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- EMDB-41914: The mTORC1 cholesterol sensor LYCHOS (GPR155) with tryptophan -

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Basic information

Entry
Database: EMDB / ID: EMD-41914
TitleThe mTORC1 cholesterol sensor LYCHOS (GPR155) with tryptophan
Map dataFinal combined map, filtered to Gold-standard resolution. Not sharpened.
Sample
  • Complex: Homodimeric complex of LYCHOS (GPR155)
    • Protein or peptide: Integral membrane protein GPR155
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsPIN-FORMED / GPCR / Cholesterol / auxin / transporter / cell-growth / mTORC1 / cancer / 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 / cognition / transmembrane transport / 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: 2.45 Å
AuthorsBayly-Jones C / Lupton CJ / Ellisdon AM
Funding support Australia, United States, 3 items
OrganizationGrant numberCountry
Australian Research Council (ARC)DE240100992 Australia
Other governmentMCRF21036
Department of Defense (DOD, United States)W81XWH-19-1-0182 United States
CitationJournal: Science / Year: 2022
Title: Lysosomal GPCR-like protein LYCHOS signals cholesterol sufficiency to mTORC1.
Authors: Hijai R Shin / Y Rose Citron / Lei Wang / Laura Tribouillard / Claire S Goul / Robin Stipp / Yusuke Sugasawa / Aakriti Jain / Nolwenn Samson / Chun-Yan Lim / Oliver B Davis / David Castaneda- ...Authors: Hijai R Shin / Y Rose Citron / Lei Wang / Laura Tribouillard / Claire S Goul / Robin Stipp / Yusuke Sugasawa / Aakriti Jain / Nolwenn Samson / Chun-Yan Lim / Oliver B Davis / David Castaneda-Carpio / Mingxing Qian / Daniel K Nomura / Rushika M Perera / Eunyong Park / Douglas F Covey / Mathieu Laplante / Alex S Evers / Roberto Zoncu /
Abstract: Lysosomes coordinate cellular metabolism and growth upon sensing of essential nutrients, including cholesterol. Through bioinformatic analysis of lysosomal proteomes, we identified lysosomal ...Lysosomes coordinate cellular metabolism and growth upon sensing of essential nutrients, including cholesterol. Through bioinformatic analysis of lysosomal proteomes, we identified lysosomal cholesterol signaling (LYCHOS, previously annotated as G protein-coupled receptor 155), a multidomain transmembrane protein that enables cholesterol-dependent activation of the master growth regulator, the protein kinase mechanistic target of rapamycin complex 1 (mTORC1). Cholesterol bound to the amino-terminal permease-like region of LYCHOS, and mutating this site impaired mTORC1 activation. At high cholesterol concentrations, LYCHOS bound to the GATOR1 complex, a guanosine triphosphatase (GTPase)-activating protein for the Rag GTPases, through a conserved cytoplasm-facing loop. By sequestering GATOR1, LYCHOS promotes cholesterol- and Rag-dependent recruitment of mTORC1 to lysosomes. Thus, LYCHOS functions in a lysosomal pathway for cholesterol sensing and couples cholesterol concentrations to mTORC1-dependent anabolic signaling.
History
DepositionSep 12, 2023-
Header (metadata) releaseSep 18, 2024-
Map releaseSep 18, 2024-
UpdateSep 18, 2024-
Current statusSep 18, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_41914.png

Downloads & links

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Map

FileDownload / File: emd_41914.map.gz / Format: CCP4 / Size: 98.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationFinal combined map, filtered to Gold-standard resolution. Not sharpened.
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.97 Å/pix.
x 296 pix.
= 286.114 Å		0.97 Å/pix.
x 296 pix.
= 286.114 Å		0.97 Å/pix.
x 296 pix.
= 286.114 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.9666 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.2
Minimum - Maximum-0.4824572 - 1.2004356
Average (Standard dev.)0.0007176908 (±0.027073644)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions296296296
Spacing296296296
CellA=B=C: 286.1136 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_41914_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Homodimeric complex of LYCHOS (GPR155)

EntireName: Homodimeric complex of LYCHOS (GPR155)
Components
  • Complex: Homodimeric complex of LYCHOS (GPR155)
    • Protein or peptide: Integral membrane protein GPR155
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Homodimeric complex of LYCHOS (GPR155)

SupramoleculeName: Homodimeric complex of LYCHOS (GPR155) / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 / Details: Incubated with 10 mM Tryptophan
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 198 KDa

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Macromolecule #1: Integral membrane protein GPR155

MacromoleculeName: Integral membrane protein GPR155 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 99.276891 KDa
Recombinant expressionOrganism: Homo sapiens (human)
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 GSGSDYKDDD DKDYKDDDD K

UniProtKB: Lysosomal cholesterol signaling protein

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Macromolecule #2: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 2 / Number of copies: 2 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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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

Concentration2 mg/mL
BufferpH: 7.4
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV
DetailsIncubated with 10 mM Tryptophan

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number real images: 8204 / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.5 µm / Nominal magnification: 105000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 2293740
Startup modelType of model: NONE / Details: Ab initio
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C2 (2 fold cyclic) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 2.45 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.1.1) / Number images used: 186146
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.1.1)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.1.1)
Final 3D classificationNumber classes: 4 / Avg.num./class: 500000 / Software - Name: cryoSPARC (ver. 4.1.1)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

z3f1


Chain - Source name: AlphaFold / Chain - Initial model type: in silico model
Details: A dimeric assembly was predicted with AlphaFold and then rigid body fit into the map. Subsequent refinements were performed in ISOLDE.
RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-8u58:
The mTORC1 cholesterol sensor LYCHOS (GPR155) with tryptophan

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