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- PDB-9ed6: CryoEM map of the mLST8-Rag-Ragultor subcomplex -

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Basic information

Entry
Database: PDB / ID: 9ed6
TitleCryoEM map of the mLST8-Rag-Ragultor subcomplex
Components
  • (Ragulator complex protein ...) x 5
  • (Ras-related GTP-binding protein ...) x 2
  • Target of rapamycin complex subunit LST8
KeywordsSIGNALING PROTEIN / mTORC1 / cell growth / singaling protein / membrane
Function / homology
Function and homology information


regulation of cholesterol import / positive regulation of protein localization to lysosome / regulation of cell-substrate junction organization / Gtr1-Gtr2 GTPase complex / regulation of cholesterol efflux / FNIP-folliculin RagC/D GAP / Ragulator complex / protein localization to cell junction / positive regulation of pentose-phosphate shunt / regulation of TORC1 signaling ...regulation of cholesterol import / positive regulation of protein localization to lysosome / regulation of cell-substrate junction organization / Gtr1-Gtr2 GTPase complex / regulation of cholesterol efflux / FNIP-folliculin RagC/D GAP / Ragulator complex / protein localization to cell junction / positive regulation of pentose-phosphate shunt / regulation of TORC1 signaling / TORC2 signaling / TORC2 complex / protein localization to lysosome / TORC1 complex / regulation of TOR signaling / MTOR signalling / fibroblast migration / Amino acids regulate mTORC1 / lysosome localization / Energy dependent regulation of mTOR by LKB1-AMPK / endosome organization / TORC1 signaling / serine/threonine protein kinase complex / kinase activator activity / cellular response to osmotic stress / protein localization to membrane / endosomal transport / azurophil granule membrane / lysosome organization / small GTPase-mediated signal transduction / Macroautophagy / regulation of cell size / RHOJ GTPase cycle / Constitutive Signaling by AKT1 E17K in Cancer / positive regulation of actin filament polymerization / RHOQ GTPase cycle / TOR signaling / mTORC1-mediated signalling / CDC42 GTPase cycle / tertiary granule membrane / RHOH GTPase cycle / ficolin-1-rich granule membrane / RHOG GTPase cycle / regulation of receptor recycling / CD28 dependent PI3K/Akt signaling / RAC2 GTPase cycle / HSF1-dependent transactivation / positive regulation of TOR signaling / RAC3 GTPase cycle / enzyme-substrate adaptor activity / response to amino acid / positive regulation of lipid biosynthetic process / cellular response to nutrient levels / specific granule membrane / protein-membrane adaptor activity / RAC1 GTPase cycle / cytoskeleton organization / positive regulation of TORC1 signaling / negative regulation of autophagy / cellular response to amino acid starvation / RNA splicing / guanyl-nucleotide exchange factor activity / viral genome replication / cholesterol homeostasis / positive regulation of glycolytic process / cellular response to starvation / protein serine/threonine kinase activator activity / Regulation of PTEN gene transcription / tumor necrosis factor-mediated signaling pathway / VEGFR2 mediated vascular permeability / positive regulation of interleukin-8 production / TP53 Regulates Metabolic Genes / regulation of actin cytoskeleton organization / cellular response to amino acid stimulus / phosphoprotein binding / regulation of cell growth / MAP2K and MAPK activation / positive regulation of protein localization to nucleus / response to virus / GDP binding / late endosome membrane / Regulation of TP53 Degradation / intracellular protein localization / late endosome / glucose homeostasis / PIP3 activates AKT signaling / E3 ubiquitin ligases ubiquitinate target proteins / GTPase binding / positive regulation of cell growth / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / protein-macromolecule adaptor activity / cellular response to hypoxia / molecular adaptor activity / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / lysosome / positive regulation of canonical NF-kappaB signal transduction / positive regulation of MAPK cascade / endosome membrane / intracellular signal transduction / membrane raft
Similarity search - Function
