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- PDB-7t3c: GATOR1-RAG-RAGULATOR - Dual Complex -

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Basic information

Entry
Database: PDB / ID: 7t3c
TitleGATOR1-RAG-RAGULATOR - Dual Complex
Components
  • (GATOR complex protein ...) x 3
  • (Ragulator complex protein ...) x 5
  • (Ras-related GTP-binding protein ...) x 3
KeywordsHYDROLASE / Complex / GTPase activating protein / nutrient sensing / metabolism
Function / homology
Function and homology information


GATOR1 complex / 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 / aorta morphogenesis ...GATOR1 complex / 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 / aorta morphogenesis / protein localization to cell junction / regulation of TORC1 signaling / protein localization to lysosome / TORC1 signaling / regulation of TOR signaling / endosome organization / MTOR signalling / Amino acids regulate mTORC1 / fibroblast migration / lysosome localization / Energy dependent regulation of mTOR by LKB1-AMPK / negative regulation of TOR signaling / kinase activator activity / cardiac muscle tissue development / protein localization to membrane / enzyme-substrate adaptor activity / vacuolar membrane / azurophil granule membrane / ventricular septum development / endosomal transport / negative regulation of kinase activity / regulation of cell size / Macroautophagy / lysosome organization / small GTPase-mediated signal transduction / roof of mouth development / RHOJ GTPase cycle / RHOQ GTPase cycle / mTORC1-mediated signalling / cellular response to nutrient levels / tertiary granule membrane / RHOH GTPase cycle / CDC42 GTPase cycle / ficolin-1-rich granule membrane / RHOG GTPase cycle / positive regulation of TOR signaling / regulation of receptor recycling / RAC2 GTPase cycle / RAC3 GTPase cycle / response to amino acid / specific granule membrane / positive regulation of autophagy / protein-membrane adaptor activity / negative regulation of TORC1 signaling / positive regulation of TORC1 signaling / tumor necrosis factor-mediated signaling pathway / cellular response to amino acid starvation / RAC1 GTPase cycle / cellular response to starvation / GTPase activator activity / viral genome replication / negative regulation of autophagy / guanyl-nucleotide exchange factor activity / RNA splicing / Regulation of PTEN gene transcription / cholesterol homeostasis / positive regulation of interleukin-8 production / regulation of cell growth / 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 / MAP2K and MAPK activation / negative regulation of cysteine-type endopeptidase activity involved in apoptotic process / protein localization / small GTPase binding / positive regulation of protein localization to nucleus / GDP binding / late endosome / glucose homeostasis / E3 ubiquitin ligases ubiquitinate target proteins / GTPase binding / late endosome membrane / positive regulation of NF-kappaB transcription factor activity / positive regulation of canonical NF-kappaB signal transduction / positive regulation of MAPK cascade / lysosome / molecular adaptor activity / endosome membrane / intracellular signal transduction / membrane raft / protein heterodimerization activity / lysosomal membrane / focal adhesion / intracellular membrane-bounded organelle / GTPase activity / DNA-templated transcription / apoptotic process / ubiquitin protein ligase binding
Similarity search - Function
: / Nitrogen permease regulator 3 / Nitrogen permease regulator 2 / Vacuolar membrane-associated protein Iml1 / DEPDC5 protein, C-terminal / Nitrogen Permease regulator of amino acid transport activity 3 / Nitrogen permease regulator 2 / Vacuolar membrane-associated protein Iml1 / DEPDC5 protein C-terminal region / LAMTOR1/MEH1 ...: / Nitrogen permease regulator 3 / Nitrogen permease regulator 2 / Vacuolar membrane-associated protein Iml1 / DEPDC5 protein, C-terminal / Nitrogen Permease regulator of amino acid transport activity 3 / Nitrogen permease regulator 2 / Vacuolar membrane-associated protein Iml1 / DEPDC5 protein C-terminal region / 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 / Gtr1/RagA G protein / RagC/D / Gtr1/RagA G protein conserved region / Ragulator complex protein LAMTOR2-like / Roadblock/LAMTOR2 domain / Roadblock/LC7 domain / Roadblock/LC7 domain / 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 / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
ALUMINUM FLUORIDE / GUANOSINE-5'-DIPHOSPHATE / Ragulator complex protein LAMTOR5 / GATOR1 complex protein DEPDC5 / Ragulator complex protein LAMTOR4 / GATOR1 complex protein NPRL3 / Ragulator complex protein LAMTOR1 / Ras-related GTP-binding protein A / GATOR1 complex protein NPRL2 / Ras-related GTP-binding protein C ...ALUMINUM FLUORIDE / GUANOSINE-5'-DIPHOSPHATE / Ragulator complex protein LAMTOR5 / GATOR1 complex protein DEPDC5 / Ragulator complex protein LAMTOR4 / GATOR1 complex protein NPRL3 / Ragulator complex protein LAMTOR1 / Ras-related GTP-binding protein A / GATOR1 complex protein NPRL2 / 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: 4 Å
AuthorsEgri, S.B. / Shen, K.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI) United States
CitationJournal: Mol Cell / Year: 2022
Title: Cryo-EM structures of the human GATOR1-Rag-Ragulator complex reveal a spatial-constraint regulated GAP mechanism.
Authors: Shawn B Egri / Christna Ouch / Hui-Ting Chou / Zhiheng Yu / Kangkang Song / Chen Xu / Kuang Shen /
Abstract: mTORC1 controls cellular metabolic processes in response to nutrient availability. Amino acid signals are transmitted to mTORC1 through the Rag GTPases, which are localized on the lysosomal surface ...mTORC1 controls cellular metabolic processes in response to nutrient availability. Amino acid signals are transmitted to mTORC1 through the Rag GTPases, which are localized on the lysosomal surface by the Ragulator complex. The Rag GTPases receive amino acid signals from multiple upstream regulators. One negative regulator, GATOR1, is a GTPase activating protein (GAP) for RagA. GATOR1 binds to the Rag GTPases via two modes: an inhibitory mode and a GAP mode. How these two binding interactions coordinate to process amino acid signals is unknown. Here, we resolved three cryo-EM structural models of the GATOR1-Rag-Ragulator complex, with the Rag-Ragulator subcomplex occupying the inhibitory site, the GAP site, and both binding sites simultaneously. When the Rag GTPases bind to GATOR1 at the GAP site, both Rag subunits contact GATOR1 to coordinate their nucleotide loading states. These results reveal a potential GAP mechanism of GATOR1 during the mTORC1 inactivation process.
History
DepositionDec 7, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 6, 2022Provider: repository / Type: Initial release
Revision 1.1Jun 1, 2022Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.page_first

