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- PDB-9f44: cryo-EM structure of LST2 TOS peptide bound to human mTOR complex 1 -

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Basic information

Entry
Database: PDB / ID: 9f44
Titlecryo-EM structure of LST2 TOS peptide bound to human mTOR complex 1
Components
  • Lateral signaling target protein 2 homolog
  • Regulatory-associated protein of mTOR
  • Serine/threonine-protein kinase mTOR
  • Target of rapamycin complex subunit LST8
KeywordsSIGNALING PROTEIN / MTOR / MTORC1 / LST2 / ZFYVE28 / EGFR / TOS
Function / homology
Function and homology information


negative regulation of epidermal growth factor-activated receptor activity / positive regulation of SCF-dependent proteasomal ubiquitin-dependent catabolic process / RNA polymerase III type 2 promoter sequence-specific DNA binding / RNA polymerase III type 1 promoter sequence-specific DNA binding / positive regulation of cytoplasmic translational initiation / regulation of locomotor rhythm / T-helper 1 cell lineage commitment / positive regulation of pentose-phosphate shunt / positive regulation of wound healing, spreading of epidermal cells / regulation of membrane permeability ...negative regulation of epidermal growth factor-activated receptor activity / positive regulation of SCF-dependent proteasomal ubiquitin-dependent catabolic process / RNA polymerase III type 2 promoter sequence-specific DNA binding / RNA polymerase III type 1 promoter sequence-specific DNA binding / positive regulation of cytoplasmic translational initiation / regulation of locomotor rhythm / T-helper 1 cell lineage commitment / positive regulation of pentose-phosphate shunt / positive regulation of wound healing, spreading of epidermal cells / regulation of membrane permeability / TORC2 complex / cellular response to leucine starvation / TFIIIC-class transcription factor complex binding / heart valve morphogenesis / voluntary musculoskeletal movement / positive regulation of odontoblast differentiation / negative regulation of lysosome organization / TORC1 complex / calcineurin-NFAT signaling cascade / positive regulation of transcription of nucleolar large rRNA by RNA polymerase I / RNA polymerase III type 3 promoter sequence-specific DNA binding / positive regulation of keratinocyte migration / regulation of osteoclast differentiation / MTOR signalling / energy reserve metabolic process / regulation of lysosome organization / cellular response to L-leucine / Energy dependent regulation of mTOR by LKB1-AMPK / cellular response to nutrient / regulation of autophagosome assembly / Amino acids regulate mTORC1 / phosphatidylinositol-3-phosphate binding / cellular response to methionine / negative regulation of cell size / positive regulation of osteoclast differentiation / TORC2 signaling / cellular response to osmotic stress / cell projection organization / anoikis / inositol hexakisphosphate binding / cardiac muscle cell development / negative regulation of calcineurin-NFAT signaling cascade / positive regulation of ubiquitin-dependent protein catabolic process / regulation of myelination / negative regulation of protein localization to nucleus / positive regulation of transcription by RNA polymerase III / positive regulation of ruffle assembly / regulation of cell size / positive regulation of myotube differentiation / negative regulation of macroautophagy / Macroautophagy / Constitutive Signaling by AKT1 E17K in Cancer / positive regulation of actin filament polymerization / germ cell development / oligodendrocyte differentiation / TORC1 signaling / positive regulation of oligodendrocyte differentiation / negative regulation of epidermal growth factor receptor signaling pathway / behavioral response to pain / response to amino acid / positive regulation of translational initiation / TOR signaling / mTORC1-mediated signalling / CD28 dependent PI3K/Akt signaling / HSF1-dependent transactivation / regulation of macroautophagy / positive regulation of TOR signaling / protein kinase activator activity / enzyme-substrate adaptor activity / protein serine/threonine kinase inhibitor activity / 'de novo' pyrimidine nucleobase biosynthetic process / positive regulation of epithelial to mesenchymal transition / social behavior / positive regulation of lipid biosynthetic process / positive regulation of G1/S transition of mitotic cell cycle / vascular endothelial cell response to laminar fluid shear stress / heart morphogenesis / regulation of cellular response to heat / positive regulation of lamellipodium assembly / neuronal action potential / T cell costimulation / phagocytic vesicle / positive regulation of stress fiber assembly / cardiac muscle contraction / positive regulation of endothelial cell proliferation / negative regulation of insulin receptor signaling pathway / 14-3-3 protein binding / cytoskeleton organization / endomembrane system / cellular response to nutrient levels / positive regulation of glycolytic process / cellular response to amino acid starvation / cellular response to starvation / Regulation of PTEN gene transcription / regulation of signal transduction by p53 class mediator / negative regulation of autophagy / VEGFR2 mediated vascular permeability / protein serine/threonine kinase activator activity / regulation of autophagy / post-embryonic development
