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- PDB-8dhb: Active FLCN GAP complex -

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Basic information

Entry
Database: PDB / ID: 8dhb
TitleActive FLCN GAP complex
Components
  • (Ragulator complex protein ...) x 5
  • (Ras-related GTP-binding protein ...) x 2
  • Folliculin
  • Folliculin-interacting protein 2
  • Glutathione S-transferase class-mu 26 kDa isozyme,Sodium-coupled neutral amino acid transporter 9 chimera
KeywordsSIGNALING PROTEIN / FLCN / Rag-Ragulator / GTPase Activating Protein / mTORC1 signaling
Function / homology
Function and homology information


asparagine transport / L-asparagine transmembrane transporter activity / sterol sensor activity / negative regulation of cell proliferation involved in kidney development / cell proliferation involved in kidney development / negative regulation of post-translational protein modification / L-arginine transmembrane transport / regulation of cholesterol import / L-arginine transmembrane transporter activity / positive regulation of protein localization to lysosome ...asparagine transport / L-asparagine transmembrane transporter activity / sterol sensor activity / negative regulation of cell proliferation involved in kidney development / cell proliferation involved in kidney development / negative regulation of post-translational protein modification / L-arginine transmembrane transport / regulation of cholesterol import / L-arginine transmembrane transporter activity / positive regulation of protein localization to lysosome / regulation of cell-substrate junction organization / regulation of cholesterol efflux / Gtr1-Gtr2 GTPase complex / L-glutamine transmembrane transporter activity / glutamine transport / FNIP-folliculin RagC/D GAP / negative regulation of brown fat cell differentiation / regulation of Ras protein signal transduction / Ragulator complex / protein localization to cell junction / L-leucine transmembrane transporter activity / amino acid transmembrane transport / regulation of TORC1 signaling / regulation of pro-B cell differentiation / L-amino acid transmembrane transporter activity / negative regulation of lysosome organization / protein localization to lysosome / regulation of TOR signaling / MTOR signalling / fibroblast migration / lysosome localization / Energy dependent regulation of mTOR by LKB1-AMPK / endosome organization / ATPase inhibitor activity / Amino acids regulate mTORC1 / TORC1 signaling / amino acid transmembrane transporter activity / cell-cell junction assembly / negative regulation of glycolytic process / kinase activator activity / negative regulation of TOR signaling / arginine binding / protein localization to membrane / negative regulation of cold-induced thermogenesis / endosomal transport / azurophil granule membrane / lysosome organization / cholesterol binding / small GTPase-mediated signal transduction / Macroautophagy / negative regulation of Rho protein signal transduction / regulation of cell size / positive regulation of transforming growth factor beta receptor signaling pathway / RHOJ GTPase cycle / RHOQ GTPase cycle / TOR signaling / mTORC1-mediated signalling / hemopoiesis / glutathione transferase / CDC42 GTPase cycle / tertiary granule membrane / RHOH GTPase cycle / glutathione transferase activity / ficolin-1-rich granule membrane / RHOG GTPase cycle / regulation of receptor recycling / RAC2 GTPase cycle / enzyme inhibitor activity / RAC3 GTPase cycle / positive regulation of TOR signaling / enzyme-substrate adaptor activity / response to amino acid / cellular response to nutrient levels / specific granule membrane / positive regulation of intrinsic apoptotic signaling pathway / energy homeostasis / protein-membrane adaptor activity / ERK1 and ERK2 cascade / RAC1 GTPase cycle / positive regulation of TORC1 signaling / glutathione metabolic process / positive regulation of autophagy / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / intrinsic apoptotic signaling pathway / transforming growth factor beta receptor signaling pathway / GTPase activator activity / negative regulation of autophagy / RNA splicing / cellular response to amino acid starvation / viral genome replication / guanyl-nucleotide exchange factor activity / cholesterol homeostasis / cellular response to starvation / epithelial cell proliferation / 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 / positive regulation of protein-containing complex assembly
Similarity search - Function
