Structure and functional analysis of the Legionella chitinase ChiA reveals a novel mechanism of metal-dependent mucin degradation
Structure and functional analysis of the Legionella chitinase ChiA reveals a novel mechanism of metal-dependent mucin degradation
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军团菌几丁质酶 ChiA 的结构和功能分析揭示了金属依赖性粘蛋白降解的新机制
DOI：
10.1101/687871
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Richardson K
中科院分区：
文献类型：
--
作者：
Richardson K
几丁质酶是重要的酶，其有助于从几丁质产生碳和氮，几丁质是在昆虫、真菌、无脊椎动物和鱼类中丰富的N-乙酰葡糖胺的长链聚合物。虽然哺乳动物不产生几丁质，但已在细菌中鉴定出几丁质酶，其是严重呼吸道、胃肠道和泌尿系统疾病的关键毒力因子。然而，目前还不清楚这些酶如何能够实现这种双重功能。嗜肺军团菌（Legionella pneumophila）是引起军团菌病（Legionnaires' disease）的病原体，其几丁质酶ChiA对军团菌的生存至关重要。嗜肺菌在这里，我们报告的第一个原子分辨率洞察致病机制的细菌几丁质酶。我们推导出一个完整的ChiA的实验模型，并显示其N-末端区域的目标ChiA分泌后的细菌表面。我们首次证明L.嗜肺菌可以结合其表面上的粘蛋白，但这不依赖于chiA。这表明，额外的外周粘蛋白结合蛋白也表达在L。嗜肺菌最后，我们表明，ChiA的C-末端几丁质酶结构域对哺乳动物粘蛋白具有新的金属依赖性肽酶活性。这些研究结果表明，ChiA促进细菌穿透肺泡粘膜和ChiA可能是一个有前途的疫苗开发的目标。
Chitinases are important enzymes that contribute to the generation of carbon and nitrogen from chitin, a long chain polymer of N-acetylglucosamine that is abundant in insects, fungi, invertebrates and fish. Although mammals do not produce chitin, chitinases have been identified in bacteria that are key virulence factors in severe respiratory, gastrointestinal and urinary diseases. However, it is unclear how these enzymes are able to carry out this dual function. Legionella pneumophila is the causative agent of Legionnaires’ disease, an often-fatal pneumonia and its chitinase ChiA is essential for the survival of L. pneumophila in the lung. Here we report the first atomic resolution insight into the pathogenic mechanism of a bacterial chitinase. We derive an experimental model of intact ChiA and show how its N-terminal region targets ChiA to the bacterial surface after its secretion. We provide the first evidence that L. pneumophila can bind mucins on its surface but this is not dependent on chiA. This demonstrates that additional peripheral mucin binding proteins are also expressed in L. pneumophila. Finally, we show that the ChiA C-terminal chitinase domain has novel metal-dependent peptidase activity against mammalian mucins. These findings suggest that ChiA facilitates bacterial penetration of the alveolar mucosa and ChiA may be a promising target for vaccine development.
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影响因子：
5.3
作者：
Clayton Evert;Tina Loesekann;G. Bhat;A. Shajahan;R. Sonon;P. Azadi;R. Hunter
通讯作者：
Clayton Evert;Tina Loesekann;G. Bhat;A. Shajahan;R. Sonon;P. Azadi;R. Hunter
DOI：
10.1107/s139900471302926x
发表时间：
2014-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
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通讯作者：
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影响因子：
4.3
作者：
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通讯作者：
Fornili A
DOI：
--
发表时间：
2005
期刊：
--
影响因子：
--
作者：
J. Painter;E. Merritt
通讯作者：
J. Painter;E. Merritt
用荧光显微镜测量小麦胚芽凝集素结合力
影响因子：
3.7
作者：
M. Model;Jennifer L. Reese;G. Fraizer
通讯作者：
G. Fraizer