Cross-reactivity and 1.4-Å crystal structure of Malassezia sympoldialis thioredoxin (Mala s 13), a member of a new pan-allergen family'
Cross-reactivity and 1.4-Å crystal structure of Malassezia sympoldialis thioredoxin (Mala s 13), a member of a new pan-allergen family'
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DOI：
10.4049/jimmunol.178.1.389
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发表时间：
2007-01-01
影响因子：
4.4
通讯作者：
Crameri, Reto
中科院分区：
文献类型：
--
作者：
Limacher, Andreas;Glaser, Andreas G.;Crameri, Reto
我们已经鉴定了与特应性湿疹发病相关的酵母马拉色菌的硫氧还蛋白(TRX)和与肺部并发症有关的真菌烟曲霉的硫氧还蛋白(TRX)是新的IgE结合蛋白。我们表明，这些Trx，包括人的酶，代表交叉反应结构，被血清IgE识别来自对交链支原体Trx致敏的个体。此外，这三种蛋白质都能在致敏个体中引发即刻类型的皮肤过敏反应，表明这是一种基于分子模仿的体液免疫反应。为了分析这些反应中所涉及的结构元素，用X射线衍射法测定了相交支原体(玛拉S 13)在1.4埃分辨率下的三维结构。通过分子置换得到晶体结构的R因子为14.0%，自由R因子为16.8%，呈现典型的Trx折叠。Mala S 13与人Trx的序列同源性为45%，所解的Mala S 13的结构与人Trx的结构重叠显示出高度的相似性，所有Cα原子的均方根偏差为1.11埃。在结合序列比对的分子表面的详细分析中，我们发现保守的溶剂暴露的氨基酸分布在两个结构的表面上，这些结构聚集成补丁，从而形成可能参与IgE介导的交叉反应和自身反应的构象B细胞表位。
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-angstrom 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 angstrom for all C alpha 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.