Folliculin / Folliculin, DENN domain / Folliculin, DENN domain, C-terminal superfamily / Folliculin C-terminal domain / Folliculin-interacting protein family / Folliculin-interacting protein, N-terminal domain / Folliculin-interacting protein, middle domain / Folliculin-interacting protein, C-terminal domain / Folliculin-interacting protein N-terminus / Folliculin-interacting protein middle domain ...Folliculin / Folliculin, DENN domain / Folliculin, DENN domain, C-terminal superfamily / Folliculin C-terminal domain / Folliculin-interacting protein family / Folliculin-interacting protein, N-terminal domain / Folliculin-interacting protein, middle domain / Folliculin-interacting protein, C-terminal domain / Folliculin-interacting protein N-terminus / Folliculin-interacting protein middle domain / Folliculin-interacting protein C-terminus / Tripartite DENN domain, FNIP1/2-type / Tripartite DENN FNIP1/2-type domain profile. / Folliculin/SMCR8, longin domain / Folliculin/SMCR8, tripartite DENN domain / Vesicle coat protein involved in Golgi to plasma membrane transport / Tripartite DENN FLCN/SMCR8-type domain profile. / Amino acid transporter, transmembrane domain / Transmembrane amino acid transporter protein / 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 / Ragulator complex protein LAMTOR2-like / Roadblock/LAMTOR2 domain / Roadblock/LC7 domain / Roadblock/LC7 domain / Glutathione S-transferase, C-terminal domain / : / Glutathione S-transferase, N-terminal domain / Glutathione transferase family / Glutathione S-transferase, C-terminal / Glutathione S-transferase, C-terminal-like / Soluble glutathione S-transferase C-terminal domain profile. / Soluble glutathione S-transferase N-terminal domain profile. / Glutathione S-transferase, N-terminal / Glutathione S-transferase, C-terminal domain superfamily / Thioredoxin-like superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
BERYLLIUM TRIFLUORIDE ION / Chem-CZC / GUANOSINE-5'-DIPHOSPHATE / Ragulator complex protein LAMTOR5 / Glutathione S-transferase class-mu 26 kDa isozyme / Ragulator complex protein LAMTOR4 / Ragulator complex protein LAMTOR1 / Ras-related GTP-binding protein A / Neutral amino acid transporter 9 / Folliculin ...BERYLLIUM TRIFLUORIDE ION / Chem-CZC / GUANOSINE-5'-DIPHOSPHATE / Ragulator complex protein LAMTOR5 / Glutathione S-transferase class-mu 26 kDa isozyme / Ragulator complex protein LAMTOR4 / Ragulator complex protein LAMTOR1 / Ras-related GTP-binding protein A / Neutral amino acid transporter 9 / Folliculin / Ras-related GTP-binding protein C / Folliculin-interacting protein 2 / Ragulator complex protein LAMTOR3 / Ragulator complex protein LAMTOR2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.53 Å
AuthorsJansen, R.M. / Hurley, J.H.
Funding support United States, Italy, 4items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM111730 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM130995 United States
National Science Foundation (NSF, United States) United States
Italian Association for Cancer Research Italy
CitationJournal: Sci Adv / Year: 2022
Title: Structural basis for FLCN RagC GAP activation in MiT-TFE substrate-selective mTORC1 regulation.
Authors: Rachel M Jansen / Roberta Peruzzo / Simon A Fromm / Adam L Yokom / Roberto Zoncu / James H Hurley /
Abstract: The mechanistic target of rapamycin complex 1 (mTORC1) regulates cell growth and catabolism in response to nutrients through phosphorylation of key substrates. The tumor suppressor folliculin (FLCN) ...The mechanistic target of rapamycin complex 1 (mTORC1) regulates cell growth and catabolism in response to nutrients through phosphorylation of key substrates. The tumor suppressor folliculin (FLCN) is a RagC/D guanosine triphosphatase (GTPase)-activating protein (GAP) that regulates mTORC1 phosphorylation of MiT-TFE transcription factors, controlling lysosome biogenesis and autophagy. We determined the cryo-electron microscopy structure of the active FLCN complex (AFC) containing FLCN, FNIP2, the N-terminal tail of SLC38A9, the RagA:RagC GTPase dimer, and the Ragulator scaffold. Relative to the inactive lysosomal FLCN complex structure, FLCN reorients by 90°, breaks contact with RagA, and makes previously unseen contacts with RagC that position its Arg finger for catalysis. Disruption of the AFC-specific interfaces of FLCN and FNIP2 with RagC eliminated GAP activity and led to nuclear retention of TFE3, with no effect on mTORC1 substrates S6K or 4E-BP1. The structure provides a basis for regulation of an mTORC1 substrate-specific pathway and a roadmap to discover MiT-TFE family selective mTORC1 antagonists.
History
DepositionJun 25, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 28, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 9, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Ras-related GTP-binding protein C
B: Ras-related GTP-binding protein A
C: Ragulator complex protein LAMTOR1
D: Ragulator complex protein LAMTOR2
E: Ragulator complex protein LAMTOR3
F: Ragulator complex protein LAMTOR4
G: Ragulator complex protein LAMTOR5
H: Glutathione S-transferase class-mu 26 kDa isozyme,Sodium-coupled neutral amino acid transporter 9 chimera
I: Folliculin-interacting protein 2
J: Folliculin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)419,24913
Polymers418,29610
Non-polymers9533
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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

