一个基基酸开关调节c-Ablbl
Oliver Hantschel1, Bhushan Nagar, Sebastian Guettler
1Developmental Biology Programme, European Molecular Biology Laboratory, 69117 Heidelberg, Germany.
Cell
|March 26, 2003
概括
与Src酶不同的是,c-Abl氨酸激酶使用myristoyl/phosphotyrosine开关进行激活. 这种开关解释了c-Abl激活和对白血病药物STI-571的敏感性.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 在瘤学瘤学.
背景情况:
- c-Abl氨酸激酶在细胞信号传递中起着至关重要的作用,其在Bcr-Abl瘤蛋白中的失调与人类白血病有关.
- 了解c-Abl抑制的精确机制对于开发有效的癌症疗法至关重要.
研究的目的:
- 为了阐明c-Abl氨酸激酶的激活机制.
- 为了研究N-终端myristoyl修饰在c-Abl调节中的作用.
- 为了解抗癌药物STI-571 (imatinib) 的作用机制提供见解.
主要方法:
- 对c-Abl和Src酶激活机制的比较分析.
- 功能性研究涉及连接体结合和蛋白质相互作用.
- 结构分析来定义分子相互作用.
- 研究STI-571对联体激活c-Abl.bl的作用.
主要成果:
- c-Abl 1b 通过类似于 Src 激酶的色胺联体被激活.
- c-Abl 的 N-终端 myristoyl 修饰会参与激酶域,取代 Src SH2 域-酸化尾相互作用.
- 在c-Abl中的一个myristoyl/phosphotyrosine开关调节SH2域对接和可访问性.
- 联体激活的c-Abl对STI-571具有高度敏感性.
结论:
- 里斯/酸开关提供了一种新的机制,通过酸酸化蛋白激活c-Abl.
- 这种开关解释了c-Abl的细胞内移动性及其对STI-571.1的敏感性.
- 这些发现为STI-571在Bcr-Abl相关白血病的治疗作用提供了新的视角.
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