Chain 1 (alpha chain) of the major cat allergen Fel d 1, a secreted secretoglobin (uteroglobin-family) glycoprotein of the domestic cat. The mature 70-residue chain 1 pairs with chain 2 (CH2) through three interchain disulfide bonds to form a heterodimer; two heterodimers associate non-covalently into the ~35-38 kDa Fel d 1 heterotetramer. The all-alpha secretoglobin fold closely resembles uteroglobin and encloses an internal hydrophobic cavity; the tetramer binds calcium ions at defined sites and binds small hydrophobic ligands, including fatty acids and steroids (e.g. lauric acid and the steroid pheromone androsterone). Fel d 1 also binds bacterial lipopolysaccharide and, by a CD14/MD2-dependent lipid-transfer mechanism, enhances TLR4/TLR2 innate immune signaling. It is secreted, produced chiefly by sebaceous glands and also found in saliva, anal glands, skin and fur, with production regulated by testosterone. Its endogenous biological function in the cat is unresolved, with proposed roles in transport/presentation of lipophilic signaling molecules (pheromones), epithelial protection and immunoregulation. It is the dominant cat allergen, recognized by IgE in the great majority of cat-allergic people.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005496 steroid binding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic (IBA) inference of steroid binding from the secretoglobin/ uteroglobin family. This is corroborated by ligand-binding data: Fel d 1 is reported to bind fatty acids and steroids with good affinity (best ligands lauric acid and androsterone, a volatile steroid pheromone), consistent with the internal hydrophobic cavity of the secretoglobin fold. The term is therefore a genuine activity, but likely one facet of a broader small- hydrophobic-ligand binding / transport role rather than the single core function, so it is retained as non-core. Reason: Beyond the family-level inference, Fel d 1 has reported affinity for steroids (androsterone) and fatty acids (lauric acid), so steroid binding is supported rather than spurious. It is kept as non-core because it represents one of several ligand-binding activities and the physiological role of this binding (e.g. pheromone transport) is not established. Supporting Evidence: PMID:34026578 binding with good affinity to some fatty acids and steroids, the best ligands being lauric acid PMID:12851385 Fel d 1 that could bind an endogenous ligand |
| GO:0005576 extracellular region | IBA GO_REF:0000033 | ACCEPT | Summary: Fel d 1 is a secreted protein, consistent with the extracellular region annotation. It is produced mainly by sebaceous glands and is also found in saliva, anal glands, skin and fur, and is ubiquitous in cat-inhabited environments. Reason: The secretoglobin Fel d 1 is experimentally established as a secreted protein, so localization to the extracellular region is well supported. Supporting Evidence: PMID:29643919 It is now recognized that the sebaceous glands, and not saliva, are the main production site |
| GO:0005496 steroid binding | IEA GO_REF:0000118 | KEEP AS NON CORE | Summary: TreeGrafter (IEA) duplicate of the steroid-binding inference. As for the IBA annotation, this is corroborated by reported binding of Fel d 1 to steroids and fatty acids, so it is retained as a non-core ligand-binding activity. Reason: Steroid binding is supported by ligand-binding data (androsterone, lauric acid) in addition to the family inference, but is one of several ligand- binding activities and not the single core function. Supporting Evidence: PMID:34026578 binding with good affinity to some fatty acids and steroids, the best ligands being lauric acid |
| GO:0005576 extracellular region | IEA GO_REF:0000120 | ACCEPT | Summary: Automated subcellular-location annotation (UniProt "Secreted") consistent with the experimentally established secretion of Fel d 1. Reason: Fel d 1 is a secreted secretoglobin; the extracellular region location is correct and corroborated by experimental localization to saliva and sebaceous gland secretions. Supporting Evidence: PMID:29643919 It is now recognized that the sebaceous glands, and not saliva, are the main production site |
