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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 / Gtr1-Gtr2 GTPase complex / regulation of cholesterol efflux / positive regulation of RNA polymerase II regulatory region sequence-specific DNA binding / FNIP-folliculin RagC/D GAP / Ragulator complex / protein localization to cell junction / positive regulation of pentose-phosphate shunt ...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 / positive regulation of RNA polymerase II regulatory region sequence-specific DNA binding / 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 / TORC1 signaling / regulation of TOR signaling / positive regulation of odontoblast differentiation / endosome organization / cellular response to L-leucine / MTOR signalling / Amino acids regulate mTORC1 / fibroblast migration / lysosome localization / Energy dependent regulation of mTOR by LKB1-AMPK / protein serine/threonine kinase inhibitor activity / kinase activator activity / cellular response to osmotic stress / positive regulation of osteoclast differentiation / protein localization to membrane / enzyme-substrate adaptor activity / positive regulation of transcription by RNA polymerase III / azurophil granule membrane / endosomal transport / Macroautophagy / regulation of cell size / lysosome organization / small GTPase-mediated signal transduction / protein kinase activator activity / RHOJ GTPase cycle / TOR signaling / RHOQ GTPase cycle / mTORC1-mediated signalling / social behavior / tertiary granule membrane / cellular response to nutrient levels / RHOH GTPase cycle / CDC42 GTPase cycle / ficolin-1-rich granule membrane / HSF1-dependent transactivation / RHOG GTPase cycle / positive regulation of TOR signaling / regulation of receptor recycling / positive regulation of G1/S transition of mitotic cell cycle / RAC3 GTPase cycle / RAC2 GTPase cycle / response to amino acid / positive regulation of lipid biosynthetic process / specific granule membrane / protein-membrane adaptor activity / positive regulation of TORC1 signaling / tumor necrosis factor-mediated signaling pathway / RAC1 GTPase cycle / cellular response to amino acid starvation / cellular response to starvation / positive regulation of endothelial cell proliferation / positive regulation of glycolytic process / viral genome replication / negative regulation of autophagy / guanyl-nucleotide exchange factor activity / cholesterol homeostasis / RNA splicing / 14-3-3 protein binding / positive regulation of peptidyl-threonine phosphorylation / Regulation of PTEN gene transcription / regulation of autophagy / positive regulation of interleukin-8 production / regulation of cell growth / cellular response to glucose stimulus / cellular response to amino acid stimulus / TP53 Regulates Metabolic Genes / phosphoprotein binding / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / response to virus / negative regulation of cysteine-type endopeptidase activity involved in apoptotic process / MAP2K and MAPK activation / protein localization / small GTPase binding / cytoplasmic stress granule / positive regulation of protein localization to nucleus / GDP binding / protein-macromolecule adaptor activity / late endosome / glucose homeostasis / E3 ubiquitin ligases ubiquitinate target proteins / GTPase binding / positive regulation of peptidyl-serine phosphorylation / late endosome membrane / positive regulation of NF-kappaB transcription factor activity / cellular response to hypoxia / positive regulation of cell growth / positive regulation of canonical NF-kappaB signal transduction
Similarity search - Function
Beta-Lactamase - #190 / LAMTOR1/MEH1 / Late endosomal/lysosomal adaptor and MAPK and MTOR activator / Late endosomal/lysosomal adaptor and MAPK and MTOR activator / Ragulator complex protein LAMTOR4 / Raptor, N-terminal CASPase-like domain / Raptor N-terminal CASPase like domain / Raptor N-terminal CASPase like domain / Regulatory associated protein of TOR / Ragulator complex protein LAMTOR3 ...Beta-Lactamase - #190 / LAMTOR1/MEH1 / Late endosomal/lysosomal adaptor and MAPK and MTOR activator / Late endosomal/lysosomal adaptor and MAPK and MTOR activator / Ragulator complex protein LAMTOR4 / Raptor, N-terminal CASPase-like domain / Raptor N-terminal CASPase like domain / Raptor N-terminal CASPase like domain / Regulatory associated protein of TOR / 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 / Gtr1/RagA G protein / RagC/D / Gtr1/RagA G protein conserved region / Ragulator complex protein LAMTOR2-like / Dynein light chain 2a, cytoplasmic / Roadblock/LAMTOR2 domain / Roadblock/LC7 domain / Roadblock/LC7 domain / HEAT repeat / HEAT repeat / Beta-Lactamase / Armadillo-like helical / Armadillo-type fold / P-loop containing nucleotide triphosphate hydrolases / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / Trp-Asp (WD) repeats circular profile. / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase / Rossmann fold / 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
Water0
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 / Guanosine 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 / Guanosine 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 FIELDBright-field microscopy
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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