Structural basis for the interaction of Bordetella pertussis adenylyl cyclase toxin with calmodulin
Structural basis for the interaction of Bordetella pertussis adenylyl cyclase toxin with calmodulin
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DOI：
10.1038/sj.emboj.7600800
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发表时间：
2005-09-21
期刊：
影响因子：
11.4
通讯作者：
Tang, WJ
中科院分区：
文献类型：
--
作者：
Guo, Q;Shen, YQ;Tang, WJ
CyaA对于百日咳病原体百日咳杆菌的定殖至关重要。在这里，我们报告的晶体结构的腺苷酸环化酶结构域（ACD）的CyaA与钙调蛋白的C-末端结构域。CyaA的四个离散区域结合钙负载的钙调蛋白，具有大的埋藏接触表面。其中，CyaA α-螺旋上的色氨酸残基（W242）与钙诱导的钙调蛋白疏水口袋广泛接触。突变分析表明，CyaA的所有四个区域都有助于钙调素结合，并且钙调素诱导的CyaA构象变化对催化活化至关重要。CyaA -钙调蛋白与阿德福韦二磷酸（一种已批准的抗病毒药物的代谢产物）的晶体结构揭示了CyaA催化位点的位置以及阿德福韦二磷酸如何紧密结合CyaA。CyaA的ACD与炭疽水肿因子（EF）具有相似的结构和激活机制。然而，CyaA与钙调素的相互作用完全不同于EF。这提供了两种结构上同源的细菌毒素如何分化地结合钙调蛋白（一种进化上保守的钙传感器）的分子细节。
CyaA is crucial for colonization by Bordetella pertussis, the etiologic agent of whooping cough. Here we report crystal structures of the adenylyl cyclase domain (ACD) of CyaA with the C-terminal domain of calmodulin. Four discrete regions of CyaA bind calcium-loaded calmodulin with a large buried contact surface. Of those, a tryptophan residue (W242) at an alpha-helix of CyaA makes extensive contacts with the calcium-induced, hydrophobic pocket of calmodulin. Mutagenic analyses show that all four regions of CyaA contribute to calmodulin binding and the calmodulin-induced conformational change of CyaA is crucial for catalytic activation. A crystal structure of CyaA - calmodulin with adefovir diphosphate, the metabolite of an approved antiviral drug, reveals the location of catalytic site of CyaA and how adefovir diphosphate tightly binds CyaA. The ACD of CyaA shares a similar structure and mechanism of activation with anthrax edema factor (EF). However, the interactions of CyaA with calmodulin completely diverge from those of EF. This provides molecular details of how two structurally homologous bacterial toxins evolved divergently to bind calmodulin, an evolutionarily conserved calcium sensor.