通过METTL1-WDR4调节的G tRNA修饰的结构基础
Jiazhi Li1,2,3, Longfei Wang2,4,5, Quentin Hahn1
1Stem Cell Program, Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.
Nature
|January 4, 2023
概括
METTL1- WDR4复合物修改了细胞功能必需的转移RNA (tRNA). 这项研究揭示了WDR4如何支架METTL1和tRNA,以及N终端酸化如何调节其甲基转移酶活性.
科学领域:
- 分子生物学
- 生物化学
- 结构生物学
背景情况:
- 化学修饰RNA,如N7-甲基氨酸 (m7G),对于生物过程至关重要.
- METTL1- WDR4复合体对特定tRNA的m7G修饰负责,其失调与癌症和发育障碍有关.
- METTL1- WDR4 tRNA的修饰及其调节的确切机制尚不清楚.
研究的目的:
- 阐明由METTL1-WDR4复合体识别tRNA基质的分子机制.
- 研究控制METTL1-WDR4甲基转移酶活动的调控机制.
- 了解METTL1-WDR4功能的结构基础及其在细胞过程中的作用.
主要方法:
- 人类METTL1-WDR4复合物的结构研究 (例如,X射线结晶学,冷EM).
- 评估甲基转移酶活性和基质结合的生物化学测试.
- 研究METTL1-WDR4的功能影响及其调节的细胞研究.
主要成果:
- WDR4作为支架,结合METTL1和tRNAT臂.
- 在tRNA结合时,METTL1会发生形状变化,其alpha C和alpha 6螺旋体稳定了tRNA变量循环.
- 之前假设的METTL1的N终端区域是催化口袋的组成部分,对甲基转移酶活性至关重要.
- 在METTL1 N端的酸化抑制了甲基转移酶的活性,通过破坏催化中心.
结论:
- 这项研究为METTL1-WDR4如何识别tRNA基质提供了详细的分子理解.
- 在S27中METTL1的酸化是抑制甲基转移酶活性的关键调节机制.
- METTL1的N终端区域被确定为甲基转移酶活性和调节的关键枢纽.
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