- EMDB-20814: Cryo-EM structure of the FLCN-FNIP2-Rag-Ragulator complex -
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Basic information
Entry
Database: EMDB / ID: EMD-20814
Title
Cryo-EM structure of the FLCN-FNIP2-Rag-Ragulator complex
Map data
Sample
Complex: Nonameric complex of FLCN-FNIP2 with its substrate Rag GTPases and the scaffolding protein complex Ragulator
Protein or peptide: x 9 types
Ligand: x 3 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 / 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 / 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 / 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 / RHOH GTPase cycle / hemopoiesis / ficolin-1-rich granule membrane / centriolar satellite / RHOG GTPase cycle / positive regulation of TOR signaling / regulation of receptor recycling / 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 / 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 / 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 / response to virus / MAP2K and MAPK activation / negative regulation of cysteine-type endopeptidase activity involved in apoptotic process / protein localization / negative regulation of ERK1 and ERK2 cascade / mitotic spindle / cilium / positive regulation of protein localization to nucleus / GDP binding 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 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: 3.31 Å
National Institutes of Health/National Cancer Institute (NIH/NCI)
R01 CA103866
United States
National Institutes of Health/National Cancer Institute (NIH/NCI)
R37 AI47389
United States
National Institutes of Health/National Cancer Institute (NIH/NCI)
R01 CA129105
United States
Lustgarten Foundation
United States
Department of Defense (DOD, United States)
W81XWH-15-1-0230
United States
Tuberous Sclerosis Association
United States
Howard Hughes Medical Institute (HHMI)
United States
Citation
Journal: Cell / Year: 2019 Title: Cryo-EM Structure of the Human FLCN-FNIP2-Rag-Ragulator Complex. Authors: Kuang Shen / Kacper B Rogala / Hui-Ting Chou / Rick K Huang / Zhiheng Yu / David M Sabatini / Abstract: mTORC1 controls anabolic and catabolic processes in response to nutrients through the Rag GTPase heterodimer, which is regulated by multiple upstream protein complexes. One such regulator, FLCN- ...mTORC1 controls anabolic and catabolic processes in response to nutrients through the Rag GTPase heterodimer, which is regulated by multiple upstream protein complexes. One such regulator, FLCN-FNIP2, is a GTPase activating protein (GAP) for RagC/D, but despite its important role, how it activates the Rag GTPase heterodimer remains unknown. We used cryo-EM to determine the structure of FLCN-FNIP2 in a complex with the Rag GTPases and Ragulator. FLCN-FNIP2 adopts an extended conformation with two pairs of heterodimerized domains. The Longin domains heterodimerize and contact both nucleotide binding domains of the Rag heterodimer, while the DENN domains interact at the distal end of the structure. Biochemical analyses reveal a conserved arginine on FLCN as the catalytic arginine finger and lead us to interpret our structure as an on-pathway intermediate. These data reveal features of a GAP-GTPase interaction and the structure of a critical component of the nutrient-sensing mTORC1 pathway.
History
Deposition
Oct 8, 2019
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Header (metadata) release
Nov 20, 2019
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Map release
Nov 20, 2019
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Update
Dec 11, 2019
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Current status
Dec 11, 2019
Processing site: RCSB / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
Supramolecule #1: Nonameric complex of FLCN-FNIP2 with its substrate Rag GTPases an...
Supramolecule
Name: Nonameric complex of FLCN-FNIP2 with its substrate Rag GTPases and the scaffolding protein complex Ragulator type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#9
Source (natural)
Organism: Homo sapiens (human)
Recombinant expression
Organism: Escherichia coli (E. coli)
Molecular weight
Theoretical: 380 KDa
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Macromolecule #1: Folliculin
Macromolecule
Name: Folliculin / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
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