- EMDB-21686: CryoEM structure of the SLC38A9-RagA-RagC-Ragulator complex in th... -
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Basic information
Entry
Database: EMDB / ID: EMD-21686
Title
CryoEM structure of the SLC38A9-RagA-RagC-Ragulator complex in the pre-GAP state
Map data
Ragulator-RagA-GDP-RagC-XTPgS-SLC38A9; density modified with Phenix ResolveCryoEM and Phenix Autoshparpen Map
Sample
Complex: Complex of pentameric Ragulator, dimeric Rag GTPases and SLC38A9
Complex: pentameric Ragulator
Protein or peptide: x 5 types
Complex: dimeric Rag GTPases
Protein or peptide: x 2 types
Complex: SLC38A9
Protein or peptide: x 1 types
Ligand: x 3 types
Keywords
small GTPase / mTORC1 activation / amino acid signaling / lysosome / SIGNALING PROTEIN
Function / homology
Function and homology information
asparagine transport / L-asparagine transmembrane transporter activity / sterol sensor activity / L-arginine transmembrane transporter activity / L-arginine transmembrane transport / 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 ...asparagine transport / L-asparagine transmembrane transporter activity / sterol sensor activity / L-arginine transmembrane transporter activity / L-arginine transmembrane transport / 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 / glutamine transport / L-glutamine transmembrane transporter activity / FNIP-folliculin RagC/D GAP / Ragulator complex / L-amino acid transmembrane transporter activity / amino acid transmembrane transport / L-leucine transmembrane transporter activity / protein localization to cell junction / regulation of TORC1 signaling / protein localization to lysosome / amino acid transmembrane transporter activity / regulation of TOR signaling / TORC1 signaling / endosome organization / fibroblast migration / MTOR signalling / Amino acids regulate mTORC1 / lysosome localization / Energy dependent regulation of mTOR by LKB1-AMPK / kinase activator activity / protein localization to membrane / enzyme-substrate adaptor activity / arginine binding / azurophil granule membrane / endosomal transport / regulation of cell size / cholesterol binding / small GTPase-mediated signal transduction / Macroautophagy / lysosome organization / RHOJ GTPase cycle / RHOQ GTPase cycle / mTORC1-mediated signalling / tertiary granule membrane / CDC42 GTPase cycle / ficolin-1-rich granule membrane / RHOH GTPase cycle / RHOG GTPase cycle / regulation of receptor recycling / positive regulation of TOR signaling / RAC2 GTPase cycle / RAC3 GTPase cycle / response to amino acid / cellular response to nutrient levels / specific granule membrane / protein-membrane adaptor activity / Regulation of PTEN gene transcription / tumor necrosis factor-mediated signaling pathway / RAC1 GTPase cycle / positive regulation of TORC1 signaling / cellular response to starvation / cellular response to amino acid starvation / viral genome replication / negative regulation of autophagy / cellular response to amino acid stimulus / RNA splicing / negative regulation of cysteine-type endopeptidase activity involved in apoptotic process / guanyl-nucleotide exchange factor activity / cholesterol homeostasis / positive regulation of interleukin-8 production / regulation of cell growth / 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 / positive regulation of protein localization to nucleus / GDP binding / protein localization / glucose homeostasis / late endosome / 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 / molecular adaptor activity / endosome membrane / lysosome / intracellular signal transduction / membrane raft / protein heterodimerization activity / lysosomal membrane / intracellular membrane-bounded organelle / focal adhesion / GTPase activity / DNA-templated transcription / ubiquitin protein ligase binding Similarity search - Function
Amino acid transporter, transmembrane domain / Transmembrane amino acid transporter protein / 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 ...Amino acid transporter, transmembrane domain / Transmembrane amino acid transporter protein / 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 / Neutral amino acid transporter 9 / Ras-related GTP-binding protein C / Ragulator complex protein LAMTOR3 / Ragulator complex protein LAMTOR2 Similarity search - Component
Biological species
Homo sapiens (human)
Method
single particle reconstruction / cryo EM / Resolution: 3.2 Å
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
R01GM111730
United States
Citation
Journal: Nat Struct Mol Biol / Year: 2020 Title: Structural mechanism for amino acid-dependent Rag GTPase nucleotide state switching by SLC38A9. Authors: Simon A Fromm / Rosalie E Lawrence / James H Hurley / Abstract: The Rag GTPases (Rags) recruit mTORC1 to the lysosomal membrane in response to nutrients, where it is then activated in response to energy and growth factor availability. The lysosomal folliculin ...The Rag GTPases (Rags) recruit mTORC1 to the lysosomal membrane in response to nutrients, where it is then activated in response to energy and growth factor availability. The lysosomal folliculin (FLCN) complex (LFC) consists of the inactive Rag dimer, the pentameric scaffold Ragulator, and the FLCN:FNIP2 (FLCN-interacting protein 2) GTPase activating protein (GAP) complex, and prevents Rag dimer activation during amino acid starvation. How the LFC is disassembled upon amino acid refeeding is an outstanding question. Here we show that the cytoplasmic tail of the human lysosomal solute carrier family 38 member 9 (SLC38A9) destabilizes the LFC and thereby triggers GAP activity of FLCN:FNIP2 toward RagC. We present the cryo-EM structures of Rags in complex with their lysosomal anchor complex Ragulator and the cytoplasmic tail of SLC38A9 in the pre- and post-GTP hydrolysis state of RagC, which explain how SLC38A9 destabilizes the LFC and so promotes Rag dimer activation.
History
Deposition
Apr 11, 2020
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Header (metadata) release
Sep 2, 2020
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Map release
Sep 2, 2020
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Update
Mar 6, 2024
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Current status
Mar 6, 2024
Processing site: RCSB / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
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