Structural basis for conserved complement factor-like function in the antimalarial protein TEN
Structural basis for conserved complement factor-like function in the antimalarial protein TEN
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DOI：
10.1073/pnas.0704967104
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发表时间：
2007-07-10
影响因子：
11.1
通讯作者：
Deisenhofer, Johann
中科院分区：
文献类型：
--
作者：
Baxter, Richard H. G.;Chang, Chung-I;Deisenhofer, Johann
含硫酯蛋白（TEPs）是昆虫对细菌和原生动物入侵的先天免疫反应的主要组成部分。TEPs形成了一个超家族的独特分支，该超家族包括泛蛋白酶抑制剂α（2）-巨球蛋白和脊椎动物补体因子。这些蛋白质的基本特征是一个螯合的硫酯键，在蛋白质的蛋白酶敏感区域切割后，被激活并共价结合到其靶标上。最近，来自疟疾载体冈比亚按蚊的TEP 1显示出介导来自疟疾寄生虫伯氏疟原虫（Plasmodium berghei）的动合子的识别和杀死，伯氏疟原虫是人类疟疾寄生虫恶性疟原虫（Plasmodium falciparum）的模型。在这里，我们提出了TEP 1亚型TEP 1 r的晶体结构。虽然TEP 1 r的整体蛋白质折叠类似于补体因子C3，但TEP 1 r结构域被重新定位，以在没有葡萄球菌毒素结构域（补体因子的中心组分）的情况下稳定分子的非活性构象（含有完整的硫酯）。TEP 1 r基因的结构为TEP 1等位基因TEP 1 r和TEP 1 s之间的差异提供了分子基础，而TEP 1 r和TEP 1 s的差异与A.冈比亚感染伯氏疟原虫。
Thioester-containing proteins (TEPs) are a major component of the innate immune response of insects to invasion by bacteria and protozoa. TEPs form a distinct clade of a superfamily that includes the pan-protease inhibitors alpha(2)-macroglobulins and vertebrate complement factors. The essential feature of these proteins is a sequestered thioester bond that, after cleavage in a protease-sensitive region of the protein, is activated and covalently binds to its target. Recently, TEP1 from the malarial vector Anopheles gambiae was shown to mediate recognition and killing of ookinetes from the malarial parasite Plasmodium berghei, a model for the human malarial parasite Plasmodium falciparum. Here, we present the crystal structure of the TEP1 isoform TEP1r. Although the overall protein fold of TEP1r resembles that of complement factor C3, the TEP1r domains are repositioned to stabilize the inactive conformation of the molecule (containing an intact thioester) in the absence of the anaphylotoxin domain, a central component of complement factors. The structure of TEP1r provides a molecular basis for the differences between TEP1 alleles TEP1r and TEP1s, which correlate with resistance of A. gambiae to infection by P. berghei.