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- PDB-6u62: Raptor-Rag-Ragulator complex -

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Basic information

Entry
Database: PDB / ID: 6u62
TitleRaptor-Rag-Ragulator complex
Components
  • (Ragulator complex protein ...) x 5
  • (Ras-related GTP-binding protein ...) x 2
  • Regulatory-associated protein of mTOR
KeywordsSIGNALING PROTEIN / signaling complex / GTPase / lysosome
Function / homology
Function and homology information


regulation of cholesterol import / positive regulation of protein localization to lysosome / regulation of cell-substrate junction organization / regulation of cholesterol efflux / Gtr1-Gtr2 GTPase complex / 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 / regulation of cholesterol efflux / Gtr1-Gtr2 GTPase complex / FNIP-folliculin RagC/D GAP / Ragulator complex / protein localization to cell junction / positive regulation of pentose-phosphate shunt / regulation of TORC1 signaling / TORC1 complex / protein localization to lysosome / positive regulation of odontoblast differentiation / regulation of TOR signaling / MTOR signalling / fibroblast migration / cellular response to L-leucine / lysosome localization / Energy dependent regulation of mTOR by LKB1-AMPK / endosome organization / Amino acids regulate mTORC1 / TORC1 signaling / serine/threonine protein kinase complex / positive regulation of osteoclast differentiation / kinase activator activity / cellular response to osmotic stress / protein localization to membrane / endosomal transport / positive regulation of transcription by RNA polymerase III / azurophil granule membrane / lysosome organization / small GTPase-mediated signal transduction / Macroautophagy / regulation of cell size / RHOJ GTPase cycle / 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 / protein serine/threonine kinase inhibitor activity / regulation of receptor recycling / social behavior / protein kinase activator activity / RAC2 GTPase cycle / HSF1-dependent transactivation / RAC3 GTPase cycle / positive regulation of TOR signaling / enzyme-substrate adaptor activity / positive regulation of G1/S transition of mitotic cell cycle / response to amino acid / positive regulation of lipid biosynthetic process / cellular response to nutrient levels / specific granule membrane / protein-membrane adaptor activity / 14-3-3 protein binding / positive regulation of endothelial cell proliferation / RAC1 GTPase cycle / positive regulation of TORC1 signaling / negative regulation of autophagy / RNA splicing / cellular response to amino acid starvation / viral genome replication / guanyl-nucleotide exchange factor activity / cholesterol homeostasis / positive regulation of glycolytic process / cellular response to starvation / Regulation of PTEN gene transcription / tumor necrosis factor-mediated signaling pathway / positive regulation of interleukin-8 production / TP53 Regulates Metabolic Genes / cellular response to amino acid stimulus / cellular response to glucose stimulus / regulation of cell growth / phosphoprotein binding / MAP2K and MAPK activation / small GTPase binding / positive regulation of protein localization to nucleus / response to virus / cytoplasmic stress granule / GDP binding / late endosome membrane / intracellular protein localization / late endosome / glucose homeostasis / E3 ubiquitin ligases ubiquitinate target proteins / GTPase binding / positive regulation of cell growth / 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 / endosome membrane / positive regulation of MAPK cascade / intracellular signal transduction
Similarity search - Function
Beta-Lactamase - #190 / Ragulator complex protein LAMTOR4 / Ragulator complex protein LAMTOR3 / Ragulator complex protein LAMTOR5 / 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 ...Beta-Lactamase - #190 / Ragulator complex protein LAMTOR4 / Ragulator complex protein LAMTOR3 / Ragulator complex protein LAMTOR5 / 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 / RagA/B / RagC/D / Gtr1/RagA G protein / Gtr1/RagA G protein conserved region / Raptor, N-terminal CASPase-like domain / Ragulator complex protein LAMTOR2-like / Raptor N-terminal CASPase like domain / Raptor N-terminal CASPase like domain / Regulatory associated protein of TOR / Dynein light chain 2a, cytoplasmic / Roadblock/LAMTOR2 domain / Roadblock/LC7 domain / Roadblock/LC7 domain / HEAT repeat / HEAT repeat / Beta-Lactamase / Armadillo-like helical / WD domain, G-beta repeat / Armadillo-type fold / P-loop containing nucleotide triphosphate hydrolases / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / Rossmann fold / P-loop containing nucleoside triphosphate hydrolase / 2-Layer Sandwich / 3-Layer(aba) Sandwich / Alpha Beta
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 / Regulatory-associated protein of mTOR / 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: 3.18 Å
AuthorsRogala, K.B. / Sabatini, D.M.
Funding support United States, United Kingdom, 8items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R01 CA103866 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)R01 CA129105 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R37 AI47389 United States
Department of Defense (DOD, United States)W81XWH-07-0448 United States
Lustgarten Foundation United States
Tuberous Sclerosis Association United Kingdom
Howard Hughes Medical Institute (HHMI) United States
American Cancer Society United States
CitationJournal: Science / Year: 2019
Title: Structural basis for the docking of mTORC1 on the lysosomal surface.
Authors: Kacper B Rogala / Xin Gu / Jibril F Kedir / Monther Abu-Remaileh / Laura F Bianchi / Alexia M S Bottino / Rikke Dueholm / Anna Niehaus / Daan Overwijn / Ange-Célia Priso Fils / Sherry X ...Authors: Kacper B Rogala / Xin Gu / Jibril F Kedir / Monther Abu-Remaileh / Laura F Bianchi / Alexia M S Bottino / Rikke Dueholm / Anna Niehaus / Daan Overwijn / Ange-Célia Priso Fils / Sherry X Zhou / Daniel Leary / Nouf N Laqtom / Edward J Brignole / David M Sabatini /
Abstract: The mTORC1 (mechanistic target of rapamycin complex 1) protein kinase regulates growth in response to nutrients and growth factors. Nutrients promote its translocation to the lysosomal surface, where ...The mTORC1 (mechanistic target of rapamycin complex 1) protein kinase regulates growth in response to nutrients and growth factors. Nutrients promote its translocation to the lysosomal surface, where its Raptor subunit interacts with the Rag guanosine triphosphatase (GTPase)-Ragulator complex. Nutrients switch the heterodimeric Rag GTPases among four different nucleotide-binding states, only one of which (RagA/B•GTP-RagC/D•GDP) permits mTORC1 association. We used cryo-electron microscopy to determine the structure of the supercomplex of Raptor with Rag-Ragulator at a resolution of 3.2 angstroms. Our findings indicate that the Raptor α-solenoid directly detects the nucleotide state of RagA while the Raptor "claw" threads between the GTPase domains to detect that of RagC. Mutations that disrupted Rag-Raptor binding inhibited mTORC1 lysosomal localization and signaling. By comparison with a structure of mTORC1 bound to its activator Rheb, we developed a model of active mTORC1 docked on the lysosome.
History
DepositionAug 29, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 30, 2019Provider: repository / Type: Initial release
Revision 1.1Nov 6, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Nov 20, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Mar 20, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

