开放式和封闭式的人类TRPML1通道结构
Philip Schmiege1,2, Michael Fine3, Günter Blobel1
1Laboratory of Cell Biology, Howard Hughes Medical Institute, The Rockefeller University, New York, New York 10065, USA.
Nature
|October 12, 2017
概括
研究人员揭示了关闭状态和开放状态的暂时受体潜在粘脂蛋白1 (TRPML1) 通道的结构. 这为信号传递,溶解体功能和IV型粘脂症提供了洞察力.
科学领域:
- 结构生物学
- 分子生物学
- 细胞生物学
背景情况:
- 过渡性受体潜在粘脂蛋白1 (TRPML1) 是一种释放的通道,对溶解体信号传递和恒温至关重要.
- TRPML1的功能障碍会导致IV型粘脂症,这是一种严重的溶酶体储存障碍.
研究的目的:
- 在封闭和开放状态下确定全长人体TRPML1的高分辨率结构.
- 阐明TRPML1通道调节和激活的分子机制.
- 提供关于IV型粘脂症的结构基础的见解.
主要方法:
- 使用电子冷显微镜 (cryo-EM) 来获得人类TRPML1的结构.
- 在pH7.0的ap (闭合) 状态和pH6.0的agonist- bound (开放) 状态下确定结构.
主要成果:
- 在高分辨率 (3.72 Å和3.49 Å) 解析了人类TRPML1的两个不同的冷EM结构.
- 由S5,S6螺旋和孔螺旋1中的特定残留物形成的独特的疏水腔被确定为激素结合部位.
- 道开放涉及下门的扩张和孔螺旋1的结构转移.
结论:
- 这项研究揭示了TRPML通道的调节机制及其激活过程.
- 这些发现提供了对粘脂类型IV病变的分子理解.
- 这项工作有助于更好地理解TRP通道的功能和调节.
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