Deoxycholate-Enhanced Shigella Virulence Is Regulated by a Rare π-Helix in the Type Three Secretion System Tip Protein IpaD,Biochemistry

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Deoxycholate-Enhanced Shigella Virulence Is Regulated by a Rare π-Helix in the Type Three Secretion System Tip Protein IpaD
Biochemistry ( IF 2.9 ) Pub Date : 2017-11-22 00:00:00 , DOI: 10.1021/acs.biochem.7b00836
Abram R. Bernard ₁ , T. Carson Jessop ₁ , Prashant Kumar ₂ , Nicholas E. Dickenson ₁

Affiliation

Type three secretion systems (T3SS) are specialized nanomachines that support infection by injecting bacterial proteins directly into host cells. The Shigella T3SS has uniquely evolved to sense environmental levels of the bile salt deoxycholate (DOC) and upregulate virulence in response to DOC. In this study, we describe a rare i + 5 hydrogen bonding secondary structure element (π-helix) within the type three secretion system tip protein IpaD that plays a critical role in DOC-enhanced virulence. Specifically, engineered mutations within the π-helix altered the pathogen’s response to DOC, with one mutant construct in particular exhibiting an unprecedented reduction in virulence following DOC exposure. Fluorescence polarization binding assays showed that these altered DOC responses are not the result of differences in affinity between IpaD and DOC, but rather differences in the DOC-dependent T3SS tip maturation resulting from binding of IpaD to translocator/effector protein IpaB. Together, these findings begin to uncover the complex mechanism of DOC-enhanced Shigella virulence while identifying an uncommon structural element that may provide a much needed target for non-antibiotic treatment of Shigella infection.

中文翻译：

脱氧胆酸盐增强的志贺氏菌毒力是由三型分泌系统尖端蛋白IpaD中的稀有π螺旋调节的。

第三类分泌系统（T3SS）是专门的纳米机器，可通过将细菌蛋白直接注入宿主细胞来支持感染。在志贺氏菌T3SS已经唯一地演变，以感测响应于DOC胆盐脱氧胆酸盐（DOC）和上调毒力的环境水平。在这项研究中，我们描述了一个罕见的我三型分泌系统尖端蛋白IpaD中的+ 5个氢键键合二级结构元件（π-螺旋）在DOC增强毒力中起关键作用。具体而言，π-螺旋内的工程突变改变了病原体对DOC的反应，尤其是一种突变体构建物在DOC暴露后表现出空前的毒力降低。荧光偏振结合试验表明，这些改变的DOC反应不是IpaD与DOC之间亲和力差异的结果，而是IpaD与易位蛋白/效应子蛋白IpaB结合导致的DOC依赖性T3SS尖端成熟度的差异。在一起，这些发现开始揭示DOC增强志贺氏菌的复杂机制在确定一种不常见的结构元素时可能会产生毒力，这可能为志贺氏菌感染的非抗生素治疗提供了急需的目标。

更新日期：2017-11-23

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