The Calcium Goes Meow: Effects of Ions and Glycosylation on Fel d 1, the Major Cat Allergen

Abstract

The major cat allergen, Fel d 1, is a structurally complex protein with two N-glycosylation sites that may be filled by different glycoforms. In addition, the protein contains three putative Ca2+ binding sites. Since the impact of these Fel d 1 structure modifications on the protein dynamics, physiology and pathology are not well established, the present work employed computational biology techniques to tackle these issues. While conformational effects brought upon by glycosylation were identified, potentially involved in cavity volume regulation, our results indicate that only the central Ca2+ ion remains coordinated to Fel d 1 in biological solutions, impairing its proposed role in modulating phospholipase A2 activity. As these results increase our understanding of Fel d 1 structural biology, they may offer new support for understanding its physiological role and impact into cat-promoted allergy.

The Major Cat Allergen Fel d 1 Binds Steroid and Fatty Acid Semiochemicals: A Combined In Silico and In Vitro Study

“…In the same way, the amino acids Glu75, Thr76, Pro78, Tyr81, Asp82, Phe85, Gly131, Thr135, and Ser138 (all corresponding to only chain 2 residues of the natural Fel d 1 [48]) displayed predicted hydrophobic interactions with the steroids. The present results are in agreement with the few steroid interactions previously described in Fel d 1 [23]. In particular, Tyr21 was previously reported to be highly conserved in several secretoglobins [25] and possibly involved in ligand binding [49,50].…”

“…Even minor changes may affect the binding activity of a protein: for instance, several authors have shown that post-translational modifications, such as phosphorylation and O-glycosylation, influence the binding profiles of pig OBP isoforms, and phosphorylation can even enhance the binding affinities for some compounds in native OBPs compared to their recombinant counterparts [45,53,54]. It was also hypothesized that the glycosylation pattern of Fel d 1 might affect its structural features, notably by reducing its cavity size, thus possibly altering/modulating its ligand-binding properties [23]. Therefore, we cannot exclude that differences between natural and recombinant forms of Fel d 1 may affect the binding properties of the protein.…”

“…Structural similarities between Fel d 1 and another secretoglobin involved in mice mate selection and communication, the mouse salivary androgen-binding protein (ABP) [18], have been previously described [24,25]. Binding of some steroids to members of the secretoglobin family was previously reported, involving interactions with their central hydrophobic cavity [19,23,26]. In particular, a recent paper extensively describes the evolutionary divergence, functional sites, and surface structural resemblance between Fel d 1 and ABP, suggesting that the first protein could be involved in semiochemical transport/processing in intra-species communication [25].…”

“…Besides, Fel d 1 immunological features have been linked to cat sex and behavior [22]. From a structural perspective, Fel d 1 also displays interesting features regarding ligand binding capabilities due to the presence of two internal cavities [23]. Structural similarities between Fel d 1 and another secretoglobin involved in mice mate selection and communication, the mouse salivary androgen-binding protein (ABP) [18], have been previously described [24,25].…”

An overview of the effect of diet on the allergenicity of cats to susceptible humans

“…It has been found that each Fel d 1 heterodimer has a cavity that is capable of interacting with ligands such as testosterone, progesterone and polychlorinated biphenyl (PCB), a steroid analog, like uteroglobin. Furthermore, it has been reported that the Fel d 1 molecule is N-glycolasylated and has three putative calcium binding sites, which may play a role in the immune response [13].…”