人类瘤抑制蛋白Pdcd4与40S小核糖体子单元的mRNA入口通道结合
Jailson Brito Querido1,2,3,4, Masaaki Sokabe5, Irene Díaz-López6
1MRC Laboratory of Molecular Biology, Cambridge, UK. jquerido@umich.edu.
Nature communications
|August 8, 2024
概括
编程细胞死亡基因4 (Pdcd4) 是一种调节翻译启动的瘤抑制剂. 结构研究显示,Pdcd4与40S核糖体亚单元结合,通过阻断eIF4A活性来抑制翻译.
科学领域:
- 分子生物学分子生物学
- 结构生物学 结构生物学
- 癌症研究 癌症研究
背景情况:
- 翻译启动是基因表达的关键调节步骤,在人类疾病中经常失调.
- 编程细胞死亡基因4 (Pdcd4) 是一种瘤抑制蛋白质,可以抑制细胞生长,入侵和转移.
- 在瘤中Pdcd4的下调,与增加的全球翻译相关.
研究的目的:
- 阐明Pdcd4调节翻译启动的结构机制.
- 了解Pdcd4与40S核糖体子单元和转化因子的相互作用.
主要方法:
- 使用单粒子冷电子显微镜 (cryo-EM) 来确定与40S核糖体子单元结合的Pdcd4的结构.
- 分析了包括Pdcd4-40S和Pdcd4-40S-eIF4A-eIF3-eIF1在内的复合体.
- 进行了定量结合和体外翻译试验.
主要成果:
- 冷-EM结构揭示了pdcd4在mRNA进入通道的40S子单元上的结合部位.
- Pdcd4的C端域 (CTD) 与eIF4A相互作用,而N端域 (NTD) 占据了mRNA通道和解码部位.
- NTD对于Pdcd4向核糖体的招募至关重要.
结论:
- Pdcd4通过直接结合40S核糖体亚单元,起到翻译抑制剂的作用.
- 在mRNA招募和5' UTR扫描期间,Pdcd4抑制了eIF4A的eIF4F独立功能.
- 这些发现通过转化控制为Pdcd4的瘤抑制功能提供了机械的见解.
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