结构基础 通过其细胞外域的调节
Eamon F X Byrne1, Ria Sircar2, Paul S Miller1
1Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Nature
|July 21, 2016
概括
刺 (Hh) 路径
科学领域:
- 生物化学
- 分子生物学
- 结构生物学
背景情况:
- 发育信号由Frizzled类G蛋白结合受体 (GPCR) 转导.
- 大型细胞外域对GPCR信号的调节尚不清楚.
- 滑化 (SMO) 是一个Hh通路转换器和蛋白GPCR.
研究的目的:
- 阐明SMO激活和调节的结构机制.
- 了解细胞外域如何影响GPCR中的膜传导信号.
主要方法:
- 进行X射线结晶学以确定SMO结构.
- 结构引导的突变发生以探测功能界面.
- 生物化学测试以评估Hh信号和胆固醇结合.
主要成果:
- 晶体结构显示SMO在跨膜域 (TMD) 和富含氨酸的域 (CRD) 中具有明显的连接位.
- 一个胆固醇分子被发现在CRD部位结合,对于Hh信号转导至关重要.
- 对抗剂与TMD的结合导致影响CRD-linker-TMD接口和胆固醇结合的形状变化.
结论:
- GPCR活动由细胞外和膜外域之间的联体诱导相互作用调节.
- 胆固醇与CRD结合对于通过SMO传递信号的Hh通路至关重要.
- CRD,链接器和TMD接口稳定了SMO的不活跃状态.
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