Fel d 1 chain 1 (CH1, UniProt P30438) — curation notes

Curation triggered by the review article PMC5891966 / PMID:29643919
(Bonnet et al. 2018, Allergy Asthma Clin Immunol, "An update on molecular cat
allergens: Fel d 1 and what else? Chapter 1: Fel d 1, the major cat allergen").

Identity

• UniProt P30438, FEL1A_FELCA, gene name CH1 (chain 1 / α-chain).
• 92 aa precursor; signal 1–22, mature chain 23–92 (~70 aa, ~8 kDa).
• The complete Fel d 1 allergen is a ~35–38 kDa heterotetramer: two heterodimers,
  each a chain 1 (CH1, this gene, P30438) + chain 2 (CH2, P30440) pair, the two
  chains covalently linked by three interchain disulfide bonds; encoded by two
  separate genes PMID:29643919.

Family / fold

• Member of the secretoglobin (uteroglobin) family; all-α fold of eight
  helices PMID:29643919.
• Crystal structure shows striking similarity to uteroglobin (a steroid-inducible,
  cytokine-like, anti-inflammatory/immunomodulatory molecule)
  PMID:12851385.

Molecular function (what is actually known vs inferred)

• Calcium ion binding — experimentally supported. The tetramer crystal
  structure reveals two distinct Ca2+-binding sites; UniProt records three Ca2+
  binding residues (68, 71, 74)
  PMID:17543334.
• Steroid/ligand binding — NOT demonstrated, only a structural possibility.
  The structures show an internal asymmetric cavity that could accommodate an
  amphipathic endogenous ligand; no steroid (or other ligand) has been shown to
  bind PMID:12851385.
  The IBA/IEA "steroid binding" GO annotation is a family-level (uteroglobin)
  inference, not evidence for this protein → treated as over-annotation.
• Phospholipase A2 modulation — speculation. By analogy to uteroglobin, Fel d 1
  is speculated to modulate PLA2 by sequestering Ca2+
  PMID:17543334.
  UniProt summarizes this as "Chelates calciums ions and may inhibit the activity of
  calcium-dependent phospholipase A2." Too tentative for a confident MF assignment.
• Biological function genuinely unknown. Proposed (unproven) roles: skin
  protection (uteroglobin analogy) or transport of lipids/steroids/hormones/
  pheromones PMID:29643919.

Localization / expression

• Secreted protein [UniProt SUBCELLULAR LOCATION: Secreted].
• Produced mainly in sebaceous glands (not saliva, as once thought); also in
  saliva, anal glands, skin and fur
  PMID:29643919.
• → "extracellular region" (GO:0005576) annotations are appropriate.

Allergen biology (context, not core evolved function)

• Major cat allergen; >80–95% of cat-allergic patients have anti-Fel d 1 IgE;
  accounts for 60–90% of cat allergenic activity; binds IgE; drives Th2 responses;
  recognized by the mannose receptor on antigen-presenting cells
  PMID:29643919.
• IgE binding (GO:0019863) is a real molecular activity but reflects allergenicity
  toward humans, not the protein's endogenous evolved function in cat.

Curation decisions (existing GOA annotations)

1. GO:0005496 steroid binding (IBA, GO_REF:0000033) → MARK_AS_OVER_ANNOTATED
   (family inference; no direct evidence Fel d 1 binds steroids).
2. GO:0005576 extracellular region (IBA, GO_REF:0000033) → ACCEPT (secreted).
3. GO:0005496 steroid binding (IEA, GO_REF:0000118) → MARK_AS_OVER_ANNOTATED.
4. GO:0005576 extracellular region (IEA, GO_REF:0000120) → ACCEPT (secreted).

core_functions: documented MF = calcium ion binding (GO:0005509) in the
extracellular region; in vivo biological role recorded as a knowledge gap.

Key references

• PMID:29643919 — review (curation target), full text in PMC.
• PMID:12851385 — monomeric crystal structure; secretoglobin/uteroglobin fold; cavity.
• PMID:17543334 — tetramer crystal structure; two Ca2+-binding sites; PLA2 speculation.
• PMID:1946388 — Fel d 1 protein sequence + cDNA cloning.
• PMID:1572548 — genomic structure of the two Fel d 1 genes.
• PMID:1712068 — biochemical structure of the major cat allergen.
• PMID:6747135 — Cat allergen 1 biochemical/antigenic/allergenic properties.

Update: Falcon deep research integration (CH1-deep-research-falcon.md)

Ran FutureHouse Falcon deep research (34 citations). Key additions beyond the
original PMC5891966-based review, with primary sources fetched and verified:

New molecular activity — LPS binding + TLR4/TLR2 enhancement (experimental)

Herre et al. 2013 (PMID:23878318, full text in PMC) is the best-characterized
molecular activity of Fel d 1:
- "Fel d 1 substantially enhances signaling through the innate receptors TLR4 and TLR2"
PMID:23878318.
- Fel d 1 binds the TLR4 agonist LPS, acting via a lipid-transfer mechanism (CD14/MD2-
dependent) rather than by mimicking MD2
PMID:23878318.
→ Supports NEW annotations: lipopolysaccharide binding (GO:0001530) and positive
regulation of toll-like receptor 4 signaling pathway (GO:0034145). This is shown
largely in the context of human allergic sensitization/innate amplification, not
confirmed cat physiology, but it is a bona fide molecular activity of the protein.

Ligand binding revises the "steroid binding" assessment

Popescu et al. 2021 (PMID:34026578) reports that Fel d 1 binds fatty acids and
steroids with good affinity:
- PMID:34026578
(lauric acid; androsterone — a volatile steroid pheromone).
→ The IBA/IEA "steroid binding" (GO:0005496) is therefore NOT merely a baseless
family inference; there is reported ligand-binding evidence. Revised from
MARK_AS_OVER_ANNOTATED to KEEP_AS_NON_CORE: a real activity, plausibly part of a
broader small-hydrophobic-ligand binding / transport (pheromone) role, but not the
single core function. Fatty acid binding (lauric acid) is also reported.

Native function still unknown; expression is androgen-regulated

• Native biological function in the cat remains formally unestablished
  (Grönlund 2010 PMID:19844127; Popescu 2021); proposed roles: lipid/steroid (pheromone)
  transport, chemical communication, epithelial/skin defense, immunoregulation.
• Production is testosterone-regulated (intact males >> neutered); secreted by
  sebaceous, salivary, lacrimal glands and anal sacs.
• Secretoglobin superfamily binds retinoids, phospholipids, steroids and calcium
  (Karn & Laukaitis 2025); no SCGB has a firmly established function.

Newly added/verified references

• PMID:23878318 — Herre 2013, Fel d 1 enhances TLR activation by lipid ligands (PMC full text).
• PMID:19844127 — Grönlund 2010, major cat allergen Fel d 1 in diagnosis and therapy (review).
• PMID:34026578 — Popescu 2021, molecular diagnosis in cat allergy (review; ligand data).
• file:FELCA/CH1/CH1-deep-research-falcon.md — Falcon deep research report.