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Assembly

Deposited unit
A: Regulatory-associated protein of mTOR
B: Ras-related GTP-binding protein A
C: Ras-related GTP-binding protein C
D: Ragulator complex protein LAMTOR1
E: Ragulator complex protein LAMTOR2
F: Ragulator complex protein LAMTOR3
G: Ragulator complex protein LAMTOR4
H: Ragulator complex protein LAMTOR5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)305,71211
Polymers304,7218
Non-polymers9913
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area24380 Å2
ΔGint-175 kcal/mol
Surface area91600 Å2

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Regulatory-associated protein of mTOR / Raptor / p150 target of rapamycin (TOR)-scaffold protein


Mass: 154915.812 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RPTOR, KIAA1303, RAPTOR / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q8N122

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Ras-related GTP-binding protein ... , 2 types, 2 molecules BC

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


Mass: 36615.168 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RRAGA / Production host: Escherichia coli (E. coli) / Strain (production host): LOBSTR(DE3) / References: UniProt: Q7L523
#3: Protein Ras-related GTP-binding protein C / RagC / GTPase-interacting protein 2 / TIB929


Mass: 44334.828 Da / Num. of mol.: 1 / Mutation: S75N, T90N
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RRAGC / Production host: Escherichia coli (E. coli) / Strain (production host): LOBSTR(DE3) / References: UniProt: Q9HB90

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

#4: 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: 17359.230 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: Escherichia coli (E. coli) / Strain (production host): LOBSTR(DE3) / References: UniProt: Q6IAA8
#5: 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: Escherichia coli (E. coli) / Strain (production host): LOBSTR(DE3) / References: UniProt: Q9Y2Q5
#6: 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: 17579.781 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: Escherichia coli (E. coli) / Strain (production host): LOBSTR(DE3) / References: UniProt: Q9UHA4
#7: Protein Ragulator complex protein LAMTOR4 / Late endosomal/lysosomal adaptor and MAPK and MTOR activator 4


Mass: 10776.206 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LAMTOR4, C7orf59 / Production host: Escherichia coli (E. coli) / Strain (production host): LOBSTR(DE3) / References: UniProt: Q0VGL1
#8: 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: Escherichia coli (E. coli) / Strain (production host): LOBSTR(DE3) / References: UniProt: O43504

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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 / Feature type: SUBJECT OF INVESTIGATION / 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 / Feature type: SUBJECT OF INVESTIGATION
#11: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


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

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Details

Has ligand of interestY

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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: Raptor-Rag-Ragulator / Type: COMPLEX / Entity ID: #1-#8 / Source: MULTIPLE SOURCES
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli) / Strain: LOBSTR(DE3)
Buffer solutionpH: 7.5
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: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 42 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.17.1_3660: / Classification: refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.18 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 112037 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 61.68 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00417381
ELECTRON MICROSCOPYf_angle_d0.55123628
ELECTRON MICROSCOPYf_dihedral_angle_d21.3162394
ELECTRON MICROSCOPYf_chiral_restr0.0432733
ELECTRON MICROSCOPYf_plane_restr0.0043015

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