| GO:0005509 calcium ion binding | IDA PMID:17543334 Structural characterization of the tetrameric form of the ma... | NEW | Summary: NEW (proposed). The crystal structure of the tetrameric form of Fel d 1 resolves two distinct calcium-binding sites, and UniProt records three calcium-coordinating residues (68, 71, 74) in chain 1. Calcium binding is the only ligand-binding activity experimentally demonstrated for Fel d 1 and is not currently captured in the GOA annotations. Reason: Direct structural evidence supports calcium ion binding by the Fel d 1 tetramer, with chain 1 contributing calcium-coordinating residues. This is a better-supported molecular function than the family-propagated steroid binding term and should be added. Supporting Evidence: PMID:17543334 structure of tetrameric Fel d 1 reveals two different calcium-binding sites file:FELCA/CH1/CH1-uniprot.txt Chelates calciums ions and may inhibit the activity of |
| GO:0001530 lipopolysaccharide binding | IDA PMID:23878318 Allergens as immunomodulatory proteins: the cat dander prote... | NEW | Summary: NEW (proposed). Fel d 1 directly binds the TLR4 agonist lipopolysaccharide (LPS) and is proposed to act via a lipid-transfer mechanism (CD14/MD2- dependent), enhancing innate immune signaling. This is the best-characterized molecular activity of the protein and is not captured in GOA. Reason: Direct experimental evidence (Herre et al. 2013) shows Fel d 1 binds LPS, explaining its ability to enhance TLR4/TLR2 signaling. Largely demonstrated in the context of human innate-immune amplification/allergenicity rather than confirmed cat physiology, but it is a bona fide molecular function. Supporting Evidence: PMID:23878318 bind to the TLR4 agonist LPS file:FELCA/CH1/CH1-deep-research-falcon.md facilitating lipid transfer to CD14 and the TLR signaling complex |
| GO:0034145 positive regulation of toll-like receptor 4 signaling pathway | IDA PMID:23878318 Allergens as immunomodulatory proteins: the cat dander prote... | NEW | Summary: NEW (proposed). By binding LPS and transferring it to the TLR4 receptor complex, Fel d 1 substantially enhances signaling through TLR4 (and TLR2), potentiating innate immune (TNF-alpha) responses to bacterial lipid ligands. Reason: Herre et al. 2013 showed Fel d 1 enhances TLR4/TLR2 signaling in response to lipid agonists. This immunomodulatory activity is the proposed basis of its allergenicity; well supported as a molecular activity though distinct from the cat's own (unknown) physiology. Supporting Evidence: PMID:23878318 enhances signaling through the innate receptors TLR4 and TLR2 |
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Download this section (compressed HTML)Q: What is the endogenous amphipathic ligand (if any) that occupies the internal cavity of the Fel d 1 tetramer, and does chain 1 contribute to its binding?
Q: Does Fel d 1 modulate calcium-dependent phospholipase A2 activity in vivo, as has been speculated by analogy to uteroglobin?
Q: Is the physiological role of Fel d 1 in the cat one of skin/epithelial barrier protection, lipid/pheromone transport, or something else?
Experiment: Perform untargeted lipidomics/metabolomics on ligands co-purifying with native Fel d 1 isolated from cat sebaceous secretions, and confirm direct binding and affinity of candidate ligands to recombinant Fel d 1 by isothermal titration calorimetry and co-crystallization.
Hypothesis: The Fel d 1 internal cavity binds a specific endogenous amphipathic ligand (e.g. a steroid, fatty acid, or pheromone).
Type: ligand identification / biophysical binding assay
Experiment: Reconstitute a calcium-dependent PLA2 activity assay in the presence and absence of folded recombinant Fel d 1 (and Ca2+-binding-site mutants) to test for PLA2 inhibition and its calcium dependence.
Hypothesis: Calcium binding by the Fel d 1 tetramer enables sequestration that inhibits calcium-dependent phospholipase A2 activity.
Type: enzymatic / biochemical assay
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