Becker Argentina, Kannan T R, Taylor Alexander B, Pakhomova Olga N, Zhang Yanfeng, Somarajan Sudha R, Galaleldeen Ahmad, Holloway Stephen P, Baseman Joel B, Hart P John
Department of Biochemistry.
Department of Microbiology and Immunology/Center for Airway Inflammation Research, and.
Proc Natl Acad Sci U S A. 2015 Apr 21;112(16):5165-70. doi: 10.1073/pnas.1420308112. Epub 2015 Apr 6.
Mycoplasma pneumoniae (Mp) infections cause tracheobronchitis and "walking" pneumonia, and are linked to asthma and other reactive airway diseases. As part of the infectious process, the bacterium expresses a 591-aa virulence factor with both mono-ADP ribosyltransferase (mART) and vacuolating activities known as Community-Acquired Respiratory Distress Syndrome Toxin (CARDS TX). CARDS TX binds to human surfactant protein A and annexin A2 on airway epithelial cells and is internalized, leading to a range of pathogenetic events. Here we present the structure of CARDS TX, a triangular molecule in which N-terminal mART and C-terminal tandem β-trefoil domains associate to form an overall architecture distinct from other well-recognized ADP-ribosylating bacterial toxins. We demonstrate that CARDS TX binds phosphatidylcholine and sphingomyelin specifically over other membrane lipids, and that cell surface binding and internalization activities are housed within the C-terminal β-trefoil domain. The results enhance our understanding of Mp pathogenicity and suggest a novel avenue for the development of therapies to treat Mp-associated asthma and other acute and chronic airway diseases.
肺炎支原体（Mp）感染可引发气管支气管炎和“迁延性”肺炎，并与哮喘及其他气道反应性疾病相关。作为感染过程的一部分，该细菌表达一种具有单ADP核糖基转移酶（mART）和空泡化活性的591个氨基酸的毒力因子，即社区获得性呼吸窘迫综合征毒素（CARDS TX）。CARDS TX与气道上皮细胞上的人表面活性蛋白A和膜联蛋白A2结合并被内化，从而引发一系列致病事件。在此，我们展示了CARDS TX的结构，它是一种三角形分子，其中N端的mART和C端的串联β-三叶结构域相互关联，形成了一种与其他公认的ADP核糖基化细菌毒素截然不同的整体结构。我们证明，CARDS TX与磷脂酰胆碱和鞘磷脂的结合特异性高于其他膜脂，且细胞表面结合和内化活性存在于C端的β-三叶结构域内。这些结果增进了我们对Mp致病性的理解，并为开发治疗Mp相关哮喘及其他急慢性气道疾病的疗法提供了一条新途径。
