- 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 transport / L-arginine transmembrane transporter activity / regulation of cholesterol import / positive regulation of protein localization to lysosome / regulation of cell-substrate junction organization / glutamine transport / L-glutamine transmembrane transporter activity ...asparagine transport / L-asparagine transmembrane transporter activity / sterol sensor activity / L-arginine transmembrane transport / L-arginine transmembrane transporter activity / 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 / L-amino acid transmembrane transporter activity / FNIP-folliculin RagC/D GAP / Ragulator complex / L-leucine transmembrane transporter activity / amino acid transmembrane transport / protein localization to cell junction / regulation of TORC1 signaling / amino acid transmembrane transporter activity / protein localization to lysosome / TORC1 signaling / regulation of TOR signaling / endosome organization / 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 / arginine binding / azurophil granule membrane / endosomal transport / regulation of cell size / Macroautophagy / small GTPase-mediated signal transduction / lysosome organization / cholesterol binding / RHOJ GTPase cycle / RHOQ GTPase cycle / mTORC1-mediated signalling / cellular response to nutrient levels / tertiary granule membrane / CDC42 GTPase cycle / RHOH GTPase cycle / ficolin-1-rich granule membrane / RHOG GTPase cycle / positive regulation of TOR signaling / regulation of receptor recycling / RAC2 GTPase cycle / RAC3 GTPase cycle / response to amino acid / specific granule membrane / protein-membrane adaptor activity / positive regulation of TORC1 signaling / tumor necrosis factor-mediated signaling pathway / RAC1 GTPase cycle / cellular response to amino acid starvation / cellular response to starvation / negative regulation of autophagy / viral genome replication / RNA splicing / guanyl-nucleotide exchange factor activity / 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 / response to virus / MAP2K and MAPK activation / negative regulation of cysteine-type endopeptidase activity involved in apoptotic process / protein localization / positive regulation of protein localization to nucleus / GDP binding / late endosome / E3 ubiquitin ligases ubiquitinate target proteins / GTPase binding / glucose homeostasis / 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 / lysosome / endosome membrane / intracellular signal transduction / membrane raft / protein heterodimerization activity / lysosomal membrane / intracellular membrane-bounded organelle / focal adhesion / GTPase activity / DNA-templated transcription / apoptotic process 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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