Structural Variations within the Transferrin Binding Site on Transferrin-binding Protein B, TbpB
Structural Variations within the Transferrin Binding Site on Transferrin-binding Protein B, TbpB
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DOI：
10.1074/jbc.m110.206102
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发表时间：
2011-04-08
影响因子：
4.8
通讯作者：
Moraes, Trevor F.
中科院分区：
文献类型：
--
作者：
Calmettes, Charles;Yu, Rong-hua;Moraes, Trevor F.
病原菌通过专门的摄取途径获得必需元素铁，这在宿主的铁限制环境中是必需的。革兰氏阴性奈瑟氏球菌科和巴斯德氏菌科的成员已经适应通过由转铁结合蛋白（Tbp）A和B组成的受体复合物从宿主铁结合糖蛋白转铁蛋白（Tf）获得铁。由于它们在宿主中发挥的关键作用，这些表面暴露的蛋白质总是存在于临床分离株中，因此被认为是主要的疫苗靶标。TbpB和Tf之间的特异性相互作用是必不可少的，并最终可能被利用来创建广谱疫苗。在这项研究中，我们报告的TbpBs的结构，从两个猪病原体，胸膜肺炎放线杆菌和猪。奇怪的是，尽管有共同的Tf靶标，但这些猪相关的TbpB在其Tf结合位点显示出实质性的序列变异。TbpB的结构，支持对接模拟，表面等离子体共振和氢/氘交换实验与野生型和突变型TbpB，解释了为什么有结构保守的元素TbpB同源物，尽管主要的序列变异所需的结合Tf。
Pathogenic bacteria acquire the essential element iron through specialized uptake pathways that are necessary in the iron-limiting environments of the host. Members of the Gram-negative Neisseriaceae and Pasteurellaceae families have adapted to acquire iron from the host iron binding glycoprotein, transferrin (Tf), through a receptor complex comprised of transferring-binding protein (Tbp) A and B. Because of the critical role they play in the host, these surface-exposed proteins are invariably present in clinical isolates and thus are considered prime vaccine targets. The specific interactions between TbpB and Tf are essential and ultimately might be exploited to create a broad-spectrum vaccine. In this study, we report the structure of TbpBs from two porcine pathogens, Actinobacillus pleuropneumoniae and suis. Paradoxically, despite a common Tf target, these swine related TbpBs show substantial sequence variation in their Tf-binding site. The TbpB structures, supported by docking simulations, surface plasmon resonance and hydrogen/deuterium exchange experiments with wild-type and mutant TbpBs, explain why there are structurally conserved elements within TbpB homologs despite major sequence variation that are required for binding Tf.