人类的结构及其与本地棕豆结合的声音的复合物
Xiaofeng Qi1, Philip Schmiege1, Elias Coutavas2
1Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Nature
|July 12, 2018
概括
刺 (HH) 信号对于发育和健康至关重要. 这项研究揭示了HH蛋白如何与补丁1 (PTCH1) 结合的原子结构,阐明了HH通路激活的关键步骤及其在癌症等疾病中的作用.
科学领域:
- 分子生物学
- 结构生物学
- 生物化学
背景情况:
- 刺 (HH) 信号对于胚胎发育和组织维护至关重要.
- HH信号的失调与出生缺陷和癌症有关.
- 通过其受体补丁 (PTCH) 识别HH蛋白的确切机制尚不清楚.
研究的目的:
- 通过补丁1 (PTCH1) 阐明 (HH) 蛋白识别的结构基础.
- 提供HHN终端域 (HH-N) 和PTCH1之间的相互作用接口的原子洞察力.
- 了解HH信号通路激活的分子框架及其对疾病的影响.
主要方法:
- 使用冷电子显微镜 (cryo-EM) 单独确定PTCH1的结构,并与声音刺N终端域 (SHH-N) 复合.
- 进行了生物化学测定,以研究替代的结合界面和条件.
主要成果:
- 冷EM结构揭示了PTCH1的详细结构,包括其跨膜核心和细胞外域.
- 观察到SHH-N的棕化N端插入PTCH1的细胞外域之间的腔,定义主要的相互作用接口.
- 生物化学数据表明,SHH-N可以通过一个独特的接口来招募PTCH1,即使没有它的palmitate修饰,这表明它对共受体有绑定作用.
结论:
- 这项研究提供了PTCH1-SHH-N复合体的第一个原子层次视图,阐明了HH蛋白如何被识别.
- 这些发现为理解HH-N与PTCH1和潜在的共同受体的结合提供了结构基础.
- 这项研究建立了一个关键的分子框架来理解HH信号,其调节以及它在人类疾病中的异常作用.
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