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- PDB-7pec: cryo-EM structure of DEPTOR bound to human mTOR complex 1, DEPt-b... -

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Basic information

Entry
Database: PDB / ID: 7pec
Titlecryo-EM structure of DEPTOR bound to human mTOR complex 1, DEPt-bound subset local refinement
Components
  • DEP domain-containing mTOR-interacting protein
  • Regulatory-associated protein of mTOR
  • Serine/threonine-protein kinase mTOR
  • Target of rapamycin complex subunit LST8
KeywordsSIGNALING PROTEIN / DEPTOR / mTOR / regulator / inhibitor / mTORC1 / DEP-domain / PDZ-domain
Function / homology
Function and homology information


regulation of extrinsic apoptotic signaling pathway / 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 ...regulation of extrinsic apoptotic signaling pathway / 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 / negative regulation of lysosome organization / voluntary musculoskeletal movement / positive regulation of odontoblast differentiation / negative regulation of TORC2 signaling / 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 / cellular response to L-leucine / regulation of lysosome organization / regulation of autophagosome assembly / Energy dependent regulation of mTOR by LKB1-AMPK / cellular response to nutrient / Amino acids regulate mTORC1 / phosphatidic acid binding / cellular response to methionine / TORC2 signaling / negative regulation of cell size / positive regulation of osteoclast differentiation / negative regulation of TOR signaling / cellular response to osmotic stress / anoikis / cell projection organization / 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 / negative regulation of macroautophagy / Macroautophagy / positive regulation of myotube differentiation / Constitutive Signaling by AKT1 E17K in Cancer / germ cell development / protein kinase inhibitor activity / positive regulation of actin filament polymerization / oligodendrocyte differentiation / TORC1 signaling / positive regulation of oligodendrocyte differentiation / behavioral response to pain / TOR signaling / mTORC1-mediated signalling / response to amino acid / positive regulation of translational initiation / CD28 dependent PI3K/Akt signaling / HSF1-dependent transactivation / regulation of macroautophagy / positive regulation of TOR signaling / protein kinase activator activity / protein serine/threonine kinase inhibitor activity / enzyme-substrate adaptor 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 / negative regulation of protein kinase activity / 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 / phagocytic vesicle / T cell costimulation / cardiac muscle contraction / positive regulation of stress fiber assembly / negative regulation of TORC1 signaling / positive regulation of endothelial cell proliferation / negative regulation of insulin receptor signaling pathway / 14-3-3 protein binding / endomembrane system / cytoskeleton organization / positive regulation of autophagy / guanyl-nucleotide exchange factor activity / cellular response to nutrient levels / positive regulation of glycolytic process / cellular response to amino acid starvation / Regulation of PTEN gene transcription / regulation of signal transduction by p53 class mediator
Similarity search - Function
DEP domain-containing mTOR-interacting protein, DEP domain 1 / DEP domain-containing mTOR-interacting protein, DEP domain 2 / Raptor, N-terminal CASPase-like domain / Raptor N-terminal CASPase like domain / Raptor N-terminal CASPase like domain / Regulatory associated protein of TOR / : / Target of rapamycin complex subunit LST8 / Domain of unknown function DUF3385, target of rapamycin protein / Serine/threonine-protein kinase mTOR domain ...DEP domain-containing mTOR-interacting protein, DEP domain 1 / DEP domain-containing mTOR-interacting protein, DEP domain 2 / Raptor, N-terminal CASPase-like domain / Raptor N-terminal CASPase like domain / Raptor N-terminal CASPase like domain / Regulatory associated protein of TOR / : / Target of rapamycin complex subunit LST8 / Domain of unknown function DUF3385, target of rapamycin protein / Serine/threonine-protein kinase mTOR domain / Domain of unknown function / FKBP12-rapamycin binding domain / Serine/threonine-protein kinase TOR / FKBP12-rapamycin binding domain superfamily / FKBP12-rapamycin binding domain / HEAT repeat / HEAT repeat / Rapamycin binding domain / : / Serine/threonine-protein kinase ATR-like, HEAT repeats / Domain found in Dishevelled, Egl-10, and Pleckstrin (DEP) / DEP domain profile. / Domain found in Dishevelled, Egl-10, and Pleckstrin / DEP domain / : / 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 / PDZ domain profile. / Domain present in PSD-95, Dlg, and ZO-1/2. / PDZ domain / PDZ superfamily / Armadillo-like helical / Tetratricopeptide-like helical domain superfamily / WD domain, G-beta repeat / Armadillo-type fold / Winged helix DNA-binding domain superfamily / 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 / Winged helix-like DNA-binding domain superfamily / 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 / DEP domain-containing mTOR-interacting protein / Target of rapamycin complex subunit LST8
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.24 Å
AuthorsWaelchli, M. / Maier, T.
Funding support Switzerland, 1items
OrganizationGrant numberCountry
Swiss National Science Foundation179323 Switzerland
CitationJournal: Elife / Year: 2021
Title: Regulation of human mTOR complexes by DEPTOR.
Authors: Matthias Wälchli / Karolin Berneiser / Francesca Mangia / Stefan Imseng / Louise-Marie Craigie / Edward Stuttfeld / Michael N Hall / Timm Maier /
Abstract: The vertebrate-specific DEP domain-containing mTOR interacting protein (DEPTOR), an oncoprotein or tumor suppressor, has important roles in metabolism, immunity, and cancer. It is the only protein ...The vertebrate-specific DEP domain-containing mTOR interacting protein (DEPTOR), an oncoprotein or tumor suppressor, has important roles in metabolism, immunity, and cancer. It is the only protein that binds and regulates both complexes of mammalian target of rapamycin (mTOR), a central regulator of cell growth. Biochemical analysis and cryo-EM reconstructions of DEPTOR bound to human mTOR complex 1 (mTORC1) and mTORC2 reveal that both structured regions of DEPTOR, the PDZ domain and the DEP domain tandem (DEPt), are involved in mTOR interaction. The PDZ domain binds tightly with mildly activating effect, but then acts as an anchor for DEPt association that allosterically suppresses mTOR activation. The binding interfaces of the PDZ domain and DEPt also support further regulation by other signaling pathways. A separate, substrate-like mode of interaction for DEPTOR phosphorylation by mTOR complexes rationalizes inhibition of non-stimulated mTOR activity at higher DEPTOR concentrations. The multifaceted interplay between DEPTOR and mTOR provides a basis for understanding the divergent roles of DEPTOR in physiology and opens new routes for targeting the mTOR-DEPTOR interaction in disease.
History
DepositionAug 9, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 8, 2021Provider: repository / Type: Initial release
Revision 1.1Sep 29, 2021Group: Data collection / Database references
Category: citation / citation_author ...citation / citation_author / em_admin / pdbx_database_proc / pdbx_seq_map_depositor_info
Item: _citation.journal_volume / _citation.pdbx_database_id_PubMed ..._citation.journal_volume / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name / _em_admin.last_update / _pdbx_seq_map_depositor_info.one_letter_code_mod
Revision 1.2Jul 17, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_3d_fitting_list / em_admin / pdbx_initial_refinement_model
Item: _em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id ..._em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id / _em_3d_fitting_list.source_name / _em_3d_fitting_list.type / _em_admin.last_update

