Yu Shang, Ding Jin-Hui, Wang Jia-le, Wang Weize, Zuo Peng, Yang Ao, Dai Zonglin, Yin Yuxin, Sun Jin-Peng, Liang Ling
Department of Biophysics, State Key Laboratory of Natural and Biomimetic Drugs, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
Department of Physiology and Pathophysiology, School of Basic Medical Sciences; State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China.
Nat Commun. 2025 Jul 23;16(1):6792. doi: 10.1038/s41467-025-61966-w.
The lysosomal cholesterol sensor LYCHOS regulates mTORC1 signaling by coupling cholesterol sensing to GATOR1-Rag GTPase modulation, yet its structural mechanisms remain unclear. Here we report six cryo-electron microscopy structures of human LYCHOS, depicting five distinct states. These are categorized into a contracted state when complexed with a sufficient amount of the cholesterol analogue cholesteryl hemisuccinate (CHS), and an expanded state when CHS is deficient. The structure forms a homodimer, within each monomer the transmembrane region is divided into a permease-like domain (PLD) and a GPCR-like domain (GLD) with two clearly defined adjacent cholesterol binding sites between them. Cholesterol binding induces a translation of GLD towards PLD and exposes the cytosolic extension of transmembrane 15, which interacts with GATOR1. Our results elucidate the structural mechanism of cholesterol sensing by the mTORC1 pathway, providing a structural basis for developing inhibitors that selectively target mTORC1 pathway by blocking LYCHOS in its expanded state.
溶酶体胆固醇传感器LYCHOS通过将胆固醇感应与GATOR1-Rag GTP酶调节相耦合来调控mTORC1信号传导，但其结构机制仍不清楚。在此，我们报告了人类LYCHOS的六个冷冻电镜结构，描绘了五种不同状态。当与足量的胆固醇类似物半琥珀酸胆固醇（CHS）结合时，这些状态被归类为收缩状态；当CHS不足时，则为扩张状态。该结构形成一个同型二聚体，在每个单体中，跨膜区域被分为一个通透酶样结构域（PLD）和一个GPCR样结构域（GLD），它们之间有两个明确定义的相邻胆固醇结合位点。胆固醇结合诱导GLD向PLD平移，并暴露跨膜15的胞质延伸部分，该部分与GATOR1相互作用。我们的结果阐明了mTORC1途径对胆固醇感应的结构机制，为开发通过阻断处于扩张状态的LYCHOS来选择性靶向mTORC1途径的抑制剂提供了结构基础。
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