粘附GPCR信号传导的分子特征
bioRxiv : the preprint server for biology
|September 2, 2025
概括
粘附G蛋白合受体 (aGPCR) 使用不同的机械力通路来发出信号,要么通过丢弃GAIN域,要么通过完整的合. 这项研究揭示了力量方向如何控制这些aGPCR激活机制.
科学领域:
- 细胞机械生物学
- 分子和结构生物学
- 生物物理
背景情况:
- 细胞过程依赖于膜受体的机械信号转导,例如粘附G蛋白合受体 (aGPCR).
- 已知aGPCRs的不同激活模式,包括分泌依赖和分泌独立的途径,但在分子层面上尚不清楚.
研究的目的:
- 阐明ADGRG1机械传导的结构和动态机制.
- 了解机械力量如何调节GPCR激活通路.
主要方法:
- 单分子力光谱,分子动力学模拟和基于细胞的测试的整合.
- 通过深度学习引导GAIN域变体的设计.
主要成果:
- 剪切应激会诱导明显的GAIN域变形路径,在脱落之前暴露绑定的激应剂.
- 全长ADGRG1信号传递是通过无GAIN脱落的全oster结合激动剂发生的,这取决于GAIN导向和7TM核心相互作用.
- 施加力的方向性决定了激活路径:GAIN脱落或完整的GAIN-7TM合.
- 工程 GAIN 变种显示信号灵敏度的可预测变化.
结论:
- 建立一个GPCR激活的统一框架,由GAIN域动态和方向控制.
- 机制将机械和异质受体功能模型连接起来.
- 这些发现为工程机敏受体和开发精确疗法提供了策略.
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