LAMTOR1/MEH1 / Late endosomal/lysosomal adaptor and MAPK and MTOR activator / Late endosomal/lysosomal adaptor and MAPK and MTOR activator / Ragulator complex protein LAMTOR4 / Ragulator complex protein LAMTOR3 / Ragulator complex protein LAMTOR5 / RagA/B / Mitogen-activated protein kinase kinase 1 interacting / Ragulator complex protein LAMTOR5 / Mitogen-activated protein kinase kinase 1 interacting ...LAMTOR1/MEH1 / Late endosomal/lysosomal adaptor and MAPK and MTOR activator / Late endosomal/lysosomal adaptor and MAPK and MTOR activator / Ragulator complex protein LAMTOR4 / Ragulator complex protein LAMTOR3 / Ragulator complex protein LAMTOR5 / RagA/B / Mitogen-activated protein kinase kinase 1 interacting / Ragulator complex protein LAMTOR5 / Mitogen-activated protein kinase kinase 1 interacting / RagC/D / Gtr1/RagA G protein / Gtr1/RagA G protein conserved region / Ragulator complex protein LAMTOR2-like / Target of rapamycin complex subunit LST8 / Roadblock/LAMTOR2 domain / Roadblock/LC7 domain / Roadblock/LC7 domain / Quinoprotein alcohol dehydrogenase-like superfamily / WD domain, G-beta repeat / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
GUANOSINE-5'-DIPHOSPHATE / GUANOSINE-5'-TRIPHOSPHATE / Ragulator complex protein LAMTOR5 / Ragulator complex protein LAMTOR4 / Ragulator complex protein LAMTOR1 / Ras-related GTP-binding protein A / Target of rapamycin complex subunit LST8 / Ras-related GTP-binding protein C / Ragulator complex protein LAMTOR3 / Ragulator complex protein LAMTOR2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.98 Å
AuthorsCui, Z. / Hurley, J.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)CA285366 United States
CitationJournal: Nature / Year: 2025
Title: Structural basis for mTORC1 activation on the lysosomal membrane.
Authors: Zhicheng Cui / Alessandra Esposito / Gennaro Napolitano / Andrea Ballabio / James H Hurley /
Abstract: The mechanistic target of rapamycin complex 1 (mTORC1) integrates growth factor (GF) and nutrient signals to stimulate anabolic processes connected to cell growth and inhibit catabolic processes such ...The mechanistic target of rapamycin complex 1 (mTORC1) integrates growth factor (GF) and nutrient signals to stimulate anabolic processes connected to cell growth and inhibit catabolic processes such as autophagy. GF signalling through the tuberous sclerosis complex regulates the lysosomally localized small GTPase RAS homologue enriched in brain (RHEB). Direct binding of RHEB-GTP to the mTOR kinase subunit of mTORC1 allosterically activates the kinase by inducing a large-scale conformational change. Here we reconstituted mTORC1 activation on membranes by RHEB, RAGs and Ragulator. Cryo-electron microscopy showed that RAPTOR and mTOR interact directly with the membrane. Full engagement of the membrane anchors is required for optimal alignment of the catalytic residues in the mTOR kinase active site. Converging signals from GFs and nutrients drive mTORC1 recruitment to and activation on lysosomal membrane in a four-step process, consisting of (1) RAG-Ragulator-driven recruitment to within ~100 Å of the lysosomal membrane; (2) RHEB-driven recruitment to within ~40 Å; (3) RAPTOR-membrane engagement and intermediate enzyme activation; and (4) mTOR-membrane engagement and full enzyme activation. RHEB and membrane engagement combined leads to full catalytic activation and structurally explains GF and nutrient signal integration at the lysosome.
History
DepositionNov 15, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 10, 2025Provider: repository / Type: Initial release
Revision 1.0Sep 10, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Sep 10, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Sep 10, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Sep 10, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Sep 10, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Sep 10, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Oct 1, 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_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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: Ras-related GTP-binding protein A
E: Ragulator complex protein LAMTOR2
F: Ragulator complex protein LAMTOR3
H: Ragulator complex protein LAMTOR5
I: Target of rapamycin complex subunit LST8
C: Ras-related GTP-binding protein C
D: Ragulator complex protein LAMTOR1
G: Ragulator complex protein LAMTOR4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)183,09411
Polymers182,1038
Non-polymers9913
Water00
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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Ras-related GTP-binding protein ... , 2 types, 2 molecules BC

#1: Protein Ras-related GTP-binding protein A / Rag A / RagA / Adenovirus E3 14.7 kDa-interacting protein 1 / FIP-1


Mass: 36600.195 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RRAGA / Production host: Homo sapiens (human) / Strain (production host): HEK 293F gnti-
References: UniProt: Q7L523, Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement
#6: Protein Ras-related GTP-binding protein C / RagC / GTPase-interacting protein 2 / TIB929