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Structure visualization

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Structure viewerMolecule:
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Assembly

Deposited unit
A: Serine/threonine-protein kinase mTOR
C: Target of rapamycin complex subunit LST8
E: Regulatory-associated protein of mTOR
I: DEP domain-containing mTOR-interacting protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)526,3835
Polymers525,7234
Non-polymers6601
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area8150 Å2
ΔGint-21 kcal/mol
Surface area174580 Å2

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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: 287484.156 Da / Num. of mol.: 1
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.: 1
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: 155963.094 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
#4: Protein DEP domain-containing mTOR-interacting protein / DEP domain-containing protein 6


Mass: 46365.832 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DEPTOR, DEPDC6 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q8TB45
#5: Chemical ChemComp-IHP / INOSITOL HEXAKISPHOSPHATE / MYO-INOSITOL HEXAKISPHOSPHATE / INOSITOL 1,2,3,4,5,6-HEXAKISPHOSPHATE


Mass: 660.035 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H18O24P6
Has ligand of interestN

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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 its regulator DEPTOR / Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT
Molecular weightValue: 1.04 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
Buffer component
IDConc.NameFormulaBuffer-ID
1100 mMsodium chlorideNaCl1
220 mMbicine1
35 mMmagnesium chlorideMgCl21
42 mMTCEP1
50.25 %glycerol1
SpecimenConc.: 1.4 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

MicroscopyModel: TFS GLACIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 50 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19_4092: / Classification: refinement
EM software
IDNameVersionCategory
4cryoSPARC3.2.0CTF correction
9PHENIX1.19-4092model refinement
10cryoSPARC3.2.0initial Euler assignment
11cryoSPARC3.2.0final Euler assignment
12cryoSPARC3.2.0classification
13cryoSPARC3.2.03D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 4.24 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 211021 / Symmetry type: POINT
Atomic model buildingPDB-ID: 6BCX

6bcx


Accession code: 6BCX / Source name: PDB / Type: experimental model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00231567
ELECTRON MICROSCOPYf_angle_d0.46942808
ELECTRON MICROSCOPYf_dihedral_angle_d14.47611686
ELECTRON MICROSCOPYf_chiral_restr0.0384840
ELECTRON MICROSCOPYf_plane_restr0.0045460

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