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- EMDB-39851: Cryo-EM structure of LYCHOS -

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Basic information

Entry
Database: EMDB / ID: EMD-39851
TitleCryo-EM structure of LYCHOS
Map data
Sample
  • Complex: LYCHOS
    • Protein or peptide: Lysosomal cholesterol signaling protein,Fluorescent Protein
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: [(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyloxy-propan-2-yl] (~{Z})-octadec-9-enoate
  • Ligand: CHOLESTEROL
  • Ligand: [(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyloxy-propan-2-yl] (4~{Z},7~{Z},10~{Z},13~{Z},16~{Z},19~{Z})-docosa-4,7,10,13,16,19-hexaenoate
  • Ligand: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine
  • Ligand: SODIUM ION
  • Ligand: water
KeywordsLysosome / GPCR-like / Transporter / Cholesterol / 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) / synthetic construct (others)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.11 Å
AuthorsXiong Q / Zhu Z / Li T / Zhou Z / Chao Y / Qu Q / Li D
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)82151215 China
CitationJournal: Nat Struct Mol Biol / Year: 2025
Title: Molecular architecture of human LYCHOS involved in lysosomal cholesterol signaling.
Authors: Qi Xiong / Zhini Zhu / Tingting Li / Xiaotian Li / Zixuan Zhou / Yulin Chao / Chuanhui Yang / Suihan Feng / Qianhui Qu / Dianfan Li /
Abstract: Lysosomal membrane protein LYCHOS (lysosomal cholesterol signaling) translates cholesterol abundance to mammalian target of rapamycin activation. Here we report the 2.11-Å structure of human LYCHOS, ...Lysosomal membrane protein LYCHOS (lysosomal cholesterol signaling) translates cholesterol abundance to mammalian target of rapamycin activation. Here we report the 2.11-Å structure of human LYCHOS, revealing a unique fusion architecture comprising a G-protein-coupled receptor (GPCR)-like domain and a transporter domain that mediates homodimer assembly. The NhaA-fold transporter harbors a previously uncharacterized intramembrane Na pocket. The GPCR-like domain is stabilized, by analogy to canonical GPCRs, in an inactive state through 'tethered antagonism' by a lumenal loop and strong interactions at the cytosol side preventing the hallmark swing of the sixth transmembrane helix seen in active GPCRs. A cholesterol molecule and an associated docosahexaenoic acid (DHA)-phospholipid are entrapped between the transporter and GPCR-like domains, with the DHA-phospholipid occupying a pocket previously implicated in cholesterol sensing, indicating inter-domain coupling via dynamic lipid-protein interactions. Our work provides a high-resolution framework for functional investigations of the understudied LYCHOS protein.
History
DepositionApr 22, 2024-
Header (metadata) releaseJan 1, 2025-
Map releaseJan 1, 2025-
UpdateJun 4, 2025-
Current statusJun 4, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_39851.png

Downloads & links

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Map

FileDownload / File: emd_39851.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.93 Å/pix.
x 360 pix.
= 335.52 Å		0.93 Å/pix.
x 360 pix.
= 335.52 Å		0.93 Å/pix.
x 360 pix.
= 335.52 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.932 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.592
Minimum - Maximum-2.435748 - 4.076315
Average (Standard dev.)-0.00043140023 (±0.07980392)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 335.52 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: #1

Fileemd_39851_additional_1.map
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Half map: #1

Fileemd_39851_half_map_1.map
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Half map: #2

Fileemd_39851_half_map_2.map
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Sample components

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Entire : LYCHOS

EntireName: LYCHOS
Components
  • Complex: LYCHOS
    • Protein or peptide: Lysosomal cholesterol signaling protein,Fluorescent Protein
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: [(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyloxy-propan-2-yl] (~{Z})-octadec-9-enoate
  • Ligand: CHOLESTEROL
  • Ligand: [(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyloxy-propan-2-yl] (4~{Z},7~{Z},10~{Z},13~{Z},16~{Z},19~{Z})-docosa-4,7,10,13,16,19-hexaenoate
  • Ligand: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine
  • Ligand: SODIUM ION
  • Ligand: water

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Supramolecule #1: LYCHOS

SupramoleculeName: LYCHOS / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 127 KDa

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Macromolecule #1: Lysosomal cholesterol signaling protein,Fluorescent Protein

