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- EMDB-61313: Cryo-EM structure of the human LYCHOS in complex with lipids in t... -

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Basic information

Entry
Database: EMDB / ID: EMD-61313
TitleCryo-EM structure of the human LYCHOS in complex with lipids in the expanded state
Map data
Sample
  • Complex: Homodimer of GPR155
    • Protein or peptide: Lysosomal cholesterol signaling protein
  • Ligand: 1,2-Distearoyl-sn-glycerophosphoethanolamine
  • Ligand: O-[(R)-{[(2R)-2,3-bis(octadecanoyloxy)propyl]oxy}(hydroxy)phosphoryl]-L-serine
  • Ligand: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE
  • Ligand: OLEIC ACID
Keywordspermease-like domain / GPCR-like domain / cholesterol / mTORC1 / MEMBRANE 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
Lysosomal cholesterol signaling protein
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.76 Å
AuthorsYu S / Liang L
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32171224 China
CitationJournal: Nat Commun / Year: 2025
Title: Structural insights into cholesterol sensing by the LYCHOS-mTORC1 pathway.
Authors: Shang Yu / Jin-Hui Ding / Jia-le Wang / Weize Wang / Peng Zuo / Ao Yang / Zonglin Dai / Yuxin Yin / Jin-Peng Sun / Ling Liang /
Abstract: The lysosomal cholesterol sensor LYCHOS regulates mTORC1 signaling by coupling cholesterol sensing to GATOR1-Rag GTPase modulation, yet its structural mechanisms remain unclear. Here we report six ...The lysosomal cholesterol sensor LYCHOS regulates mTORC1 signaling by coupling cholesterol sensing to GATOR1-Rag GTPase modulation, yet its structural mechanisms remain unclear. Here we report six cryo-electron microscopy structures of human LYCHOS, depicting five distinct states. These are categorized into a contracted state when complexed with a sufficient amount of the cholesterol analogue cholesteryl hemisuccinate (CHS), and an expanded state when CHS is deficient. The structure forms a homodimer, within each monomer the transmembrane region is divided into a permease-like domain (PLD) and a GPCR-like domain (GLD) with two clearly defined adjacent cholesterol binding sites between them. Cholesterol binding induces a translation of GLD towards PLD and exposes the cytosolic extension of transmembrane 15, which interacts with GATOR1. Our results elucidate the structural mechanism of cholesterol sensing by the mTORC1 pathway, providing a structural basis for developing inhibitors that selectively target mTORC1 pathway by blocking LYCHOS in its expanded state.
History
DepositionAug 27, 2024-
Header (metadata) releaseJul 16, 2025-
Map releaseJul 16, 2025-
UpdateAug 27, 2025-
Current statusAug 27, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_61313.png

Downloads & links

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Map

FileDownload / File: emd_61313.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.81 Å/pix.
x 400 pix.
= 323.2 Å		0.81 Å/pix.
x 400 pix.
= 323.2 Å		0.81 Å/pix.
x 400 pix.
= 323.2 Å

Surface

Projections

Slices (1/3)

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.808 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.2
Minimum - Maximum-0.68608385 - 1.023816
Average (Standard dev.)-0.0006820451 (±0.026499674)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 323.2 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_61313_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

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Histogram (log scale)

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Half map: #2

Fileemd_61313_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : Homodimer of GPR155

EntireName: Homodimer of GPR155
Components
  • Complex: Homodimer of GPR155
    • Protein or peptide: Lysosomal cholesterol signaling protein
  • Ligand: 1,2-Distearoyl-sn-glycerophosphoethanolamine
  • Ligand: O-[(R)-{[(2R)-2,3-bis(octadecanoyloxy)propyl]oxy}(hydroxy)phosphoryl]-L-serine
  • Ligand: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE
  • Ligand: OLEIC ACID

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Supramolecule #1: Homodimer of GPR155

SupramoleculeName: Homodimer of GPR155 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Lysosomal cholesterol signaling protein

