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- PDB-8u54: The mTORC1 cholesterol sensor LYCHOS (GPR155) -

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Basic information

Entry
Database: PDB / ID: 8u54
TitleThe mTORC1 cholesterol sensor LYCHOS (GPR155)
ComponentsIntegral membrane protein GPR155
KeywordsMEMBRANE PROTEIN / PIN-FORMED / GPCR / Cholesterol / auxin / transporter / cell-growth / mTORC1 / cancer
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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.65 Å
AuthorsBayly-Jones, C. / Lupton, C.J. / Ellisdon, A.M.
Funding support Australia, United States, 3items
OrganizationGrant numberCountry
Australian Research Council (ARC)DE240100992 Australia
Other governmentMCRF21036 Australia
Department of Defense (DOD, United States)W81XWH-19-1-0182 United States
Citation
Journal: Nature / Year: 2024
Title: LYCHOS is a human hybrid of a plant-like PIN transporter and a GPCR.
Authors: Charles Bayly-Jones / Christopher J Lupton / Alastair C Keen / Shuqi Dong / Chantel Mastos / Wentong Luo / Chunyi Qian / Gareth D Jones / Hari Venugopal / Yong-Gang Chang / Ronald J Clarke / ...Authors: Charles Bayly-Jones / Christopher J Lupton / Alastair C Keen / Shuqi Dong / Chantel Mastos / Wentong Luo / Chunyi Qian / Gareth D Jones / Hari Venugopal / Yong-Gang Chang / Ronald J Clarke / Michelle L Halls / Andrew M Ellisdon /
Abstract: Lysosomes have crucial roles in regulating eukaryotic metabolism and cell growth by acting as signalling platforms to sense and respond to changes in nutrient and energy availability. LYCHOS (GPR155) ...Lysosomes have crucial roles in regulating eukaryotic metabolism and cell growth by acting as signalling platforms to sense and respond to changes in nutrient and energy availability. LYCHOS (GPR155) is a lysosomal transmembrane protein that functions as a cholesterol sensor, facilitating the cholesterol-dependent activation of the master protein kinase mechanistic target of rapamycin complex 1 (mTORC1). However, the structural basis of LYCHOS assembly and activity remains unclear. Here we determine several high-resolution cryo-electron microscopy structures of human LYCHOS, revealing a homodimeric transmembrane assembly of a transporter-like domain fused to a G-protein-coupled receptor (GPCR) domain. The class B2-like GPCR domain is captured in the apo state and packs against the surface of the transporter-like domain, providing an unusual example of a GPCR as a domain in a larger transmembrane assembly. Cholesterol sensing is mediated by a conserved cholesterol-binding motif, positioned between the GPCR and transporter domains. We reveal that the LYCHOS transporter-like domain is an orthologue of the plant PIN-FORMED (PIN) auxin transporter family, and has greater structural similarity to plant auxin transporters than to known human transporters. Activity assays support a model in which the LYCHOS transporter and GPCR domains coordinate to sense cholesterol and regulate mTORC1 activation.
#1: Journal: 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, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 18, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 23, 2024Group: Data collection / Database references / Structure summary
Category: citation / citation_author ...citation / citation_author / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _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 / _pdbx_entry_details.has_protein_modification
Revision 1.2Nov 13, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID / _em_admin.last_update
Revision 1.3Nov 20, 2024Group: Data collection / Category: em_admin / Item: _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Integral membrane protein GPR155
B: Integral membrane protein GPR155
hetero molecules


Theoretical massNumber of molelcules
Total (without water)198,9964
Polymers198,5542
Non-polymers4422
Water00
1


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

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Components

#1: Protein Integral membrane protein GPR155


Mass: 99276.891 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GPR155 / Cell line (production host): HEK293 / 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
Has ligand of interestN
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: Homodimeric complex of LYCHOS (GPR155) / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.198 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Cell: HEK293 / Plasmid: pcDNA3.1
Buffer solutionpH: 7.4
SpecimenConc.: 2 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 magnification: 105000 X / Nominal defocus max: 2000 nm / Nominal defocus min: 500 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm / Alignment procedure: ZEMLIN TABLEAU
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of real images: 6863

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Processing

EM software
IDNameVersionCategory
1Topazparticle selection
2EPU2.12.1.2782image acquisition
4cryoSPARC4.1.1CTF correction
7ISOLDE1.1.0model fitting
8Coot0.9.2model fitting
10PHENIX1.20.1model refinement
11cryoSPARC4.1.1initial Euler assignment
12cryoSPARC4.1.1final Euler assignment
13cryoSPARC4.1.1classification
14cryoSPARC4.1.13D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 2892753
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 2.65 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 85794 / Algorithm: FOURIER SPACE / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Atomic model buildingAccession code: Q7Z3F1
Details: A dimeric assembly was predicted with AlphaFold and then rigid body fit into the map. Subsequent refinements were performed in ISOLDE.
Source name: AlphaFold / Type: in silico model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00511196
ELECTRON MICROSCOPYf_angle_d0.7915196
ELECTRON MICROSCOPYf_dihedral_angle_d12.3763982
ELECTRON MICROSCOPYf_chiral_restr0.0531808
ELECTRON MICROSCOPYf_plane_restr0.0061854

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