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: GATOR complex protein NPRL2
A: GATOR complex protein DEPDC5
H: Ragulator complex protein LAMTOR3
G: Ragulator complex protein LAMTOR2
J: Ragulator complex protein LAMTOR5
I: Ragulator complex protein LAMTOR4
F: Ragulator complex protein LAMTOR1
C: GATOR complex protein NPRL3
D: Ras-related GTP-binding protein A
E: Ras-related GTP-binding protein C
O: Ragulator complex protein LAMTOR3
N: Ragulator complex protein LAMTOR2
Q: Ragulator complex protein LAMTOR5
P: Ragulator complex protein LAMTOR4
M: Ragulator complex protein LAMTOR1
K: Ras-related GTP-binding protein A
L: Ras-related GTP-binding protein C
hetero molecules


Theoretical massNumber of molelcules
Total (without water)582,76523
Polymers581,18317
Non-polymers1,5826
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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GATOR complex protein ... , 3 types, 3 molecules BAC

#1: Protein GATOR complex protein NPRL2 / Gene 21 protein / G21 protein / Nitrogen permease regulator 2-like protein / NPR2-like protein / ...Gene 21 protein / G21 protein / Nitrogen permease regulator 2-like protein / NPR2-like protein / Tumor suppressor candidate 4


Mass: 43711.395 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NPRL2, TUSC4 / Production host: Homo sapiens (human) / References: UniProt: Q8WTW4
#2: Protein GATOR complex protein DEPDC5 / DEP domain-containing protein 5


Mass: 181478.000 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DEPDC5, KIAA0645 / Production host: Homo sapiens (human) / References: UniProt: O75140
#8: Protein GATOR complex protein NPRL3 / -14 gene protein / Alpha-globin regulatory element-containing gene protein / Nitrogen permease ...-14 gene protein / Alpha-globin regulatory element-containing gene protein / Nitrogen permease regulator 3-like protein / Protein CGTHBA


Mass: 63680.820 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NPRL3, C16orf35, CGTHBA, MARE / Production host: Homo sapiens (human) / References: UniProt: Q12980

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Ragulator complex protein ... , 5 types, 10 molecules HOGNJQIPFM

#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.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LAMTOR3, MAP2K1IP1, MAPKSP1, PRO2783 / Production host: Homo sapiens (human) / References: UniProt: Q9UHA4
#4: 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.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LAMTOR2, MAPBPIP, ROBLD3, HSPC003 / Production host: Homo sapiens (human) / References: UniProt: Q9Y2Q5
#5: 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.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LAMTOR5, HBXIP, XIP / Production host: Homo sapiens (human) / References: UniProt: O43504
#6: Protein Ragulator complex protein LAMTOR4 / Late endosomal/lysosomal adaptor and MAPK and MTOR activator 4


Mass: 10753.236 Da / Num. of mol.: 2
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
#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.: 2
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

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Ras-related GTP-binding protein ... , 3 types, 4 molecules DKEL

#9: 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.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RRAGA / Production host: Homo sapiens (human) / References: UniProt: Q7L523
#10: Protein Ras-related GTP-binding protein C / Rag C / RagC / GTPase-interacting protein 2 / TIB929


Mass: 44195.734 Da / Num. of mol.: 1 / Mutation: F92A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RRAGC / Production host: Homo sapiens (human)
References: UniProt: Q9HB90, Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement
#11: Protein Ras-related GTP-binding protein C / RagC / GTPase-interacting protein 2 / TIB929


Mass: 44298.859 Da / Num. of mol.: 1 / Mutation: S75N
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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Non-polymers , 2 types, 6 molecules

#12: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE / Guanosine diphosphate


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: GDP, energy-carrying molecule*YM
#13: Chemical ChemComp-AF3 / ALUMINUM FLUORIDE / Aluminium fluoride


Mass: 83.977 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: AlF3 / Feature type: SUBJECT OF INVESTIGATION

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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: GATOR1-RAG-RAGULATOR - Dual Complex / Type: COMPLEX / Entity ID: #1-#11 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
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: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: -3000 nm / Nominal defocus min: -1500 nm
Image recordingElectron dose: 52.6 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.18.2_3874: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 56117 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00733120
ELECTRON MICROSCOPYf_angle_d1.36844845
ELECTRON MICROSCOPYf_dihedral_angle_d10.0754395
ELECTRON MICROSCOPYf_chiral_restr0.0755097
ELECTRON MICROSCOPYf_plane_restr0.0085716

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