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Open data
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Basic information
Entry | Database: PDB / ID: 8dhb | |||||||||||||||
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Title | Active FLCN GAP complex | |||||||||||||||
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![]() | SIGNALING PROTEIN / FLCN / Rag-Ragulator / GTPase Activating Protein / mTORC1 signaling | |||||||||||||||
Function / homology | ![]() asparagine transport / L-asparagine transmembrane transporter activity / sterol sensor activity / negative regulation of cell proliferation involved in kidney development / L-arginine transmembrane transport / L-arginine transmembrane transporter activity / negative regulation of post-translational protein modification / cell proliferation involved in kidney development / regulation of cholesterol import / 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 / L-arginine transmembrane transport / L-arginine transmembrane transporter activity / negative regulation of post-translational protein modification / cell proliferation involved in kidney development / regulation of cholesterol import / positive regulation of protein localization to lysosome / regulation of cell-substrate junction organization / glutamine transport / L-glutamine transmembrane transporter activity / 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 / negative regulation of brown fat cell differentiation / L-amino acid transmembrane transporter activity / regulation of Ras protein signal transduction / L-leucine transmembrane transporter activity / amino acid transmembrane transport / protein localization to cell junction / regulation of TORC1 signaling / negative regulation of lysosome organization / regulation of pro-B cell differentiation / amino acid transmembrane transporter activity / protein localization to lysosome / TORC1 signaling / regulation of TOR signaling / endosome organization / ATPase inhibitor activity / MTOR signalling / Amino acids regulate mTORC1 / fibroblast migration / lysosome localization / Energy dependent regulation of mTOR by LKB1-AMPK / protein localization to membrane / kinase activator activity / enzyme-substrate adaptor activity / negative regulation of glycolytic process / enzyme inhibitor activity / negative regulation of TOR signaling / arginine binding / cell-cell junction assembly / negative regulation of cold-induced thermogenesis / negative regulation of Rho protein signal transduction / azurophil granule membrane / endosomal transport / regulation of cell size / Macroautophagy / small GTPase-mediated signal transduction / lysosome organization / cholesterol binding / positive regulation of transforming growth factor beta receptor signaling pathway / RHOJ GTPase cycle / RHOQ GTPase cycle / mTORC1-mediated signalling / cellular response to nutrient levels / tertiary granule membrane / CDC42 GTPase cycle / glutathione transferase / RHOH GTPase cycle / hemopoiesis / ficolin-1-rich granule membrane / centriolar satellite / glutathione transferase activity / RHOG GTPase cycle / regulation of receptor recycling / positive regulation of TOR signaling / TOR signaling / RAC2 GTPase cycle / RAC3 GTPase cycle / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / response to amino acid / positive regulation of autophagy / specific granule membrane / energy homeostasis / positive regulation of intrinsic apoptotic signaling pathway / protein-membrane adaptor activity / positive regulation of TORC1 signaling / tumor necrosis factor-mediated signaling pathway / RAC1 GTPase cycle / ERK1 and ERK2 cascade / cellular response to amino acid starvation / cellular response to starvation / negative regulation of autophagy / viral genome replication / intrinsic apoptotic signaling pathway / RNA splicing / glutathione metabolic process / phosphatidylinositol 3-kinase/protein kinase B signal transduction / GTPase activator activity / transforming growth factor beta receptor signaling pathway / guanyl-nucleotide exchange factor activity / epithelial cell proliferation / Regulation of PTEN gene transcription / positive regulation of interleukin-8 production / cholesterol homeostasis Similarity search - Function | |||||||||||||||
Biological species | ![]() | |||||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.53 Å | |||||||||||||||
![]() | Jansen, R.M. / Hurley, J.H. | |||||||||||||||
Funding support | ![]() ![]()
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![]() | ![]() 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 |
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 388.4 KB | Display | ![]() |
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PDB format | ![]() | 288.2 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Summary document | ![]() | 1.6 MB | Display | ![]() |
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Full document | ![]() | 1.6 MB | Display | |
Data in XML | ![]() | 73.7 KB | Display | |
Data in CIF | ![]() | 109 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 27435MC M: map data used to model this data C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
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Assembly
Deposited unit | ![]()
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Components
-Ras-related GTP-binding protein ... , 2 types, 2 molecules AB
#1: Protein | Mass: 44384.004 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() References: UniProt: Q9HB90, Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement |
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#2: Protein | Mass: 39362.078 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
-Ragulator complex protein ... , 5 types, 5 molecules CDEFG
#3: Protein | Mass: 18325.350 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
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#4: Protein | Mass: 13645.579 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
#5: Protein | Mass: 13637.678 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
#6: Protein | Mass: 10753.236 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
#7: Protein | Mass: 18178.520 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
-Protein , 3 types, 3 molecules HIJ
#8: Protein | Mass: 41000.711 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() References: UniProt: P08515, UniProt: Q8NBW4, glutathione transferase |
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#9: Protein | Mass: 149865.641 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
#10: Protein | Mass: 69143.070 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
-Non-polymers , 3 types, 3 molecules ![](data/chem/img/CZC.gif)
![](data/chem/img/BEF.gif)
![](data/chem/img/GDP.gif)
![](data/chem/img/BEF.gif)
![](data/chem/img/GDP.gif)
#11: Chemical | ChemComp-CZC / [( |
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#12: Chemical | ChemComp-BEF / |
#13: Chemical | ChemComp-GDP / |
-Details
Has ligand of interest | Y |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
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Sample preparation
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Molecular weight |
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Source (recombinant) |
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Buffer solution | pH: 7.4 | ||||||||||||||||||||||||
Specimen | Conc.: 1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | ||||||||||||||||||||||||
Vitrification | Cryogen 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 |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: ![]() |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm |
Image recording | Electron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
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Processing
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION |
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3D reconstruction | Resolution: 3.53 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 177018 / Symmetry type: POINT |