通过干细胞因子激素激活受体氨酸激酶KIT的结构基础
Satoru Yuzawa1, Yarden Opatowsky, Zhongtao Zhang
1Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
Cell
|July 31, 2007
概括
干细胞因子 (SCF) 与KIT受体结合,导致它们二元化,从而激活氨酸激酶. 这项结构性研究揭示了KIT受体二分化和激活是如何发生的,为相关受体氨酸激酶提供了洞察力.
科学领域:
- 生物化学 生物化学
- 结构生物学 结构生物学
- 细胞信号传递 细胞信号传递
背景情况:
- 干细胞因子 (SCF) 与KIT受体氨酸激酶结合,启动细胞信号通路.
- 了解KIT激活的结构基础对于破译它在正常生理学和疾病中的作用至关重要.
研究的目的:
- 阐明由干细胞因子 (SCF) 激活KIT受体ectodomain的结构机制.
- 为了确定驱动KIT二分化和随后的氨酸激酶激活的关键分子相互作用.
主要方法:
- 在SCF刺激之前和之后,X射线晶体学以确定KITectodomain的结构.
- 基于细胞的测试,以调查特定突变对KIT激活的功能影响.
主要成果:
- 晶体结构显示,SCF结合通过将两个受体分子结合在一起来诱导KIT受体二分化.
- 经二分化之后,出现了构造变化,使相邻的KIT分子的D4域之间产生横向相互作用.
- 影响D4-D4接口的突变会损害KIT激活,而致癌突变会在D5-D5接口聚集.
结论:
- 基因受体激活是SCF诱导的二分化的直接结果,由特定的受体间域相互作用介导.
- 已确定的KIT激活机制,涉及连接体诱导的二分化和域交换,可能在其他受体氨酸激酶中保持.
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