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两个Patched分子在Hedgehog上接触不同的位置,产生一个信号竞争复合体

Xiaofeng Qi¹, Philip Schmiege¹, Elias Coutavas²

¹Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Science (New York, N.Y.)

|August 25, 2018

概括

异常的刺 (HH) 信号与癌症有关. 这项研究揭示了Sonic Hedgehog (SHH-N) 通过不同的接口同时结合两个Patched-1 (PTCH1) 受体,从而实现有效的细胞信号传输.

科学领域:

分子生物学分子生物学
结构生物学结构生物学
生物化学生物化学

背景情况:

异常刺 (HH) 信号与各种癌症和发育异常有关.
N-终端棕化HH通过结合其受体Patched-1 (PTCH1) 来启动信号传输.
之前的结构研究为PTCH1-HH绑定接口提供了相互矛盾的模型.

研究的目的:

为了协调关于 PTCH1-HH 结合位点的不同发现.
阐明Sonic Hedgehog (SHH-N) 与PTCH1.1的相互作用的结构基础.
为了确定在HH信号传输中识别的结合接口的功能意义.

主要方法:

低温电子显微镜 (cryo-EM) 用于确定与PTCH1.1复合的SHH-N的3.5安格斯特罗姆分辨率结构.
在复合体形成过程中利用生理度.
使用PTCH1和SHH-N.的位点定向突变发生的功能性试验.

主要成果:

一个新的不对称复合结构揭示了一个SHH-N分子与两个PTCH1受体结合.
在PTCH1.1上,SHH-N参与了棕酸盐介导和明显的介导表位.
任何一种结合接口的突变性干扰都会显著降低HH信号传输效率.

结论:

该研究通过展示双接口绑定机制来协调相互冲突的模型.
棕酸盐和介导接口的同时激活对于PTCH1-SHH信号传输至关重要.
这种结构和功能洞察力为了解健康和疾病中的HH通路调节提供了基础.

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