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Fel d 1

The domestic cat (Felis domesticus) is one of the most common household pets as well as a significant source of indoor allergens. IgE-mediated sensitization to allergens from F. domesticus affects approximately 10% of the Western world. The severity of symptoms ranges from mild rhinitis to life-threatening asthmatic responses. F. domesticus allergen 1 (Fel d 1) is the most prominent and potent allergen in cat dander and was first identified more than three decades ago.

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Function

It has been suggested that its role is to protect the skin, by homology with the uteroglobin whose function is to protect mucosa. Other authors believe that Fel d 1 would rather have a role in the transport of lipid molecules, especially steroids, hormones or pheromones.

Disease

The crystal structure of the recombinant FEL d 1 has seen to be extremely similar to the structure of uteroglobin, a steroid-inducible cytokine-like molecule with potent anti-inflammatory and immunomodulatory properties known for being a founding member of the secretoglobin family.The uteroglobin Clara Cell 16 (CC16) is a known member of this family.


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CC16 is known to have the lung as the major site of CC16 production. Studies with a CC16 knock out has been showed to be providing a protective effect in the lungs against several pathogens, and playing a role in the control of inflammation. CC16 were downregulated in patients with allergic rhinitis. Human secretoglobin gene has been mapped to a region of chromosome 11 previously linked to both atopy and bronchial hyperresponsiveness.

It has been demonstrated that uteroglobin are potent inhibitors of extracellular phospholipase A2 (PLA2) activity and that these anti-inflammatory activities appear to reside in a nonapeptide region of the third α-helix of uteroglobin. Modulation of PLA2 may affect the biosynthesis of eicosanoids and platelet-activating factors, potent mediators of inflammatory and allergic responses. Uteroglobin only inhibits the function of the enzyme PLA2 when the concentration of Ca2+, an essential cofactor for PLA2, becomes limiting. It has also been proposed that uteroglobin may inhibit PLA2 by sequestering Ca ions.

The striking structural similarity of the major cat allergen to uteroglobin, coupled to the identification in the present study of a common Ca2+-binding site, let speculate that Fel d 1 could provoke an allergic response through the modulation of phospholipase A2, by sequestering Ca ions in a similar manner as previously suggested for uteroglobin.

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Structural highlights

3D image of Fel d 1 molecule

Fel d 1 has been reported as a 35 kDa tetrameric glycoprotein formed by two heterodimers, consisting of named H1–H4 (corresponding to chain 1) and H5–H8 (corresponding to chain 2). Each heterodimer consists of one 70 residue peptide and one 85, 90, or 92 residue peptide (i.e. chains 1 and 2, respectively) encoded by separate genes. These chains are linked within each heterodimer through three disulfide bonds, formed between cysteine residues Cys3 and Cys73, Cys44 and Cys48, and Cys70 and Cys7, in chains 1 and 2, respectively.

In the image below, we can see the 3 disulfide bonds in red:

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Crystal structure

The crystal structure of Fel d 1 tetramer, at 1.6 Å resolution, displays a globular all helical fold that composed of two , having four Ca ions, 270 water molecules, a and a . As said before each subunit of the Fel d 1 consists of eight helices named H1–H4 (corresponding to chain 1) and H5–H8 (corresponding to chain 2).

A total of four Ca ions are present in the crystal structure of the Fel d 1. One Ca2+ (site 1) is bound within the dimerization interface, resulting in profound local conformational changes. The binding of the Ca2+ in this region of the Fel d 1 interface most probably stabilizes the tetrameric form, since the presence of such a positively charged ion allows for the packing of acidic residues ( Asp130 in subunits A and B) in the Fel d 1 tetramer interface. However, at the same time it also results in profound local conformational changes that affect the size and form of the different cavities. Two additional Ca2+-binding sites are also present on both sides of the tetramer, localized at exactly the same position as suggested for Ca2+ binding sites in uteroglobin, one on each of the heterodimeric subunits A and B. At last Ca2+ site has been shown, however the position of this ion is most probably due to the packing of the molecules in the asymmetric unit.

In the image below, the CA2+ ions are represented in red. In (A) we can see two Ca2+-binding site localized at exactly the same position as suggested for Ca2+ binding sites in uteroglobin. (B) Ca2+ bound within the dimerization interface. (C) amplified vision of the Ca2+-binding site localized at exactly the same position as suggested for Ca2+ binding sites in uteroglobin. (D) amplified Ca2+ bound within the dimerization interface. (Kaiser, 2007)

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The crystal structure of Fel d 1 also suggests a potential portal for two waterfilled cavities of different size, one in each monomer.


The binding of a Ca2+ in the dimerization interface results in a profound local conformational change

The dimerization interface in the crystal structure of Fel d 1 (1 + 2), mainly composed of helices H5 and H8 from chain 2 in each subunit The Fel d 1 (1 + 2) dimerization interface is composed of 65 residues, 31 and 34 from subunits A and B, respectively. Additionally, 46 water molecules and one Ca2+ are present between the two subunits. Six residues (Phe85, Gly131 and Leu132 from subunits A and B) form a . Ca2+ in this region of the Fel d 1 interface stabilizes the tetrameric form, since the presence of such a positively charged ion allows for the packing of acidic residues (Asp130 in subunits A and B) in the Fel d 1 tetramer interface. As consequence of that it also changes conformation affecting the size and form of the different cavities.

In the image below, we see the CA2+ located in the dimerization interface in red and its interection with the surounding (Kaiser, 2007).

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References

Karn RC. The mouse salivary androgen-binding protein (ABP) alpha subunit closely resembles chain 1 of the cat allergen Fel dI. Biochem Genet. 1994;32:271–277.

Vervloet D, Birnbaum J. Origine des allergènes du chat. Rev Fr Allergol. 1995;35:533–538.

Kaiser L, Velickovic TC, Badia-Martinez D, Adedoyin J, Thunberg S, Hallén D, et al. Structural characterization of the tetrameric form of the major cat allergen Fel d 1. J Mol Biol. 2007;370:714–727.

Kaiser L, Grönlund H, Sandalova T, Ljunggren H-G, van Hage-Hamsten M, Achour A, et al. The crystal structure of the major cat allergen Fel d 1, a member of the secretoglobin family. J Biol Chem. 2003;278:37730–37735.

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Alice Kei Endo

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