MacromoleculeName: Lysosomal cholesterol signaling protein,Fluorescent Protein
type: protein_or_peptide / ID: 1
Details: The protein is a fusion protein with expression tag. Residues 1-3 is the initial methionine and GS linker. Residues 4-873 is LYCHOS (uniport ID Q7Z3F1). Residues 874-889 is the linker with a ...Details: The protein is a fusion protein with expression tag. Residues 1-3 is the initial methionine and GS linker. Residues 4-873 is LYCHOS (uniport ID Q7Z3F1). Residues 874-889 is the linker with a 3 C protease digestion site. Residues 890-1114 is a thermostable green fluorescent protein fusion (PDB entry 4TZA, residue 5-229). Residues 1115-1144 is the linker with an expression tag
Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 127.213109 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MGSMNSNLPA ENLTIAVNMT KTLPTAVTHG FNSTNDPPSM SITRLFPALL ECFGIVLCGY IAGRANVITS TQAKGLGNFV SRFALPALL FKNMVVLNFS NVDWSFLYSI LIAKASVFFI VCVLTLLVAS PDSRFSKAGL FPIFATQSND FALGYPIVEA L YQTTYPEY ...String:
MGSMNSNLPA ENLTIAVNMT KTLPTAVTHG FNSTNDPPSM SITRLFPALL ECFGIVLCGY IAGRANVITS TQAKGLGNFV SRFALPALL FKNMVVLNFS NVDWSFLYSI LIAKASVFFI VCVLTLLVAS PDSRFSKAGL FPIFATQSND FALGYPIVEA L YQTTYPEY LQYIYLVAPI SLMMLNPIGF IFCEIQKWKD TQNASQNKIK IVGLGLLRVL QNPIVFMVFI GIAFNFILDR KV PVYVENF LDGLGNSFSG SALFYLGLTM VGKIKRLKKS AFVVLILLIT AKLLVLPLLC REMVELLDKG DSVVNHTSLS NYA FLYGVF PVAPGVAIFA TQFNMEVEII TSGMVISTFV SAPIMYVSAW LLTFPTMDPK PLAYAIQNVS FDISIVSLIS LIWS LAILL LSKKYKQLPH MLTTNLLIAQ SIVCAGMMIW NFVKEKNFVG QILVFVLLYS SLYSTYLWTG LLAISLFLLK KRERV QIPV GIIIISGWGI PALLVGVLLI TGKHNGDSID SAFFYGKEQM ITTAVTLFCS ILIAGISLMC MNQTAQAGSY EGFDQS QSH KVVEPGNTAF EESPAPVNEP ELFTSSIPET SCCSCSMGNG ELHCPSIEPI ANTSTSEPVI PSFEKNNHCV SRCNSQS CI LAQEEEQYLQ SGDQQLTRHV LLCLLLIIGL FANLSSCLWW LFNQEPGRLY VELQFFCAVF NFGQGFISFG IFGLDKHL I ILPFKRRLEF LWNNKDTAEN RDSPVSEEIK MTCQQFIHYH RDLCIRNIVK ERRCGAKTSA GTFCGCDLVS WLIEVGLAS DRGEAVIYGD RLVQGGVIQH ITNEYEFRDE YLFYRFLQKS PEQSPPAINA NTLQQERYKE IEHSSPPSHS PKTGTLEVLF QGPGGSGGS ASVIKPEMKI KLRMEGAVNG HKFVIEGEGI GKPYEGTQTL DLTVEEGAPL PFSYDILTPA FQYGNRAFTK Y PEDIPDYF KQAFPEGYSW ERSMTYEDQG ICIATSDITM EGDCFFYEIR FDGTNFPPNG PVMQKKTLKW EPSTEKMYVE DG VLKGDVE MALLLEGGGH YRCDFKTTYK AKKDVRLPDA HEVDHRIEIL SHDKDYNKVR LYEHAEARYS GGGSGGGSAW SHP QFEKGG GSGGGSGGSA WSHPQFEK

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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Macromolecule #3: [(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyl...

MacromoleculeName: [(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyloxy-propan-2-yl] (~{Z})-octadec-9-enoate
type: ligand / ID: 3 / Number of copies: 6 / Formula: 6OU
Molecular weightTheoretical: 717.996 Da
Chemical component information

ChemComp-6OU:
[(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyloxy-propan-2-yl] (~{Z})-octadec-9-enoate / phospholipid*YM

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Macromolecule #4: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 4 / Number of copies: 2 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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Macromolecule #5: [(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyl...

MacromoleculeName: [(2~{R})-1-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-3-hexadecanoyloxy-propan-2-yl] (4~{Z},7~{Z},10~{Z},13~{Z},16~{Z},19~{Z})-docosa-4,7,10,13,16,19-hexaenoate
type: ligand / ID: 5 / Number of copies: 2 / Formula: A1L1C
Molecular weightTheoretical: 764.023 Da

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Macromolecule #6: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine

MacromoleculeName: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine / type: ligand / ID: 6 / Number of copies: 2 / Formula: LBN
Molecular weightTheoretical: 760.076 Da
Chemical component information

ChemComp-LBN:
1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine / phospholipid*YM

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Macromolecule #7: SODIUM ION

MacromoleculeName: SODIUM ION / type: ligand / ID: 7 / Number of copies: 2
Molecular weightTheoretical: 22.99 Da

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Macromolecule #8: water

MacromoleculeName: water / type: ligand / ID: 8 / Number of copies: 2 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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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

Concentration9 mg/mL
BufferpH: 8
Component:
ConcentrationFormulaName
0.001 %LMNGlauryl maltose neopentyl glycol
150.0 mMNaClsodium chloride
50.0 mMTris-HClTris(hydroxymethyl)aminomethane hydrochloride
0.2 mMTCEPtris(2-carboxyethyl)phosphine

Details: 0.001 % LMNG, 150 mM NaCl, 0.2 mM TECP, 50 mM Tris HCl pH 8.0
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 50 sec. / Pretreatment - Atmosphere: AIR / Pretreatment - Pressure: 0.026000000000000002 kPa
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k 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: 1.5 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: NONE
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 2.11 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 355557
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL
Output model

PDB-8z8z:
Cryo-EM structure of LYCHOS

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