通过GATOR1复合体调节Rheb GTPase
bioRxiv : the preprint server for biology
|January 9, 2026
概括
研究人员在C. elegans和人类细胞中发现了Rheb和GATOR1复合体之间的营养调节相互作用. 这一发现揭示了增长因子和调节mTORC1.1.的氨基酸信号通路之间的新的上游联系.
科学领域:
- 细胞生物学 细胞生物学
- 分子信号传输的方法
- 调节新陈代谢的规则
背景情况:
- 拉巴胺素复合体1 (mTORC1) 途径的机械标集成了氨基酸和生长因子信号,以控制细胞生长和新陈代谢.
- 两个关键的上游调节者是Rag GTPases (氨基酸感应) 和Rheb GTPase (生长因子感应),由GATOR1和TSC复合体分别抑制.
- 这些分支之间的精确上游交叉和协调,特别是在缺乏TSC复合体的生物体中,仍然不太了解.
研究的目的:
- 为了调查mTORC1信号传输的Rag和Rheb GTPase分支之间的潜在上游交叉声.
- 确定在缺乏TSC复合体的生物体中协调mTORC1调节的分子机制,例如C. elegans.
- 阐明管理营养和生长因子输入到mTORC1信号的整合的直接物理相互作用.
主要方法:
- 在C. elegans中进行无偏的定量蛋白质组学,以确定Rheb ortholog,RHEB-1的新型相互作用体.
- 在人类细胞中进行生物化学验证,包括拉下测试和分析具有改变核酸结合状态的Rheb突变物.
- 使用AlphaFold3进行结构建模,以预测Rheb和GATOR1子单元之间的绑定接口和相互作用模式.
主要成果:
- 鉴定出GATOR1复合体是C. elegans中的RHEB-1的一个新型相互作用体.
- 无核酸的Rheb直接与人体细胞中GATOR1复合物的Nprl2-Nprl3子单元结合,这种相互作用是由营养应激引起的.
- 结构建模表明,Rheb通过非催化机制将GATOR1与Rag GTPase GAP活动在一个不同的位置结合.
结论:
- 在Rheb和GATOR1复合体 (Nprl2/3子单元) 之间存在着保存的,营养调节的物理相互作用.
- 这种相互作用代表了增长因子和mTORC1信号传导的氨基酸感应分支之间以前未知的融合点.
- 这些发现提供了Rag和Rheb路径之间的直接分子联系,解释了营养压力如何微调mTORC1活动.
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