通过Clostridium difficile毒素B识别状蛋白质的结构基础
Peng Chen1, Liang Tao2, Tianyu Wang1
1Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA.
Science (New York, N.Y.)
|May 12, 2018
概括
困难毒素B通过脂肪酸共受体与Frizzled受体结合. 这种相互作用阻断了Wnt信号,揭示了治疗C. difficile感染的新目标.
科学领域:
- 结构生物学
- 疾病的分子机制
- 微生物学
背景情况:
- 困难菌感染 (CDI) 是抗生素相关的腹的主要原因.
- 主要毒性因子Clostridium difficile毒素B (TcdB) 通过Frizzled (FZD) Wnt受体向结肠表皮.
- 对于FZD的TcdB识别的精确机制在很大程度上是未知的.
研究的目的:
- 阐明TcdB与Frizzled受体的结合的结构基础.
- 了解共受体在TcdB-FZD相互作用中的作用.
- 确定潜在的治疗策略,针对CDI中的Wnt信号.
主要方法:
- 使用X射线结晶学来确定与人类FZD2富含氨酸的TcdB片段的结构.
- 在2.5安格斯特罗姆的高分辨率结构分析.
- 生物化学测定以评估Wnt结合和信号抑制.
主要成果:
- 晶体结构显示了与FZD2结合的内源性脂肪酸,作为TcdB的关键共受体.
- 这种脂质占据了通常与Wnt相关的棕酸结合的部位,防止Wnt的结合.
- TcdB结合有效地隔离脂肪酸,抑制FZD介导的Wnt信号传递.
结论:
- 脂肪酸在FZD介导的TcdB病变中起着关键作用.
- TcdB使用脂肪酸共受体机制来破坏Wnt信号.
- 通过调节Wnt信号通路,这些发现为Clostridium difficile感染提供了新的治疗策略.
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