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| Title | Structural basis for cholesterol sensing of LYCHOS and its interaction with indoxyl sulfate. |
|---|---|
| Journal, issue, pages | Nat Commun, Vol. 16, Issue 1, Page 2815, Year 2025 |
| Publish date | Mar 21, 2025 |
Authors | Zhenhua Wang / Jingjing He / Yufan Yang / Yonglin He / Hongwu Qian / ![]() |
| PubMed Abstract | The lysosome serves as an essential nutrient-sensing hub within the cell, where the mechanistic target of rapamycin complex 1 (mTORC1) is activated. Lysosomal cholesterol signaling (LYCHOS), a ...The lysosome serves as an essential nutrient-sensing hub within the cell, where the mechanistic target of rapamycin complex 1 (mTORC1) is activated. Lysosomal cholesterol signaling (LYCHOS), a lysosome membrane protein, has been identified as a cholesterol sensor that couples cholesterol concentration to mTORC1 activation. However, the molecular basis is unknown. Here, we determine the cryo-electron microscopy (cryo-EM) structure of human LYCHOS at a resolution of 3.1 Å, revealing a cholesterol-like density at the interface between the permease and G-protein coupled receptor (GPCR) domains. Advanced 3D classification reveals two distinct states of LYCHOS. Comparative structural analysis between these two states demonstrated a cholesterol-related movement of GPCR domain relative to permease domain, providing structural insights into how LYCHOS senses lysosomal cholesterol levels. Additionally, we identify indoxyl sulfate (IS) as a binding ligand to the permease domain, confirmed by the LYCHOS-IS complex structure. Overall, our study provides a foundation and indicates additional directions for further investigation of the essential role of LYCHOS in the mTORC1 signaling pathway. |
External links | Nat Commun / PubMed:40118871 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 3.1 - 3.5 Å |
| Structure data | EMDB-37761, PDB-8wr3: EMDB-61127, PDB-9j3x: EMDB-61128, PDB-9j3z: EMDB-61129, PDB-9j40: |
| Chemicals | ![]() ChemComp-CLR: ![]() ChemComp-POV: ![]() ChemComp-NAG: ![]() ChemComp-IOS: ![]() ChemComp-TRP: |
| Source |
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Keywords | TRANSPORT PROTEIN / lysosome / tranporter / amino acids / LIPID BINDING PROTEIN |
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