Cross-reactivity and 1.4-A crystal structure of Malassezia sympodialis thioredoxin (Mala s 13), a member of a new pan-allergen family.
We have identified thioredoxins (Trx) of Malassezia sympodialis, a yeast involved in the pathogenesis of atopic eczema, and of Aspergillus fumigatus, a fungus involved in pulmonary complications, as novel IgE-binding proteins. We show that these Trx, including the human enzyme, represent cross-reactive structures recognized by serum IgE from individuals sensitized to M. sympodialis Trx. Moreover, all three proteins were able to elicit immediate-type allergic skin reactions in sensitized individuals, indicating a humoral immune response based on molecular mimicry. To analyze structural elements involved in these reactions, the three-dimensional structure of M. sympodialis Trx (Mala s 13) has been determined at 1.4-A resolution by x-ray diffraction analysis. The structure was solved by molecular replacement and refined to a crystallographic R factor of 14.0% and a free R factor of 16.8% and shows the typical Trx fold. Mala s 13 shares 45% sequence identity with human Trx and superposition of the solved Mala s 13 structure with those of human Trx reveals a high similarity with a root mean square deviation of 1.11 A for all Calpha atoms. In a detailed analysis of the molecular surface in combination with sequence alignment, we identified conserved solvent-exposed amino acids scattered over the surface in both structures which cluster to patches, thus forming putative conformational B cell epitopes potentially involved in IgE-mediated cross- and autoreactivity.
Limacher
Andreas
A
Swiss Institute of Allergy and Asthma Research (SIAF), Davos, Switzerland.
Glaser
Andreas G
AG
Meier
Christa
C
Schmid-Grendelmeier
Peter
P
Zeller
Sabine
S
Scapozza
Leonardo
L
Crameri
Reto
R
D000328:Adult; D000485:Allergens / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D000595:Amino Acid Sequence; D000908:Antibodies, Fungal / Q000097:blood; D003001:Cloning, Molecular; D003429:Cross Reactions; D018360:Crystallography, X-Ray; D005260:Female; D005656:Fungal Proteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology; D008290:Malassezia / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D013879:Thioredoxins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*
D000485:Allergens; D000908:Antibodies, Fungal; D005656:Fungal Proteins; D011994:Recombinant Proteins; D007073:Immunoglobulin E; D013879:Thioredoxins