细胞外和膜外域之间的 conformational 合调节全粘附 GPCR 功能.
Szymon P Kordon1,2,3,4, Kristina Cechova5, Sumit J Bandekar1,2,3,4
1Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL, USA.
Nature communications
|December 3, 2024
概括
粘附G蛋白结合受体 (aGPCRs) 使用其细胞外区域进行信号传递. 这项研究揭示了GAIN域如何增长.
科学领域:
- 结构生物学是结构生物学.
- 蜂信号传输是如何进行的
- 生物化学 生物化学
背景情况:
- 粘附G蛋白结合受体 (aGPCRs) 是重要的细胞粘附分子,调节各种生理过程.
- aGPCRs具有大型的细胞外区域 (ECRs),其保存的GAIN域在它们的七通跨膜 (7TM) 域之前.
- 对于ECR影响7TM活动的机制,特别是ECR与7TM相比的方向和动态,人们对其理解程度仍然不佳.
研究的目的:
- 在aGPCR中阐明ECR和7TM之间的结构和动态关系.
- 研究GAIN域的方向和运动如何影响GPCR功能.
- 探索GAIN-7TM接口变化的功能后果.
主要方法:
- 电子显微镜 (cryo-EM) 用于拉特罗菲林3/ADGRL3.3的高分辨率结构重建.
- 单分子弗斯特共振能量转移 (smFRET) 探测ECR-7TM动态.
- 功能性测试评估受体信号响应GAIN向抗体和突变的反应.
主要成果:
- 冷-EM结构显示了GAIN域相对于移动性受限的7TM区域的平行方向.
- smFRET实验确定了ECR相对于7TM的三个不同的,缓慢相互转换的形状状态.
- 针对GAIN域或GAIN-7TM接口的修改改变了这些构造状态,冷-EM结构和受体信号活动.
结论:
- 在aGPCR中显示了ECR和7TM之间的直接形状和功能合.
- 表明ECR,特别是GAIN域,调解aGPCR激活的机制.
- 强调GAIN-7TM接口在调节aGPCR信号通路方面的重要性.
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