致癌的CCDC6-RET融合蛋白是一种双重ATP和ADP依赖的激酶
Ana Martín-Hurtado1, Julia Contreras1, Jana Sánchez-Wandelmer2
1Protein Phosphorylation and Cancer Group, Structural Biology Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
Nature communications
|March 6, 2026
概括
一个癌症驱动因素的CCDC6-RET融合蛋白作为双ATP/ADP依赖的二元激酶起作用. 结构研究揭示了其自主激活机制,涉及核酸结合和激活段交叉交谈.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 结构生物学 结构生物学
背景情况:
- 涉及蛋白质激酶的基因融合驱动人类癌症.
- 这些融合蛋白是个性化癌症治疗的关键点.
- 聚变激酶活性的结构和功能决定因素在很大程度上仍然未知.
研究的目的:
- 阐明控制CCDC6-RET融合蛋白活性的分子和结构机制.
- 为了了解这种致癌性激酶的自主激活过程.
主要方法:
- 时间分辨率质谱法
- 生物化学和生物物理特性表征.
- 单粒子电子显微镜 (spEM) 是一种单粒子电子显微镜.
- 微角X射线散射 (SAXS) 是一种微角X射线散射技术.
- 在的分子动力学模拟中.
- 交叉连接质谱法 (XL-MS) 是一种质谱法.
主要成果:
- CCDC6-RET形成了一个高度活跃的同位体.
- 它的功能是双ATP和ADP依赖的激酶.
- 在C端和激活段之间的交叉声控制活动.
- 结构分析显示,在不活跃状态下,面对面的二元体具有交联的激活段.
- 核酸结合诱导域重排,通过cis机制促进激活环酸化.
结论:
- CCDC6-RET通过一种新的机制自动激活,涉及核酸依赖的构造变化.
- 了解这些决定因素,可以深入了解针对CCDC6-RET驱动癌症的向疗法开发.
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