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- PDB-9j3z: Cryo-EM structure of lysosome cholesterol sencing protein in L state -

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Basic information

Entry
Database: PDB / ID: 9j3z
TitleCryo-EM structure of lysosome cholesterol sencing protein in L state
ComponentsLysosomal cholesterol signaling protein,G protein-coupled receptor 155 fusion protein
KeywordsLIPID BINDING PROTEIN
Function / homology
Function and homology information


cellular response to cholesterol / cholesterol binding / negative regulation of BMP signaling pathway / positive regulation of TORC1 signaling / cellular response to amino acid starvation / transmembrane transport / cognition / intracellular signal transduction / lysosomal membrane / extracellular exosome
Similarity search - Function
Integral membrane protein GPR155, DEP domain / Membrane transport protein / Membrane transport protein / : / Domain found in Dishevelled, Egl-10, and Pleckstrin (DEP) / DEP domain profile. / Domain found in Dishevelled, Egl-10, and Pleckstrin / DEP domain / Winged helix DNA-binding domain superfamily / Winged helix-like DNA-binding domain superfamily
Similarity search - Domain/homology
Chem-POV / G protein-coupled receptor 155 / Lysosomal cholesterol signaling protein
Similarity search - Component
Biological speciesNomascus leucogenys (northern white-cheeked gibbon)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsQian, H.W. / Wang, Z.H.
Funding support China, 1items
OrganizationGrant numberCountry
Other privateKY9100000034 China
CitationJournal: Nat Commun / Year: 2025
Title: Structural basis for cholesterol sensing of LYCHOS and its interaction with indoxyl sulfate.
Authors: Zhenhua Wang / Jingjing He / Yufan Yang / Yonglin He / Hongwu Qian /
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.
History
DepositionAug 8, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 2, 2025Provider: repository / Type: Initial release
Revision 1.1Apr 9, 2025Group: Data collection / Database references / Category: citation / em_admin
Item: _citation.page_last / _citation.pdbx_database_id_PubMed ..._citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Lysosomal cholesterol signaling protein,G protein-coupled receptor 155 fusion protein
B: Lysosomal cholesterol signaling protein,G protein-coupled receptor 155 fusion protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)197,4728
Polymers193,9892
Non-polymers3,4836
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Lysosomal cholesterol signaling protein,G protein-coupled receptor 155 fusion protein / LYCHOS / G-protein coupled receptor PGR22


Mass: 96994.695 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Nomascus leucogenys (northern white-cheeked gibbon), (gene. exp.) Homo sapiens (human)
Gene: GPR155 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q7Z3F1, UniProt: G1R1S1
#2: Chemical
ChemComp-POV / (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / POPC


Mass: 760.076 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C42H82NO8P / Feature type: SUBJECT OF INVESTIGATION / Comment: phospholipid*YM
#3: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Lysosomal cholesterol signaling protein LYCHOS in loose-state
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Nomascus leucogenys (northern white-cheeked gibbon)61853
31Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
31Homo sapiens (human)9606
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1500 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: NONE
3D reconstructionResolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 103110 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0058673
ELECTRON MICROSCOPYf_angle_d1.05511810
ELECTRON MICROSCOPYf_dihedral_angle_d12.1671326
ELECTRON MICROSCOPYf_chiral_restr0.0621410
ELECTRON MICROSCOPYf_plane_restr0.0071458

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