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- PDB-9f43: cryo-EM structure of human LST2 bound to human mTOR complex 1, fo... -

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Basic information

Entry
Database: PDB / ID: 9f43
Titlecryo-EM structure of human LST2 bound to human mTOR complex 1, focused on RAPTOR
Components
  • Lateral signaling target protein 2 homolog
  • Regulatory-associated protein of mTOR
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 pentose-phosphate shunt / TORC1 complex / positive regulation of odontoblast differentiation / Amino acids regulate mTORC1 / cellular response to L-leucine / MTOR signalling / Energy dependent regulation of mTOR by LKB1-AMPK / TORC1 signaling / serine/threonine protein kinase complex ...negative regulation of epidermal growth factor-activated receptor activity / positive regulation of pentose-phosphate shunt / TORC1 complex / positive regulation of odontoblast differentiation / Amino acids regulate mTORC1 / cellular response to L-leucine / MTOR signalling / Energy dependent regulation of mTOR by LKB1-AMPK / TORC1 signaling / serine/threonine protein kinase complex / phosphatidylinositol-3-phosphate binding / positive regulation of osteoclast differentiation / cellular response to osmotic stress / protein serine/threonine kinase inhibitor activity / positive regulation of transcription by RNA polymerase III / positive regulation of peptidyl-threonine phosphorylation / Macroautophagy / regulation of cell size / negative regulation of epidermal growth factor receptor signaling pathway / social behavior / TOR signaling / mTORC1-mediated signalling / protein kinase activator activity / positive regulation of TOR signaling / HSF1-dependent transactivation / positive regulation of G1/S transition of mitotic cell cycle / enzyme-substrate adaptor activity / cellular response to nutrient levels / positive regulation of lipid biosynthetic process / positive regulation of peptidyl-serine phosphorylation / positive regulation of endothelial cell proliferation / 14-3-3 protein binding / negative regulation of autophagy / positive regulation of glycolytic process / cellular response to starvation / Regulation of PTEN gene transcription / TP53 Regulates Metabolic Genes / cellular response to amino acid stimulus / regulation of cell growth / cellular response to glucose stimulus / small GTPase binding / cytoplasmic stress granule / positive regulation of cell growth / early endosome membrane / protein-macromolecule adaptor activity / cellular response to hypoxia / lysosome / regulation of autophagy / response to xenobiotic stimulus / lysosomal membrane / neuronal cell body / dendrite / DNA damage response / protein-containing complex binding / protein kinase binding / zinc ion binding / nucleoplasm / cytosol / cytoplasm
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. / HEAT repeat / HEAT repeat / Zinc finger, FYVE/PHD-type / Armadillo-like helical / Armadillo-type fold / Zinc finger, RING/FYVE/PHD-type / WD domain, G-beta repeat / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
Regulatory-associated protein of mTOR / Lateral signaling target protein 2 homolog
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.49 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
E: Regulatory-associated protein of mTOR
G: Lateral signaling target protein 2 homolog


Theoretical massNumber of molelcules
Total (without water)249,3692
Polymers249,3692
Non-polymers00
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 Regulatory-associated protein of mTOR / Raptor / p150 target of rapamycin (TOR)-scaffold protein


Mass: 152764.656 Da / Num. of mol.: 1
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
#2: Protein Lateral signaling target protein 2 homolog / hLst2 / Zinc finger FYVE domain-containing protein 28


Mass: 96604.477 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ZFYVE28, KIAA1643, LST2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9HCC9

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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 / Type: COMPLEX / Entity ID: all / 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: 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: 4719

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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: 1057805
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.49 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 545524 / 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_d0.0028666
ELECTRON MICROSCOPYf_angle_d0.46511787
ELECTRON MICROSCOPYf_dihedral_angle_d3.4711146
ELECTRON MICROSCOPYf_chiral_restr0.041332
ELECTRON MICROSCOPYf_plane_restr0.0041503

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