高分辨率的微管结构揭示了在GTP水解时αβ-tubulin中的结构转变
Gregory M Alushin1, Gabriel C Lander2, Elizabeth H Kellogg3
1Biophysics Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USA.
Cell
|May 27, 2014
概括
微管的动态不稳定性,对于细胞功能至关重要,是由GTP水解驱动的. 抗癌药物Taxol通过抑制这些水解诱导的形状变化来稳定微管,揭示了关键的结构见解.
科学领域:
- 生物化学 生物化学
- 结构生物学 结构生物学
- 细胞生物学 细胞生物学
背景情况:
- 微管的动态不稳定性,以随机增长和收缩为特征,是细胞过程的基础.
- 这种不稳定性通过微管网内的GTP水解来调节.
- 众所周知,像Taxol这样的抗癌药物可以抑制微管的动态不稳定性.
研究的目的:
- 阐明了微管体动态不稳定的基础分子机制.
- 了解GTP水解和像Taxol这样的稳定剂如何影响微管结构.
- 调查Taxol抑制动态不稳定的结构基础.
主要方法:
- 使用高分辨率冷电子显微镜 (cryo-EM) 来确定结构.
- 获得了动态微管,GMPCPP稳定微管和Taxol稳定微管的结构.
- 分析的重点是纵向和横向接口的形状变化.
主要成果:
- GTP水解诱导了E位点核酸周围的晶格紧缩,并改变了氨酸亚单元构造 (α-氨酸中间域,H7螺旋环).
- 水解还会将C端螺旋移位,这可能会影响与结合伙伴的相互作用.
- 发现taxol可以抑制这些水解诱导的形状变化,诱导一种类似GMPCPP的稳定状态;横向相互作用在各种条件中保持一致.
结论:
- 微管网的稳定性主要通过GTP水解驱动的形状变化在纵向接口上进行调节.
- 塔克索尔通过异质抑制这些关键的结构动态来稳定微管,揭示了其作用机制.
- 对动态不稳定的结构洞察力为了解微管子功能和药物相互作用提供了基础.
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