Cryo-EM reveals cholesterol binding in the lysosomal GPCR-like protein LYCHOS

Jie Zhao; Qingya Shen; Xihao Yong; Xin Li; Xiaowen Tian; Suyue Sun; Zheng Xu; Xiaoyu Zhang; Lu Zhang; Hao Yang; Zhenhua Shao; Haoxing Xu; Yiyang Jiang; Yan Zhang; Wei Yan

doi:10.1038/s41594-024-01470-9

Cryo-EM reveals cholesterol binding in the lysosomal GPCR-like protein LYCHOS

Nat Struct Mol Biol. 2025 May;32(5):896-904. doi: 10.1038/s41594-024-01470-9. Epub 2025 Jan 17.

Authors

Jie Zhao^#^{1

2}, Qingya Shen^#^{3

4}, Xihao Yong^#^{1

2}, Xin Li⁵, Xiaowen Tian^{1

2}, Suyue Sun^{1

2}, Zheng Xu^{1

2}, Xiaoyu Zhang^{1

2}, Lu Zhang⁵, Hao Yang⁵, Zhenhua Shao^{6

7}, Haoxing Xu⁸, Yiyang Jiang⁹, Yan Zhang^{10

11}, Wei Yan¹²

Affiliations

¹ Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
² Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, China.
³ Department of Pathology of Sir Run Shaw Hospital, Department of Pharmacology, and Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China.
⁴ MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Medicine, Hangzhou, China.
⁵ NHC Key Lab of Transplant Engineering and Immunology, Regenerative Medicine Research Center, Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, Metabolomics and Proteomics Technology Platform, West China Hospital, Sichuan University, Chengdu, China.
⁶ Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China. zhenhuashao@scu.edu.cn.
⁷ Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, China. zhenhuashao@scu.edu.cn.
⁸ New Cornerstone Science Laboratory & Liangzhu Laboratory, the Second Affiliated Hospital & School of Basic Medical Sciences, Zhejiang University, Hangzhou, China. haoxingx@zju.edu.cn.
⁹ Department of Hepatobiliary Surgery, Innovative Institute of Tumor Immunity and Medicine (ITIM), Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy, The First Affiliated Hospital of Anhui Medical University, Hefei, China. yyjiang@ustc.edu.cn.
¹⁰ Department of Pathology of Sir Run Shaw Hospital, Department of Pharmacology, and Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China. zhang_yan@zju.edu.cn.
¹¹ MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Medicine, Hangzhou, China. zhang_yan@zju.edu.cn.
¹² Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China. weiyan2018@scu.edu.cn.

^# Contributed equally.

PMID: 39824976
DOI: 10.1038/s41594-024-01470-9

Abstract

Cholesterol plays a pivotal role in modulating the activity of mechanistic target of rapamycin complex 1 (mTOR1), thereby regulating cell growth and metabolic homeostasis. LYCHOS, a lysosome-localized G-protein-coupled receptor-like protein, emerges as a cholesterol sensor and is capable of transducing the cholesterol signal to affect the mTORC1 function. However, the precise mechanism by which LYCHOS recognizes cholesterol remains unknown. Here, using cryo-electron microscopy, we determined the three-dimensional structural architecture of LYCHOS in complex with cholesterol molecules, revealing a unique arrangement of two sequential structural domains. Through a comprehensive analysis of this structure, we elucidated the specific structural features of these two domains and their collaborative role in the process of cholesterol recognition by LYCHOS.

MeSH terms

Cholesterol* / chemistry
Cholesterol* / metabolism
Cryoelectron Microscopy
Humans
Lysosomes* / metabolism
Models, Molecular
Protein Binding
Receptors, G-Protein-Coupled* / chemistry
Receptors, G-Protein-Coupled* / metabolism
Receptors, G-Protein-Coupled* / ultrastructure

Substances

Cholesterol
Receptors, G-Protein-Coupled