- EMDB-0554: Cryo-EM Structure of the Lysosomal Folliculin Complex (FLCN-FNIP2... -
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Basic information
Entry
Database: EMDB / ID: EMD-0554
Title
Cryo-EM Structure of the Lysosomal Folliculin Complex (FLCN-FNIP2-RagA-RagC-Ragulator)
Map data
generated by non-uniform refinement from cryoSPARC v2 followed by LocScale amplitude scaling
Sample
Complex: FLCN-FNIP2-RagA-RagC-Ragulator Complex
Protein or peptide: x 9 types
Ligand: x 2 types
Function / homology
Function and homology information
negative regulation of cell proliferation involved in kidney development / 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 / 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 ...negative regulation of cell proliferation involved in kidney development / 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 / 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 / regulation of Ras protein signal transduction / protein localization to cell junction / regulation of TORC1 signaling / negative regulation of lysosome organization / regulation of pro-B cell differentiation / protein localization to lysosome / TORC1 signaling / regulation of TOR signaling / endosome organization / fibroblast migration / MTOR signalling / Amino acids regulate mTORC1 / lysosome localization / ATPase inhibitor activity / Energy dependent regulation of mTOR by LKB1-AMPK / protein localization to membrane / kinase activator activity / enzyme-substrate adaptor activity / enzyme inhibitor activity / negative regulation of TOR signaling / negative regulation of glycolytic process / cell-cell junction assembly / negative regulation of cold-induced thermogenesis / negative regulation of Rho protein signal transduction / endosomal transport / azurophil granule membrane / regulation of cell size / small GTPase-mediated signal transduction / Macroautophagy / lysosome organization / positive regulation of transforming growth factor beta receptor signaling pathway / RHOJ GTPase cycle / RHOQ GTPase cycle / mTORC1-mediated signalling / tertiary granule membrane / CDC42 GTPase cycle / hemopoiesis / RHOH GTPase cycle / ficolin-1-rich granule membrane / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / centriolar satellite / RHOG GTPase cycle / regulation of receptor recycling / positive regulation of TOR signaling / RAC2 GTPase cycle / TOR signaling / RAC3 GTPase cycle / response to amino acid / cellular response to nutrient levels / 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 / phosphatidylinositol 3-kinase/protein kinase B signal transduction / cellular response to starvation / cellular response to amino acid starvation / negative regulation of autophagy / intrinsic apoptotic signaling pathway / GTPase activator activity / viral genome replication / RNA splicing / transforming growth factor beta receptor signaling pathway / negative regulation of cysteine-type endopeptidase activity involved in apoptotic process / guanyl-nucleotide exchange factor activity / epithelial cell proliferation / Regulation of PTEN gene transcription / cholesterol homeostasis / positive regulation of interleukin-8 production / regulation of cell growth / TP53 Regulates Metabolic Genes / phosphoprotein binding / cellular response to amino acid stimulus / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / regulation of protein phosphorylation / positive regulation of protein-containing complex assembly / MAP2K and MAPK activation / response to virus / negative regulation of ERK1 and ERK2 cascade / mitotic spindle / cilium / positive regulation of protein localization to nucleus / GDP binding / negative regulation of epithelial cell proliferation 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. / 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 / P-loop containing nucleoside triphosphate hydrolase Similarity search - Domain/homology
Ragulator complex protein LAMTOR5 / Ragulator complex protein LAMTOR5 / Ragulator complex protein LAMTOR4 / Ragulator complex protein LAMTOR1 / Ras-related GTP-binding protein A / Folliculin / Ras-related GTP-binding protein C / Folliculin-interacting protein 2 / Ragulator complex protein LAMTOR3 / Ragulator complex protein LAMTOR2 Similarity search - Component
Biological species
Homo sapiens (human)
Method
single particle reconstruction / cryo EM / Resolution: 3.6 Å
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
2R01GM111730-05
United States
Citation
Journal: Science / Year: 2019 Title: Structural mechanism of a Rag GTPase activation checkpoint by the lysosomal folliculin complex. Authors: Rosalie E Lawrence / Simon A Fromm / Yangxue Fu / Adam L Yokom / Do Jin Kim / Ashley M Thelen / Lindsey N Young / Chun-Yan Lim / Avi J Samelson / James H Hurley / Roberto Zoncu / Abstract: The tumor suppressor folliculin (FLCN) enables nutrient-dependent activation of the mechanistic target of rapamycin complex 1 (mTORC1) protein kinase via its guanosine triphosphatase (GTPase) ...The tumor suppressor folliculin (FLCN) enables nutrient-dependent activation of the mechanistic target of rapamycin complex 1 (mTORC1) protein kinase via its guanosine triphosphatase (GTPase) activating protein (GAP) activity toward the GTPase RagC. Concomitant with mTORC1 inactivation by starvation, FLCN relocalizes from the cytosol to lysosomes. To determine the lysosomal function of FLCN, we reconstituted the human lysosomal FLCN complex (LFC) containing FLCN, its partner FLCN-interacting protein 2 (FNIP2), and the RagA:RagC GTPases as they exist in the starved state with their lysosomal anchor Ragulator complex and determined its cryo-electron microscopy structure to 3.6 angstroms. The RagC-GAP activity of FLCN was inhibited within the LFC, owing to displacement of a catalytically required arginine in FLCN from the RagC nucleotide. Disassembly of the LFC and release of the RagC-GAP activity of FLCN enabled mTORC1-dependent regulation of the master regulator of lysosomal biogenesis, transcription factor E3, implicating the LFC as a checkpoint in mTORC1 signaling.
History
Deposition
Feb 13, 2019
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Header (metadata) release
Feb 20, 2019
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Map release
Nov 6, 2019
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Update
Dec 2, 2020
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Current status
Dec 2, 2020
Processing site: RCSB / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
Model: C-flat-2/1 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: PLASMA CLEANING / Pretreatment - Atmosphere: OTHER / Details: 15 W
Vitrification
Cryogen name: ETHANE / Chamber humidity: 90 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV / Details: Whatman 597.
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Electron microscopy
Microscope
FEI TITAN KRIOS
Specialist optics
Energy filter - Slit width: 20 eV
Image recording
Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Number grids imaged: 1 / Number real images: 2703 / Average exposure time: 11.0 sec. / Average electron dose: 65.6 e/Å2
Electron beam
Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron optics
Illumination mode: OTHER / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 3.0 µm / Nominal defocus min: 1.0 µm
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