#1: Protein Ras-related GTP-binding protein C / Rag C / RagC / GTPase-interacting protein 2 / TIB929


Mass: 44384.004 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, Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement
#2: Protein Ras-related GTP-binding protein A / RagA / Adenovirus E3 14.7 kDa-interacting protein 1 / FIP-1


Mass: 39362.078 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RRAGA / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q7L523

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

#3: 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: 18325.350 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: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q6IAA8
#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: 13645.579 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: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9Y2Q5
#5: 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: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9UHA4
#6: 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
#7: Protein Ragulator complex protein LAMTOR5 / Hepatitis B virus x interacting protein


Mass: 18178.520 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LAMTOR5, HBXIP, hCG_40252 / Production host: Homo sapiens (human) / References: UniProt: A0A0C4DGV4

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Protein , 3 types, 3 molecules HIJ

#8: Protein Glutathione S-transferase class-mu 26 kDa isozyme,Sodium-coupled neutral amino acid transporter 9 chimera / GST 26 / Sj26 antigen / SjGST / Solute carrier family 38 member 9 / Up-regulated in lung cancer 11


Mass: 41000.711 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC38A9, URLC11 / Production host: Homo sapiens (human)
References: UniProt: P08515, UniProt: Q8NBW4, glutathione transferase
#9: Protein Folliculin-interacting protein 2 / FNIP1-like protein / O6-methylguanine-induced apoptosis 1 protein


Mass: 149865.641 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FNIP2, FNIPL, KIAA1450, MAPO1 / Production host: Homo sapiens (human) / References: UniProt: Q9P278
#10: Protein Folliculin / BHD skin lesion fibrofolliculoma protein / Birt-Hogg-Dube syndrome protein


Mass: 69143.070 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FLCN, BHD / Production host: Homo sapiens (human) / References: UniProt: Q8NFG4

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Non-polymers , 3 types, 3 molecules

#11: Chemical ChemComp-CZC / [(2~{R},3~{S},4~{R},5~{R})-5-[2,6-bis(oxidanylidene)-3~{H}-purin-9-yl]-3,4-bis(oxidanyl)oxolan-2-yl]methyl phosphono hydrogen phosphate / xanthosine diphosphate


Mass: 444.185 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H14N4O12P2 / Feature type: SUBJECT OF INVESTIGATION
#12: Chemical ChemComp-BEF / BERYLLIUM TRIFLUORIDE ION


Mass: 66.007 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: BeF3 / Feature type: SUBJECT OF INVESTIGATION
#13: 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 interestY
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

Component
IDNameTypeEntity IDParent-IDSource
1Cryo-EM structure of the Active FLCN GAP compexCOMPLEX#1-#100MULTIPLE SOURCES
2Rag-RagulatorCOMPLEX#1-#71RECOMBINANT
3FLCN:SLC-FNIP2COMPLEX#9-#101RECOMBINANT
Molecular weight
IDEntity assembly-IDExperimental value
11NO
21NO
31NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
32Homo sapiens (human)9606
43Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
32Spodoptera frugiperda (fall armyworm)7108
43Homo sapiens (human)9606
Buffer solutionpH: 7.4
SpecimenConc.: 1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen 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 defocus max: 2000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.53 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 177018 / Symmetry type: POINT

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