Similarity search - Function
Lateral signaling target protein 2, FYVE domain / : / Raptor, N-terminal CASPase-like domain / Raptor N-terminal CASPase like domain / Raptor N-terminal CASPase like domain / Regulatory associated protein of TOR / FYVE zinc finger / FYVE zinc finger / Protein present in Fab1, YOTB, Vac1, and EEA1 / Zinc finger, FYVE-related ...Lateral signaling target protein 2, FYVE domain / : / Raptor, N-terminal CASPase-like domain / Raptor N-terminal CASPase like domain / Raptor N-terminal CASPase like domain / Regulatory associated protein of TOR / FYVE zinc finger / FYVE zinc finger / Protein present in Fab1, YOTB, Vac1, and EEA1 / Zinc finger, FYVE-related / Zinc finger FYVE/FYVE-related type profile. / Target of rapamycin complex subunit LST8 / HEAT repeat / Domain of unknown function DUF3385, target of rapamycin protein / Serine/threonine-protein kinase mTOR domain / Domain of unknown function / HEAT repeat / FKBP12-rapamycin binding domain / Serine/threonine-protein kinase TOR / FKBP12-rapamycin binding domain superfamily / FKBP12-rapamycin binding domain / Rapamycin binding domain / : / Serine/threonine-protein kinase ATR-like, HEAT repeats / : / FATC domain / PIK-related kinase, FAT / FAT domain / FATC / FATC domain / PIK-related kinase / FAT domain profile. / FATC domain profile. / Quinoprotein alcohol dehydrogenase-like superfamily / Phosphatidylinositol 3- and 4-kinases signature 1. / Phosphatidylinositol 3/4-kinase, conserved site / Phosphatidylinositol 3- and 4-kinases signature 2. / Phosphatidylinositol 3-/4-kinase, catalytic domain superfamily / Phosphoinositide 3-kinase, catalytic domain / Phosphatidylinositol 3- and 4-kinase / Phosphatidylinositol 3- and 4-kinases catalytic domain profile. / Phosphatidylinositol 3-/4-kinase, catalytic domain / Zinc finger, FYVE/PHD-type / Armadillo-like helical / Tetratricopeptide-like helical domain superfamily / WD domain, G-beta repeat / Armadillo-type fold / Zinc finger, RING/FYVE/PHD-type / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / Protein kinase-like domain superfamily
Similarity search - Domain/homology
INOSITOL HEXAKISPHOSPHATE / Serine/threonine-protein kinase mTOR / Regulatory-associated protein of mTOR / Target of rapamycin complex subunit LST8 / Lateral signaling target protein 2 homolog
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.68 Å
AuthorsCraigie, L.M. / Maier, T.
Funding support Switzerland, European Union, 2items
OrganizationGrant numberCountry
Swiss National Science Foundation179323 Switzerland
H2020 Marie Curie Actions of the European Commission812830European Union
CitationJournal: Proc Natl Acad Sci U S A / Year: 2024
Title: mTORC1 phosphorylates and stabilizes LST2 to negatively regulate EGFR.
Authors: Stefania Battaglioni / Louise-Marie Craigie / Sofia Filippini / Timm Maier / Michael N Hall /
Abstract: TORC1 (target of rapamycin complex 1) is a highly conserved protein kinase that plays a central role in regulating cell growth. Given the role of mammalian TORC1 (mTORC1) in metabolism and disease, ...TORC1 (target of rapamycin complex 1) is a highly conserved protein kinase that plays a central role in regulating cell growth. Given the role of mammalian TORC1 (mTORC1) in metabolism and disease, understanding mTORC1 downstream signaling and feedback loops is important. mTORC1 recognizes some of its substrates via a five amino acid binding sequence called the TOR signaling (TOS) motif. mTORC1 binding to a TOS motif facilitates phosphorylation of a distinct, distal site. Here, we show that LST2, also known as ZFYVE28, contains a TOS motif (amino acids 401 to 405) and is directly phosphorylated by mTORC1 at serine 670 (S670). mTORC1-mediated S670 phosphorylation promotes LST2 monoubiquitination on lysine 87 (K87). Monoubiquitinated LST2 is stable and displays a broad reticular distribution. When mTORC1 is inactive, unphosphorylated LST2 is degraded by the proteasome. The absence of LST2 enhances EGFR (epidermal growth factor receptor) signaling. We propose that mTORC1 negatively feeds back on its upstream receptor EGFR via LST2.
History
DepositionApr 26, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 14, 2024Provider: repository / Type: Initial release
Revision 1.1Aug 28, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Serine/threonine-protein kinase mTOR
B: Serine/threonine-protein kinase mTOR
C: Target of rapamycin complex subunit LST8
D: Target of rapamycin complex subunit LST8
E: Regulatory-associated protein of mTOR
F: Regulatory-associated protein of mTOR
G: Lateral signaling target protein 2 homolog
H: Lateral signaling target protein 2 homolog
hetero molecules


