细胞胆固醇直接激活在刺信号中
Pengxiang Huang1, Daniel Nedelcu1, Miyako Watanabe1
1Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
Cell
|August 23, 2016
概括
这种蛋白质对发育和癌症至关重要. 这项研究揭示了胆固醇, 而不是氧化醇, 是主要的激活剂,
科学领域:
- 分子生物学
- 生物化学
- 发育生物学
背景情况:
- 在脊椎动物的胚胎生长和癌症中,
- 膜蛋白 Smoothened (SMO) 通过与其细胞外囊丰富域 (CRD) 结合的固醇被激活.
- 关于SMO的内源性固醇激活剂及其激活机制仍然存在关键问题.
研究的目的:
- 为了确定Smoothened的内源性固醇激活剂.
- 为了阐明通过固醇平滑激活的机制.
- 定义固醇-平滑相互作用的结构基础.
主要方法:
- 用X射线结晶学测定单独和复合着固醇的光滑CRD的结构.
- 位点定向的突变发生,以确定固醇识别和活性的主要残留物.
- 功能测试以评估不同类固醇和刺信号的平滑激活.
主要成果:
- 晶体结构显示,固醇结合会诱导SMOCRD结合部位的独特形状变化,足以激活.
- 刺信号取决于醇与SMO的结合,特定的残留物被确定为识别和活性.
- 胆固醇直接结合并激活SMO,而胆固醇激活的SMO突变体则取消了氧化胆固醇的作用.
结论:
- 胆固醇,而不是氧化醇,被认为是脊椎动物中Smoothened信号的内源激活剂.
- 滑化激活涉及独特的形状变化,由固醇结合驱动.
- 脊椎动物的信号可能通过控制Smoothened获得胆固醇来调节通路活动.
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