Cryo-EM structure of oxysterol-bound human Smoothened coupled to a heterotrimeric Gi,Nature

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Cryo-EM structure of oxysterol-bound human Smoothened coupled to a heterotrimeric Gi
Nature ( IF 50.5 ) Pub Date : 2019-06-05 , DOI: 10.1038/s41586-019-1286-0
Xiaofeng Qi ₁ , Heng Liu ₂ , Bonne Thompson ₃ , Jeffrey McDonald _{1,

3} , Cheng Zhang ₂ , Xiaochun Li _{1,

4}

Affiliation

The oncoprotein Smoothened (SMO), a G-protein-coupled receptor (GPCR) of the Frizzled-class (class-F), transduces the Hedgehog signal from the tumour suppressor Patched-1 (PTCH1) to the glioma-associated-oncogene (GLI) transcription factors, which activates the Hedgehog signalling pathway1,2. It has remained unknown how PTCH1 modulates SMO, how SMO is stimulated to form a complex with heterotrimeric G proteins and whether G-protein coupling contributes to the activation of GLI proteins3. Here we show that 24,25-epoxycholesterol, which we identify as an endogenous ligand of PTCH1, can stimulate Hedgehog signalling in cells and can trigger G-protein signalling via human SMO in vitro. We present a cryo-electron microscopy structure of human SMO bound to 24(S),25-epoxycholesterol and coupled to a heterotrimeric Gi protein. The structure reveals a ligand-binding site for 24(S),25-epoxycholesterol in the 7-transmembrane region, as well as a Gi-coupled activation mechanism of human SMO. Notably, the Gi protein presents a different arrangement from that of class-A GPCR–Gi complexes. Our work provides molecular insights into Hedgehog signal transduction and the activation of a class-F GPCR.Cryo-electron microscopy structure of the human Smoothened protein bound to 24(S),25-epoxycholesterol and a heterotrimeric Gi protein provides insights into the activation of a Frizzled-class G-protein-coupled receptor and Hedgehog signal transduction.

中文翻译：

氧甾醇结合人的冷冻电镜结构平滑耦合到异三聚体 Gi

癌蛋白 Smoothened (SMO) 是 Frizzled 类 (F 类) 的 G 蛋白偶联受体 (GPCR)，将来自肿瘤抑制因子 Patched-1 (PTCH1) 的 Hedgehog 信号转导至胶质瘤相关癌基因 ( GLI) 转录因子，可激活 Hedgehog 信号通路 1,2。PTCH1 如何调节 SMO、如何刺激 SMO 与异源三聚体 G 蛋白形成复合物以及 G 蛋白偶联是否有助于 GLI 蛋白的激活仍然未知。在这里，我们显示 24,25-环氧胆固醇，我们确定为 PTCH1 的内源性配体，可以刺激细胞中的 Hedgehog 信号传导，并可以在体外通过人 SMO 触发 G 蛋白信号传导。我们提出了人类 SMO 的低温电子显微镜结构，该结构与 24(S)、25-环氧胆固醇结合并与异源三聚体 Gi 蛋白偶联。该结构揭示了 24(S),25-环氧胆固醇在 7 跨膜区的配体结合位点，以及人 SMO 的 Gi 偶联激活机制。值得注意的是，Gi 蛋白呈现出与 A 类 GPCR-Gi 复合物不同的排列。我们的工作为 Hedgehog 信号转导和 F 类 GPCR 的激活提供了分子见解。与 24(S)、25-环氧胆固醇和异源三聚体 Gi 蛋白结合的人 Smoothened 蛋白的冷冻电子显微镜结构提供了对激活的见解Frizzled 类 G 蛋白偶联受体和 Hedgehog 信号转导。

更新日期：2019-06-05

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