2. Academic Validation
  3. Structural insight into GPR155-mediated cholesterol sensing and signal transduction

Structural insight into GPR155-mediated cholesterol sensing and signal transduction

  • Sci Bull (Beijing). 2025 Sep 10:S2095-9273(25)00925-9. doi: 10.1016/j.scib.2025.09.012.
Delin Li 1,  Xiaokang Zhang 2,  Jie Feng 3,  Yufeng Xie 4,  Pu Han 4,  Ming He 5,  Lin Hao 6,  Tianling Guo 7,  Xiaoyi Bai 7,  Kai Yuan 7,  Junqing Sun 8,  Xuefei Pang 7,  Yan Wu 9,  Yingxia Liu 10,  George Fu Gao 11,  Niu Huang 12,  Haixia Xiao 13,  Feng Gao 14
Affiliations

Affiliations

  • 1 Laboratory of Protein Engineering and Vaccines, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin 300308, China; Innovative Vaccine and lmmunotherapy Research Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China; Shanxi Academy of Advanced Research and Innovation, Taiyuan 030032, China.
  • 2 Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
  • 3 National Institute of Biological Sciences, Beijing 102206, China; Peking University-Tsinghua University-National Institute of Biological Sciences Joint Graduate Program, Tsinghua University, Beijing 100084, China.
  • 4 CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
  • 5 Xiaogan 3D Scientific Computing Center. Dongsheng Science and Technology Park, Beijing 100096, China.
  • 6 Innovative Vaccine and lmmunotherapy Research Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.
  • 7 Laboratory of Protein Engineering and Vaccines, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin 300308, China.
  • 8 Innovative Vaccine and lmmunotherapy Research Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China; Shanxi Academy of Advanced Research and Innovation, Taiyuan 030032, China.
  • 9 Department of Pathogen Microbiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China.
  • 10 The Third People's Hospital of Shenzhen, Shenzhen 518112, China.
  • 11 Innovative Vaccine and lmmunotherapy Research Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China; CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
  • 12 National Institute of Biological Sciences, Beijing 102206, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 100084, China. Electronic address: huangniu@nibs.ac.cn.
  • 13 Laboratory of Protein Engineering and Vaccines, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin 300308, China. Electronic address: xiao_hx@tib.cas.cn.
  • 14 Laboratory of Protein Engineering and Vaccines, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin 300308, China. Electronic address: gaofeng@tib.cas.cn.
PMID: 41058362 DOI: 10.1016/j.scib.2025.09.012
Abstract

Cholesterol (CHL) serves as a building block for membrane biogenesis and a precursor to oxysterols, steroid Hormones, bile acids, and vitamin D. The lysosome serves as a major sorting station for low-density lipoproteins (LDLs), which carry dietary CHL, and it is also the cellular site where the master growth regulator, the protein kinase mechanistic Target of Rapamycin Complex 1 (mTORC1), is activated. Recently, the lysosomal transmembrane protein GPR155 was reported to signals CHL sufficiency to mTORC1 through sequestration of the GTPase-activating protein towards the Rags 1 (GATOR1). Although the recently reported structures of GPR155 have revealed the CHL binding site, how the signal is transduced from the CHL binding site to the soluble parts of GPR155 and GATOR1 remains unknown. Here, with our three cryo-EM structures of GPR155 captured in different conformations in complex with CHL, complemented by long-time scale molecular dynamics simulations, the dynamic rearrangement of different domains was observed. CHL binding induces a widening of the crevice between the transporter and GPCR domains. The extending helix preceding transmembrane helix (TM) 16, which was unresolved in Other structures, acts as a linkage lever that transmits the rotation of the GPCR domain to the soluble parts of GPR155 in response to CHL binding. This work not only answers the question of how CHL is sensed by GPR155, but also addresses a more profound question: how the signal perceived by the TMs regions is transduced to the LED and DEP domains.

Keywords

Cholesterol; GATOR1; GPCR; LYCHOS; Transporter; mTORC1.

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