidase inhibitor complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: part_of
  review:
    summary: Refers to the stefin A:protease inhibitory complex; consistent with the inhibitor activity.
    action: KEEP_AS_NON_CORE
    reason: Describes the transient inhibitor-protease complex; supporting/non-core.
core_functions:
- description: >-
    Intracellular (cytosolic) tight-binding inhibitor of papain-like cysteine
    endopeptidases (cathepsins), thereby negatively regulating intracellular
    proteolysis. Stefin A is additionally crosslinked into the keratinocyte
    cornified envelope during epidermal differentiation (a secondary structural role).
  molecular_function:
    id: GO:0004869
    label: cysteine-type endopeptidase inhibitor activity
  directly_involved_in:
  - id: GO:0045861
    label: negative regulation of proteolysis
  supported_by:
  - reference_id: file:FELCA/CSTA/CSTA-uniprot.txt
    supporting_text: This is an intracellular thiol proteinase inhibitor.
  locations:
  - id: GO:0005829
    label: cytosol
proposed_new_terms: []
suggested_questions:
- question: >-
    Which cat cysteine proteases (cathepsin orthologs) are the physiological targets
    of Fel d 3, and does its inhibitory profile match human stefin A?
  experts: []
suggested_experiments:
- hypothesis: Fel d 3 inhibits papain-family cysteine proteases with the canonical stefin-A specificity.
  description: >-
    Express recombinant Fel d 3 and measure Ki against papain and cathepsins B/H/L
    in vitro; confirm the wedge-type active-site interaction by co-structure or
    mutagenesis of the conserved QxVxG motif.
  experiment_type: enzymatic / biochemical inhibition assay
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:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  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: file:FELCA/CSTA/CSTA-uniprot.txt
  title: UniProt entry Q8WNR9 (CYTA_FELCA), Cystatin-A / Fel d 3
  findings:
  - statement: Cat cystatin-A is an intracellular thiol (cysteine) proteinase inhibitor localized to the cytoplasm; it is an IgE-binding allergen (Fel d 3).
    supporting_text: This is an intracellular thiol proteinase inhibitor.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Curated UniProt record; source for the core cysteine-protease inhibitor activity and cytoplasmic localization.