MacromoleculeName: Lysosomal cholesterol signaling protein / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 98.03382 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MNSNLPAENL TIAVNMTKTL PTAVTHGFNS TNDPPSMSIT RLFPALLECF GIVLCGYIAG RANVITSTQA KGLGNFVSRF ALPALLFKN MVVLNFSNVD WSFLYSILIA KASVFFIVCV LTLLVASPDS RFSKAGLFPI FATQSNDFAL GYPIVEALYQ T TYPEYLQY ...String:
MNSNLPAENL TIAVNMTKTL PTAVTHGFNS TNDPPSMSIT RLFPALLECF GIVLCGYIAG RANVITSTQA KGLGNFVSRF ALPALLFKN MVVLNFSNVD WSFLYSILIA KASVFFIVCV LTLLVASPDS RFSKAGLFPI FATQSNDFAL GYPIVEALYQ T TYPEYLQY IYLVAPISLM MLNPIGFIFC EIQKWKDTQN ASQNKIKIVG LGLLRVLQNP IVFMVFIGIA FNFILDRKVP VY VENFLDG LGNSFSGSAL FYLGLTMVGK IKRLKKSAFV VLILLITAKL LVLPLLCREM VELLDKGDSV VNHTSLSNYA FLY GVFPVA PGVAIFATQF NMEVEIITSG MVISTFVSAP IMYVSAWLLT FPTMDPKPLA YAIQNVSFDI SIVSLISLIW SLAI LLLSK KYKQLPHMLT TNLLIAQSIV CAGMMIWNFV KEKNFVGQIL VFVLLYSSLY STYLWTGLLA ISLFLLKKRE RVQIP VGII IISGWGIPAL LVGVLLITGK HNGDSIDSAF FYGKEQMITT AVTLFCSILI AGISLMCMNQ TAQAGSYEGF DQSQSH KVV EPGNTAFEES PAPVNEPELF TSSIPETSCC SCSMGNGELH CPSIEPIANT STSEPVIPSF EKNNHCVSRC NSQSCIL AQ EEEQYLQSGD QQLTRHVLLC LLLIIGLFAN LSSCLWWLFN QEPGRLYVEL QFFCAVFNFG QGFISFGIFG LDKHLIIL P FKRRLEFLWN NKDTAENRDS PVSEEIKMTC QQFIHYHRDL CIRNIVKERR CGAKTSAGTF CGCDLVSWLI EVGLASDRG EAVIYGDRLV QGGVIQHITN EYEFRDEYLF YRFLQKSPEQ SPPAINANTL QQERYKEIEH SSPPSHSPKT SRENLYFQ

UniProtKB: Lysosomal cholesterol signaling protein

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Macromolecule #2: 1,2-Distearoyl-sn-glycerophosphoethanolamine

MacromoleculeName: 1,2-Distearoyl-sn-glycerophosphoethanolamine / type: ligand / ID: 2 / Number of copies: 3 / Formula: 3PE
Molecular weightTheoretical: 748.065 Da
Chemical component information

ChemComp-3PE:
1,2-Distearoyl-sn-glycerophosphoethanolamine / phospholipid*YM

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Macromolecule #3: O-[(R)-{[(2R)-2,3-bis(octadecanoyloxy)propyl]oxy}(hydroxy)phospho...

MacromoleculeName: O-[(R)-{[(2R)-2,3-bis(octadecanoyloxy)propyl]oxy}(hydroxy)phosphoryl]-L-serine
type: ligand / ID: 3 / Number of copies: 1 / Formula: P5S
Molecular weightTheoretical: 792.075 Da
Chemical component information

ChemComp-P5S:
O-[(R)-{[(2R)-2,3-bis(octadecanoyloxy)propyl]oxy}(hydroxy)phosphoryl]-L-serine

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Macromolecule #4: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE

MacromoleculeName: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / type: ligand / ID: 4 / Number of copies: 1 / Formula: PC1
Molecular weightTheoretical: 790.145 Da
Chemical component information

ChemComp-PC1:
1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / phospholipid*YM

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Macromolecule #5: OLEIC ACID

MacromoleculeName: OLEIC ACID / type: ligand / ID: 5 / Number of copies: 1 / Formula: OLA
Molecular weightTheoretical: 282.461 Da
Chemical component information

ChemComp-OLA:
OLEIC ACID

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration7.5 mg/mL
BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 50.29 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.6 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.76 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 20909
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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