The SREBP pathway controls cellular homeostasis of sterols. The key players in this pathway, Scap and Insig-1/2, are membrane-embedded sterol sensors. 25-hydroxycholesterol (25HC)-dependent association of Scap and Insigs acts as the master switch for the SREBP pathway. Here, we present cryo-EM analysis of the human Scap and Insig-2 complex in the presence of 25HC, with the transmembrane (TM) domains determined at an average resolution of 3.7 Å. The sterol sensing domain (SSD) in Scap and all six TMs in Insig-2 were resolved. A 25HC molecule is sandwiched between the S4-S6 segments in Scap and TMs 3/4 in Insig-2 in the luminal leaflet of the membrane. Unwinding of the middle of the Scap-S4 segment is crucial for 25HC binding and Insig association.

中文翻译：

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与 Insig-2 结合的人类 Scap 结构表明它们的相互作用是如何受甾醇调节的

SREBP 通路控制甾醇的细胞稳态。该途径中的关键参与者 Scap 和 Insig-1/2 是膜嵌入的甾醇传感器。Scap 和 Insigs 的 25-羟基胆固醇 (25HC) 依赖性结合充当 SREBP 通路的主开关。在这里，我们展示了在 25HC 存在下对人 Scap 和 Insig-2 复合物进行的冷冻电镜分析，其中跨膜 (TM) 结构域以 3.7 Å 的平均分辨率确定。Scap 中的甾醇传感域 (SSD) 和 Insig-2 中的所有六个 TM 均已解析。25HC 分子夹在 Scap 中的 S4-S6 段和膜腔小叶中 Insig-2 中的 TMs 3/4 之间。Scap-S4 段中间的展开对于 25HC 结合和 Insig 关联至关重要。