Cryo-EM Reveals Cholesterol Binding in the Lysosomal GPCR-like Protein LYCHOS

Overview

Journal Nat Struct Mol Biol

Date 2025 Jan 17

PMID 39824976

Authors

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

Affiliations

Soon will be listed here.

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.

References

Sezgin E, Levental I, Mayor S, Eggeling C . The mystery of membrane organization: composition, regulation and roles of lipid rafts. Nat Rev Mol Cell Biol. 2017; 18(6):361-374. PMC: 5500228. DOI: 10.1038/nrm.2017.16. View

Lawrence R, Zoncu R . The lysosome as a cellular centre for signalling, metabolism and quality control. Nat Cell Biol. 2019; 21(2):133-142. DOI: 10.1038/s41556-018-0244-7. View

Luo J, Yang H, Song B . Mechanisms and regulation of cholesterol homeostasis. Nat Rev Mol Cell Biol. 2019; 21(4):225-245. DOI: 10.1038/s41580-019-0190-7. View

Maxfield F, van Meer G . Cholesterol, the central lipid of mammalian cells. Curr Opin Cell Biol. 2010; 22(4):422-9. PMC: 2910236. DOI: 10.1016/j.ceb.2010.05.004. View

He A, Dean J, Lodhi I . Peroxisomes as cellular adaptors to metabolic and environmental stress. Trends Cell Biol. 2021; 31(8):656-670. PMC: 8566112. DOI: 10.1016/j.tcb.2021.02.005. View

Altmann S, Davis Jr H, Zhu L, Yao X, Hoos L, Tetzloff G . Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption. Science. 2004; 303(5661):1201-4. DOI: 10.1126/science.1093131. View

Ballabio A, Bonifacino J . Lysosomes as dynamic regulators of cell and organismal homeostasis. Nat Rev Mol Cell Biol. 2019; 21(2):101-118. DOI: 10.1038/s41580-019-0185-4. View

Zhang C, Li M, Ma T, Zong Y, Cui J, Feng J . Metformin Activates AMPK through the Lysosomal Pathway. Cell Metab. 2016; 24(4):521-522. DOI: 10.1016/j.cmet.2016.09.003. View

Lim C, Davis O, Shin H, Zhang J, Berdan C, Jiang X . ER-lysosome contacts enable cholesterol sensing by mTORC1 and drive aberrant growth signalling in Niemann-Pick type C. Nat Cell Biol. 2019; 21(10):1206-1218. PMC: 6936960. DOI: 10.1038/s41556-019-0391-5. View

10.

Settembre C, Zoncu R, Medina D, Vetrini F, Erdin S, Erdin S . A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB. EMBO J. 2012; 31(5):1095-108. PMC: 3298007. DOI: 10.1038/emboj.2012.32. View

11.

Sancak Y, Peterson T, Shaul Y, Lindquist R, Thoreen C, Bar-Peled L . The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science. 2008; 320(5882):1496-501. PMC: 2475333. DOI: 10.1126/science.1157535. View

12.

Bar-Peled L, Chantranupong L, Cherniack A, Chen W, Ottina K, Grabiner B . A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science. 2013; 340(6136):1100-6. PMC: 3728654. DOI: 10.1126/science.1232044. View

13.

Su M, Morris K, Kim D, Fu Y, Lawrence R, Stjepanovic G . Hybrid Structure of the RagA/C-Ragulator mTORC1 Activation Complex. Mol Cell. 2017; 68(5):835-846.e3. PMC: 5722659. DOI: 10.1016/j.molcel.2017.10.016. View

14.

Kim E, Goraksha-Hicks P, Li L, Neufeld T, Guan K . Regulation of TORC1 by Rag GTPases in nutrient response. Nat Cell Biol. 2008; 10(8):935-45. PMC: 2711503. DOI: 10.1038/ncb1753. View

15.

Yang H, Jiang X, Li B, Yang H, Miller M, Yang A . Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40. Nature. 2017; 552(7685):368-373. PMC: 5750076. DOI: 10.1038/nature25023. View

16.

Wang S, Tsun Z, Wolfson R, Shen K, Wyant G, Plovanich M . Metabolism. Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1. Science. 2015; 347(6218):188-94. PMC: 4295826. DOI: 10.1126/science.1257132. View

17.

Rebsamen M, Pochini L, Stasyk T, de Araujo M, Galluccio M, Kandasamy R . SLC38A9 is a component of the lysosomal amino acid sensing machinery that controls mTORC1. Nature. 2015; 519(7544):477-81. PMC: 4376665. DOI: 10.1038/nature14107. View

18.

Chantranupong L, Scaria S, Saxton R, Gygi M, Shen K, Wyant G . The CASTOR Proteins Are Arginine Sensors for the mTORC1 Pathway. Cell. 2016; 165(1):153-164. PMC: 4808398. DOI: 10.1016/j.cell.2016.02.035. View

19.

Wyant G, Abu-Remaileh M, Wolfson R, Chen W, Freinkman E, Danai L . mTORC1 Activator SLC38A9 Is Required to Efflux Essential Amino Acids from Lysosomes and Use Protein as a Nutrient. Cell. 2017; 171(3):642-654.e12. PMC: 5704964. DOI: 10.1016/j.cell.2017.09.046. View

20.

Castellano B, Thelen A, Moldavski O, Feltes M, van der Welle R, Mydock-McGrane L . Lysosomal cholesterol activates mTORC1 via an SLC38A9-Niemann-Pick C1 signaling complex. Science. 2017; 355(6331):1306-1311. PMC: 5823611. DOI: 10.1126/science.aag1417. View