Mass: 44298.859 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RRAGC / Production host: Homo sapiens (human) / References: UniProt: Q9HB90

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Ragulator complex protein ... , 5 types, 5 molecules EFHDG

#2: Protein Ragulator complex protein LAMTOR2 / Endosomal adaptor protein p14 / Late endosomal/lysosomal Mp1-interacting protein / Late ...Endosomal adaptor protein p14 / Late endosomal/lysosomal Mp1-interacting protein / Late endosomal/lysosomal adaptor and MAPK and MTOR activator 2 / Mitogen-activated protein-binding protein-interacting protein / MAPBP-interacting protein / Roadblock domain-containing protein 3


Mass: 13517.450 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LAMTOR2, MAPBPIP, ROBLD3, HSPC003 / Production host: Homo sapiens (human) / Strain (production host): HEK 293F gnti- / References: UniProt: Q9Y2Q5
#3: Protein Ragulator complex protein LAMTOR3 / Late endosomal/lysosomal adaptor and MAPK and MTOR activator 3 / MEK-binding partner 1 / Mp1 / ...Late endosomal/lysosomal adaptor and MAPK and MTOR activator 3 / MEK-binding partner 1 / Mp1 / Mitogen-activated protein kinase kinase 1-interacting protein 1 / Mitogen-activated protein kinase scaffold protein 1


Mass: 13637.678 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LAMTOR3, MAP2K1IP1, MAPKSP1, PRO2783 / Production host: Homo sapiens (human) / Strain (production host): HEK 293F gnti- / References: UniProt: Q9UHA4
#4: Protein Ragulator complex protein LAMTOR5 / Hepatitis B virus X-interacting protein / HBX-interacting protein / Late endosomal/lysosomal ...Hepatitis B virus X-interacting protein / HBX-interacting protein / Late endosomal/lysosomal adaptor and MAPK and MTOR activator 5


Mass: 9622.900 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LAMTOR5, HBXIP, XIP / Production host: Homo sapiens (human) / Strain (production host): HEK 293F gnti- / References: UniProt: O43504
#7: Protein Ragulator complex protein LAMTOR1 / Late endosomal/lysosomal adaptor and MAPK and MTOR activator 1 / Lipid raft adaptor protein p18 / ...Late endosomal/lysosomal adaptor and MAPK and MTOR activator 1 / Lipid raft adaptor protein p18 / Protein associated with DRMs and endosomes / p27Kip1-releasing factor from RhoA / p27RF-Rho


Mass: 17762.775 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LAMTOR1, C11orf59, PDRO, PP7157 / Production host: Homo sapiens (human) / References: UniProt: Q6IAA8
#8: Protein Ragulator complex protein LAMTOR4 / Late endosomal/lysosomal adaptor and MAPK and MTOR activator 4


Mass: 10753.236 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LAMTOR4, C7orf59 / Production host: Homo sapiens (human) / References: UniProt: Q0VGL1

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Protein , 1 types, 1 molecules I

#5: Protein Target of rapamycin complex subunit LST8 / TORC subunit LST8 / G protein beta subunit-like / Protein GbetaL / Mammalian lethal with SEC13 ...TORC subunit LST8 / G protein beta subunit-like / Protein GbetaL / Mammalian lethal with SEC13 protein 8 / mLST8


Mass: 35910.090 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MLST8, GBL, LST8 / Production host: Homo sapiens (human) / References: UniProt: Q9BVC4

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Non-polymers , 3 types, 3 molecules

#9: Chemical ChemComp-GTP / GUANOSINE-5'-TRIPHOSPHATE


Mass: 523.180 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H16N5O14P3 / Comment: GTP, energy-carrying molecule*YM
#10: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#11: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Comment: GDP, energy-carrying molecule*YM

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Details

Has ligand of interestN
Has protein modificationN

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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: mLST8-Rag-Ragultor subcomplex / Type: COMPLEX / Entity ID: #1-#8 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Strain: HEK 293F gnti-
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS 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: 900 nm
Image recordingElectron dose: 30 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.21.1_5286 / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.98 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 190751 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 108.6 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.005211452
ELECTRON MICROSCOPYf_angle_d1.123815515
ELECTRON MICROSCOPYf_chiral_restr0.05941772
ELECTRON MICROSCOPYf_plane_restr0.00681986
ELECTRON MICROSCOPYf_dihedral_angle_d8.29271549

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