X-RAY CRYSTAL-STRUCTURES OF BIRCH POLLEN PROFILIN AND PHL P2

Background: Type 1 allergy affects 20% of industrialized populations a nd thus represents a major health care issue. The symptoms of type 1 a llergy, which include rhinitis, conjunctivitis, dermatitis and asthma, are elicited by the crosslinking of IgE receptors through polyvalent allergens. A detailed understanding of the cell surface phenomena and the rational development of new therapies require high-resolution stru ctural information. Methods: The structures of two widespread allergen s, birch pollen profilin (BPP) and Phl p 2 have been solved by multipl e isomorphous replacement. Refinements are underway to 2.4 and 2.0 Ang strom, respectively. In addition, the IgE-reactive epitopes of BPP whe re identified by screening an epitope expression library with the seru m IgE of an allergic individual. Results: BPP exhibits an alpha/beta-f old which is similar to the mammalian and amoeba profilins. The struct ure of Phl p 2 is a compact eight-stranded beta-barrel. Screening an e pitope library of BPP identified three major epitopic regions involved in IgE binding, including the amino and carboxy-terminal alpha-helice s. These regions also interact with the physiologically relevant ligan ds of profilin, actin and proline-rich peptides. Conclusions: The dist ribution of IgE-binding sites on BPP allows for the productive interac tion with IgE antibodies of different epitope specificities required f or efficient signal transduction. These epitopes correspond to the mos t highly conserved regions of the profilin molecule and thus provide t he molecular basis for allergen cross-sensitivity. Due to steric consi derations, the involvement of these epitopic regions in the binding of physiologically relevant profilin ligands indicates that the native p rofilin is the species responsible for eliciting the allergic response . A comparison of the BPP and Phl p 2 structures shows that there is n o preference for secondary structural elements in the allergic respons e. The detailed chemical and physical description of the major reactiv e epitopes provides a data base for the design of tight-binding monova lent ligands which can prevent receptor aggregation and thereby reduce the allergic response.