Baxter Richard H G, Chang Chung-I, Chelliah Yogarany, Blandin Stéphanie, Levashina Elena A, Deisenhofer Johann
Howard Hughes Medical Institute and Department of Biochemistry, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390-9050, USA.
Proc Natl Acad Sci U S A. 2007 Jul 10;104(28):11615-20. doi: 10.1073/pnas.0704967104. Epub 2007 Jul 2.
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.
含硫酯蛋白（TEPs）是昆虫对细菌和原生动物入侵的固有免疫反应的主要组成部分。TEPs构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隐蔽的硫酯键，在蛋白质的蛋白酶敏感区域被切割后，该键被激活并与靶标共价结合。最近，来自疟疾媒介冈比亚按蚊的TEP1被证明可介导对伯氏疟原虫动合子的识别和杀伤，伯氏疟原虫是人类疟原虫恶性疟原虫的一个模型。在此，我们展示了TEP1同工型TEP1r的晶体结构。尽管TEP1r的整体蛋白质折叠与补体因子C3相似，但在没有补体因子的核心成分过敏毒素结构域的情况下，TEP1r结构域会重新定位以稳定分子的无活性构象（包含完整的硫酯）。TEP1r的结构为TEP1等位基因TEP1r和TEP1s之间的差异提供了分子基础，这些差异与冈比亚按蚊对伯氏疟原虫感染的抗性相关。