Theoretical massNumber of molelcules
Total (without water)960,50710
Polymers959,1878
Non-polymers1,3202
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Serine/threonine-protein kinase mTOR / FK506-binding protein 12-rapamycin complex-associated protein 1 / FKBP12-rapamycin complex- ...FK506-binding protein 12-rapamycin complex-associated protein 1 / FKBP12-rapamycin complex-associated protein / Mammalian target of rapamycin / mTOR / Mechanistic target of rapamycin / Rapamycin and FKBP12 target 1 / Rapamycin target protein 1


Mass: 289257.969 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MTOR, FRAP, FRAP1, FRAP2, RAFT1, RAPT1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P42345, non-specific serine/threonine protein kinase
#2: Protein Target of rapamycin complex subunit LST8 / TORC subunit LST8 / G protein beta subunit-like / Protein GbetaL / Mammalian lethal with SEC13 ...TORC subunit LST8 / G protein beta subunit-like / Protein GbetaL / Mammalian lethal with SEC13 protein 8 / mLST8


Mass: 35910.090 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MLST8, GBL, LST8 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9BVC4
#3: Protein Regulatory-associated protein of mTOR / Raptor / p150 target of rapamycin (TOR)-scaffold protein


Mass: 152764.656 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RPTOR, KIAA1303, RAPTOR / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q8N122
#4: Protein/peptide Lateral signaling target protein 2 homolog / hLst2 / Zinc finger FYVE domain-containing protein 28


Mass: 1660.733 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q9HCC9
#5: Chemical ChemComp-IHP / INOSITOL HEXAKISPHOSPHATE / MYO-INOSITOL HEXAKISPHOSPHATE / INOSITOL 1,2,3,4,5,6-HEXAKISPHOSPHATE


Mass: 660.035 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C6H18O24P6 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: mTORC1 in complex with LST2 TOS peptide / Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 8
SpecimenConc.: 1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 200 divisions/in. / Grid type: Quantifoil R2/1
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 281 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 48.43 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 4470

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
4cryoSPARCCTF correction
7UCSF ChimeraXmodel fitting
9PHENIXmodel refinement
10cryoSPARCinitial Euler assignment
11cryoSPARCfinal Euler assignment
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 2126474
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 3.68 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 782845 / Symmetry type: POINT
Atomic model buildingPDB-ID: 7PEB

7peb


Accession code: 7PEB / Source name: PDB / Type: experimental model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00258062
ELECTRON MICROSCOPYf_angle_d0.47778782
ELECTRON MICROSCOPYf_dihedral_angle_d13.40521390
ELECTRON MICROSCOPYf_chiral_restr0.0388946
ELECTRON MICROSCOPYf_plane_restr0.00410028

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