人类CFTR离子通道的分子结构
Fangyu Liu1, Zhe Zhang2, László Csanády3
1Laboratory of Membrane Biophysics and Biology, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA; Tri-Institutional Training Program in Chemical Biology, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
Cell
|March 25, 2017
概括
一个新的冷EM结构揭示了如何阻断脱化囊性纤维化膜传导调节器 (CFTR) 的开放. 这一发现有助于解释CFTR
科学领域:
- 结构生物学
- 离子通道生理学
- 生物化学
背景情况:
- 囊性纤维化跨膜导电调节器 (CFTR) 是一种具有独特离子通道功能的ATP结合盒 (ABC) 传输器.
- 了解CFTR结构对于阐明其关闭机制和开发治疗方法至关重要.
研究的目的:
- 确定人体 CFTR 的高分辨率结构.
- 确定调节CFTR通道活动的结构特征.
- 根据其结构和动力学提出CFTR激活机制.
主要方法:
- 使用电子冷显微镜 (cryo-EM) 确定了3. 9 Å的脱化人体CFTR结构.
- 与斑马鱼CFTR和其他ABC载体 (例如MRP1) 进行了比较.
- 对CFTR电流激活动态的sigmoid时间过程的分析.
主要成果:
- 获得了3. 9 Å 的非化人类CFTR的冷EM结构.
- 一个以前未解决的R域螺旋被发现停靠在细胞内前庭,防止通道开放.
- 超膜螺旋8中的独特螺旋环过渡区分CFTR与其他ABC传送器.
结论:
- 停靠的R域螺旋解释了非化CFTR的封闭状态.
- PKA化可能促进R域脱,使通道开放.
- 在TM8中螺旋环过渡被提出为CFTR离子通道功能的结构基础.
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