在黑信号中平滑激活的结构基础
Pengxiang Huang1, Sanduo Zheng2, Bradley M Wierbowski1
1Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
Cell
|May 29, 2018
概括
胆固醇与Smoothened结合 (SMO) 通过重新定位其丰富的囊蛋白域 (CRD) 来激活刺信号. 这种结构变化打破了抑制锁,开辟了固醇运动和受体激活的途径.
科学领域:
- 生物化学
- 分子生物学
- 结构生物学
背景情况:
- 它是刺信号中的关键蛋白质,对胚胎发育和癌症的进展至关重要.
- 通过胆固醇与其细胞外的囊丰富域 (CRD) 结合来触发SMO的激活.
- 结合胆固醇与SMO激活的确切机制尚不清楚.
研究的目的:
- 阐明醇中介SMO激活的基础结构机制.
- 定义胆固醇与CRD结合如何影响跨膜域 (TMD) 构造.
- 描述对抗剂SMO抑制的结构基础.
主要方法:
- 用X射线结晶学来确定醇激活的SMO的结构.
- 结构分析以比较活跃和非活跃的SMO结构.
- 生物化学测定以调查 π-锁和疏水道的作用.
主要成果:
- 晶体结构显示,在固醇结合后的CRD重定位会以异质方式激活TMD,模仿活性G蛋白结合受体.
- 在SMO中,一种独特的抑制性π-锁在激活时被破坏,而这种锁在致癌突变物中被改变.
- 激活SMO会产生一种疏水道,这表明胆固醇从内膜小片转移到CRD的途径.
- SMO抗体主要与TMD结合,阻断疏水道;然而,环胺也与CRD结合,诱导活性TMD构造.
结论:
- 该研究定义了由胆固醇激活SMO和抗剂抑制的结构机制.
- CRD重定位和随后的TMD形状变化是SMO激活的核心.
- 鉴定到的疏水道和π-锁为SMO的全调节和药物向提供了洞察力.
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