一个RAS/RAF招募综合体的冷电磁结构
Eunyoung Park1,2,3, Shaun Rawson2, Anna Schmoker1
1Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
Nature communications
|July 29, 2023
概括
像BRAF这样的RAS家族激酶是由RAS蛋白激活的. 新的结构显示RAS结合BRAF而没有激活它,这表明针对这种预激活状态的新治疗策略.
科学领域:
- 分子生物学分子生物学
- 细胞信号传递 细胞信号传递
- 结构生物学是结构生物学.
背景情况:
- 在被GTP结合的RAS.激活后,RAF家族激酶通过MAP激酶级联启动信号传递.
- 之前的结构研究检查了RAF的孤立RAS结合和富含氨酸的域,而不是完整的BRAF.
研究的目的:
- 用完整的BRAF来确定RAS-BRAF相互作用的结构基础.
- 调查膜招募在RASBRAF激活中的作用.
- 探索针对RAS-BRAF相互作用的潜在治疗策略.
主要方法:
- 使用冷电子显微镜 (cryo-EM) 来确定结构.
- 分析了与完整的BRAF,MEK1和14-3-3二次体结合的KRAS复合体.
- 进行了体外激活试验,以评估BRAF活性.
主要成果:
- 冷EM揭示了与MEK1和14-3-3在自抑制状态下与完整的BRAF结合的KRAS结构.
- 在两个不同的方向上,KRAS与BRAF的RAS绑定领域结合.
- 单独结合KRAS并不能激活BRAF;膜招募是必不可少的.
结论:
- RAS结合和BRAF激活是可以分离的过程.
- 稳定预激活KRAS/BRAF复合体是一种潜在的治疗策略.
- 了解RAS-BRAF复杂结构,可以深入了解MAP激酶通路调节.
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