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- PDB-8z8z: Cryo-EM structure of LYCHOS -

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Basic information

Entry
Database: PDB / ID: 8z8z
TitleCryo-EM structure of LYCHOS
ComponentsLysosomal cholesterol signaling protein,Fluorescent Protein
KeywordsMEMBRANE PROTEIN / Lysosome / GPCR-like / Transporter / Cholesterol
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-6OU / : / CHOLESTEROL / 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine / Lysosomal cholesterol signaling protein
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single 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, 1items
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, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 1, 2025Provider: repository / Type: Initial release
Revision 1.1Feb 5, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _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,Fluorescent Protein
B: Lysosomal cholesterol signaling protein,Fluorescent Protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)263,04418
Polymers254,4262
Non-polymers8,61816
Water362
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein / Sugars , 2 types, 4 molecules AB

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


Mass: 127213.109 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
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
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) synthetic construct (others)
Gene: GPR155, PGR22 / Production host: Homo sapiens (human) / References: UniProt: Q7Z3F1
#2: 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

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Non-polymers , 6 types, 16 molecules

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


Mass: 717.996 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C39H76NO8P / Comment: phospholipid*YM
#4: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H46O
#5: Chemical ChemComp-A1L1C / [(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


Mass: 764.023 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C43H74NO8P / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-LBN / 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine / (2R)-2-[(9Z)-9-Octadecenoyloxy]-3-(palmitoyloxy)propyl 2-(trimethylammonio)ethyl phosphate


Mass: 760.076 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C42H82NO8P / Comment: phospholipid*YM
#7: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: H2O

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Details

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: LYCHOS / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.127 MDa / Experimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
11Homo sapiens (human)9606
21synthetic construct (others)32630
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
Details: 0.001 % LMNG, 150 mM NaCl, 0.2 mM TECP, 50 mM Tris HCl pH 8.0
Buffer component
IDConc.NameFormulaBuffer-ID
10.001 %lauryl maltose neopentyl glycolLMNG1
2150 mMsodium chlorideNaCl1
350 mMTris(hydroxymethyl)aminomethane hydrochlorideTris-HCl1
40.2 mMtris(2-carboxyethyl)phosphineTCEP1
SpecimenConc.: 9 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277.15 K

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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: FEI FALCON IV (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 2.11 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 355557 / Symmetry type: POINT
Atomic model buildingSpace: REAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0189590
ELECTRON MICROSCOPYf_angle_d1.16512966
ELECTRON MICROSCOPYf_dihedral_angle_d25.5851600
ELECTRON MICROSCOPYf_chiral_restr0.0781528
ELECTRON MICROSCOPYf_plane_restr0.0071539

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