Structural basis for the recognition of Sonic Hedgehog by human Patchedl
Structural basis for the recognition of Sonic Hedgehog by human Patchedl
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DOI：
10.1126/science.aas8935
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发表时间：
2018-08-10
期刊：
影响因子：
56.9
通讯作者：
Yan, Nieng
中科院分区：
文献类型：
--
作者：
Gong, Xin;Qian, Hongwu;Yan, Nieng
参与发育和再生的 Hedgehog (Hh) 途径是通过 Hh 与膜受体 Patched (Ptch) 的胞外结合而激活的。我们报告了人 Ptchl 的单独结构以及与人 Sonic Hedgehog (ShhN) N 端结构域复合物的结构，分辨率分别为 3.9 和 3.6 埃，通过冷冻电子显微镜测定。 Ptch1 包含两个相互作用的胞外结构域 ECD1 和 ECD2，以及 12 个跨膜片段 (TM)，其中 TM 2 至 6 构成甾醇感应结构域 (SSD)。两种结构中都解析出了两种类固醇形状的密度，一种由 ECD1/2 封闭，另一种位于 SSD 面向膜的空腔中。结构引导突变分析表明，ShhN 和 Ptch1 之间的相互作用是类固醇依赖性的。类固醇结合缺陷的 Ptch1 突变体的结构表现出明显的构象重排。
The Hedgehog (Hh) pathway involved in development and regeneration is activated by the extracellular binding of Hh to the membrane receptor Patched (Ptch). We report the structures of human Ptchl alone and in complex with the N-terminal domain of human Sonic hedgehog (ShhN) at resolutions of 3.9 and 3.6 angstroms, respectively, as determined by cryo-electron microscopy. Ptch1 comprises two interacting extracellular domains, ECD1 and ECD2, and 12 transmembrane segments (TMs), with TMs 2 to 6 constituting the sterol-sensing domain (SSD). Two steroid-shaped densities are resolved in both structures, one enclosed by ECD1/2 and the other in the membrane-facing cavity of the SSD. Structure-guided mutational analysis shows that interaction between ShhN and Ptch1 is steroid-dependent. The structure of a steroid binding-deficient Ptch1 mutant displays pronounced conformational rearrangements.