8WR3
Cryo-EM structure of lysosomal protein LYCHOS
Summary for 8WR3
| Entry DOI | 10.2210/pdb8wr3/pdb |
| EMDB information | 37761 |
| Descriptor | Lysosomal cholesterol signaling protein, CHOLESTEROL, (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate, ... (4 entities in total) |
| Functional Keywords | lysosome, tranporter, amino acids, transport protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 164423.73 |
| Authors | Wang, Z.H.,Qian, H.W. (deposition date: 2023-10-12, release date: 2025-01-15, Last modification date: 2025-07-02) |
| Primary citation | Wang, Z.,He, J.,Yang, Y.,He, Y.,Qian, H. Structural basis for cholesterol sensing of LYCHOS and its interaction with indoxyl sulfate. Nat Commun, 16:2815-2815, 2025 Cited by 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 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. PubMed: 40118871DOI: 10.1038/s41467-025-58087-9 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.1 Å) |
Structure validation
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