The functional ClpXP protease of Chlamydia trachomatis requires distinct clpP genes from separate genetic loci
The functional ClpXP protease of Chlamydia trachomatis requires distinct clpP genes from separate genetic loci
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DOI：
10.1038/s41598-019-50505-5
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发表时间：
2019-10-01
影响因子：
4.6
通讯作者：
Sass, Peter
中科院分区：
文献类型：
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作者：
Pan, Stefan;Malik, Imran T.;Sass, Peter
Clp蛋白酶在细菌生理学中起着核心作用，对于某些细菌物种来说，甚至是生存所必需的。此外，由于它们在包括重要的人类病原体的细菌中的保守性，Clp蛋白酶最近作为抗生素靶标引起了相当大的关注。在这里，我们功能重建和特点的ClpXP蛋白酶的沙眼衣原体（ctClpXP），一个专性细胞内病原体和广泛的性传播疾病在人类的病原体。我们的体外数据表明，ctClpXP是由一个异源十四聚体蛋白水解核心，由两个不同的同源物ClpP（ctClpP1和ctClpP2），与unfoldase ctClpX通过ctClpP2调节蛋白质降解。ADEP类抗生素通过阻止ctClpX与ctClpP1P2的相互作用并激活原本休眠的蛋白水解核心以进行不受调节的蛋白水解来干扰蛋白酶功能。因此，我们的结果揭示了ctClpXP功能的分子洞察力，验证了这种蛋白酶作为抗菌靶标。
Clp proteases play a central role in bacterial physiology and, for some bacterial species, are even essential for survival. Also due to their conservation among bacteria including important human pathogens, Clp proteases have recently attracted considerable attention as antibiotic targets. Here, we functionally reconstituted and characterized the ClpXP protease of Chlamydia trachomatis (ctClpXP), an obligate intracellular pathogen and the causative agent of widespread sexually transmitted diseases in humans. Our in vitro data show that ctClpXP is formed by a hetero-tetradecameric proteolytic core, composed of two distinct homologs of ClpP (ctClpP1 and ctClpP2), that associates with the unfoldase ctClpX via ctClpP2 for regulated protein degradation. Antibiotics of the ADEP class interfere with protease functions by both preventing the interaction of ctClpX with ctClpP1P2 and activating the otherwise dormant proteolytic core for unregulated proteolysis. Thus, our results reveal molecular insight into ctClpXP function, validating this protease as an antibacterial target.