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- EMDB-63104: Cryo-EM structure of GPR155 monomer in complex with cholesterol -

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Basic information

Entry
Database: EMDB / ID: EMD-63104
TitleCryo-EM structure of GPR155 monomer in complex with cholesterol
Map dataEM map of monomer with CHL
Sample
  • Complex: GPR155 in complex with cholesterol
    • Protein or peptide: Lysosomal cholesterol signaling protein
  • Ligand: CHOLESTEROL
Keywordscholesterol / mTORC1 regulation / GPCR / transceptor / 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: 3.46 Å
AuthorsGao F / Zhang X / Li D / Pu H
Funding support China, 2 items
OrganizationGrant numberCountry
Other government202403021211192 China
National Natural Science Foundation of China (NSFC)32161133022 China
CitationJournal: Sci Bull (Beijing) / Year: 2025
Title: Structural insight into GPR155-mediated cholesterol sensing and signal transduction.
Authors: Delin Li / Xiaokang Zhang / Jie Feng / Yufeng Xie / Pu Han / Ming He / Lin Hao / Tianling Guo / Xiaoyi Bai / Kai Yuan / Junqing Sun / Xuefei Pang / Yan Wu / Yingxia Liu / George Fu Gao / Niu ...Authors: Delin Li / Xiaokang Zhang / Jie Feng / Yufeng Xie / Pu Han / Ming He / Lin Hao / Tianling Guo / Xiaoyi Bai / Kai Yuan / Junqing Sun / Xuefei Pang / Yan Wu / Yingxia Liu / George Fu Gao / Niu Huang / Haixia Xiao / Feng Gao /
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- ...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.
History
DepositionJan 13, 2025-
Header (metadata) releaseDec 10, 2025-
Map releaseDec 10, 2025-
UpdateDec 10, 2025-
Current statusDec 10, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_63104.png

Downloads & links

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Map

FileDownload / File: emd_63104.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationEM map of monomer with CHL
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 400 pix.
= 340. Å		0.85 Å/pix.
x 400 pix.
= 340. Å		0.85 Å/pix.
x 400 pix.
= 340. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.85 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.351
Minimum - Maximum-1.5571309 - 2.2977788
Average (Standard dev.)-0.00018385843 (±0.024147226)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 340.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half map A of monomer with CHL

Fileemd_63104_half_map_1.map
AnnotationHalf map A of monomer with CHL
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map A of monomer with CHL

Fileemd_63104_half_map_2.map
AnnotationHalf map A of monomer with CHL
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : GPR155 in complex with cholesterol

EntireName: GPR155 in complex with cholesterol
Components
  • Complex: GPR155 in complex with cholesterol
    • Protein or peptide: Lysosomal cholesterol signaling protein
  • Ligand: CHOLESTEROL

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Supramolecule #1: GPR155 in complex with cholesterol

SupramoleculeName: GPR155 in complex with cholesterol / 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: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 101.046047 KDa
Recombinant expressionOrganism: Schizosaccharomyces pombe (fission yeast)
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 AAAENLYFQG LWSHPQFEK GGGSGGGSGG SAWSHPQFEK

UniProtKB: Lysosomal cholesterol signaling protein

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Macromolecule #2: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 2 / Number of copies: 7 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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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

Concentration3.3 mg/mL
BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: -2.0 µm / Nominal defocus min: -1.0 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: OTHER / Details: ab initio 3d by cryoSPARC
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.46 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 645636
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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