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- PDB-7pe8: cryo-EM structure of DEPTOR bound to human mTOR complex 2, focuss... -

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Basic information

Entry
Database: PDB / ID: 7pe8
Titlecryo-EM structure of DEPTOR bound to human mTOR complex 2, focussed on one protomer
Components
  • (Target of rapamycin complex ...) x 2
  • DEP domain-containing mTOR-interacting protein
  • Rapamycin-insensitive companion of mTOR
  • Serine/threonine-protein kinase mTOR
KeywordsSIGNALING PROTEIN / DEPTOR / mTOR / regulator / inhibitor / mTORC2 / DEP-domain / PDZ-domain
Function / homology
Function and homology information


regulation of extrinsic apoptotic signaling pathway / 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 / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of wound healing, spreading of epidermal cells / TORC2 signaling ...regulation of extrinsic apoptotic signaling pathway / 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 / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of wound healing, spreading of epidermal cells / TORC2 signaling / TORC2 complex / regulation of membrane permeability / cellular response to leucine starvation / negative regulation of lysosome organization / heart valve morphogenesis / TFIIIC-class transcription factor complex binding / TORC1 complex / positive regulation of transcription of nucleolar large rRNA by RNA polymerase I / voluntary musculoskeletal movement / regulation of cellular response to oxidative stress / negative regulation of TORC2 signaling / calcineurin-NFAT signaling cascade / regulation of osteoclast differentiation / RNA polymerase III type 3 promoter sequence-specific DNA binding / positive regulation of keratinocyte migration / regulation of lysosome organization / phosphatidic acid binding / MTOR signalling / Amino acids regulate mTORC1 / cellular response to L-leucine / cellular response to nutrient / energy reserve metabolic process / regulation of autophagosome assembly / Energy dependent regulation of mTOR by LKB1-AMPK / TORC1 signaling / ruffle organization / negative regulation of Ras protein signal transduction / serine/threonine protein kinase complex / embryo development ending in birth or egg hatching / phosphatidylinositol-3,4-bisphosphate binding / cellular response to methionine / negative regulation of cell size / positive regulation of ubiquitin-dependent protein catabolic process / inositol hexakisphosphate binding / cellular response to osmotic stress / phosphatidylinositol-3,5-bisphosphate binding / negative regulation of TOR signaling / anoikis / negative regulation of protein localization to nucleus / cardiac muscle cell development / regulation of myelination / negative regulation of calcineurin-NFAT signaling cascade / regulation of establishment of cell polarity / positive regulation of transcription by RNA polymerase III / negative regulation of macroautophagy / Macroautophagy / lipid biosynthetic process / positive regulation of myotube differentiation / regulation of cell size / protein kinase inhibitor activity / positive regulation of actin filament polymerization / Constitutive Signaling by AKT1 E17K in Cancer / germ cell development / phosphatidylinositol-3,4,5-trisphosphate binding / TOR signaling / behavioral response to pain / mTORC1-mediated signalling / oligodendrocyte differentiation / positive regulation of oligodendrocyte differentiation / positive regulation of translational initiation / protein serine/threonine kinase inhibitor activity / CD28 dependent PI3K/Akt signaling / positive regulation of TOR signaling / HSF1-dependent transactivation / regulation of macroautophagy / enzyme-substrate adaptor activity / response to amino acid / 'de novo' pyrimidine nucleobase biosynthetic process / positive regulation of epithelial to mesenchymal transition / heart morphogenesis / vascular endothelial cell response to laminar fluid shear stress / neuronal action potential / positive regulation of lipid biosynthetic process / cellular response to nutrient levels / regulation of cellular response to heat / positive regulation of lamellipodium assembly / cardiac muscle contraction / negative regulation of protein kinase activity / phagocytic vesicle / T cell costimulation / positive regulation of stress fiber assembly / negative regulation of TORC1 signaling / phosphatidylinositol-4,5-bisphosphate binding / positive regulation of endothelial cell proliferation / cytoskeleton organization / positive regulation of autophagy / substantia nigra development / endomembrane system / negative regulation of autophagy / negative regulation of insulin receptor signaling pathway
Similarity search - Function
Rapamycin-insensitive companion of mTOR, N-terminal domain / Pianissimo family / Rapamycin-insensitive companion of mTOR, phosphorylation-site / Rapamycin-insensitive companion of mTOR, middle domain / Rapamycin-insensitive companion of mTOR, domain 5 / Rapamycin-insensitive companion of mTOR, domain 4 / DEP domain-containing mTOR-interacting protein, DEP domain 1 / DEP domain-containing mTOR-interacting protein, DEP domain 2 / Rapamycin-insensitive companion of mTOR RasGEF_N domain / Rapamycin-insensitive companion of mTOR, N-term ...Rapamycin-insensitive companion of mTOR, N-terminal domain / Pianissimo family / Rapamycin-insensitive companion of mTOR, phosphorylation-site / Rapamycin-insensitive companion of mTOR, middle domain / Rapamycin-insensitive companion of mTOR, domain 5 / Rapamycin-insensitive companion of mTOR, domain 4 / DEP domain-containing mTOR-interacting protein, DEP domain 1 / DEP domain-containing mTOR-interacting protein, DEP domain 2 / Rapamycin-insensitive companion of mTOR RasGEF_N domain / Rapamycin-insensitive companion of mTOR, N-term / Rapamycin-insensitive companion of mTOR, phosphorylation-site / Rapamycin-insensitive companion of mTOR, middle domain / Rapamycin-insensitive companion of mTOR, domain 5 / Rapamycin-insensitive companion of mTOR RasGEF_N domain / Rapamycin-insensitive companion of mTOR, middle domain / Rapamycin-insensitive companion of mTOR, N-term / Rapamycin-insensitive companion of mTOR, phosphorylation-site / Rapamycin-insensitive companion of mTOR, domain 5 / Sin1, N-terminal / Stress-activated map kinase interacting protein 1 (SIN1) / TORC2 component Sin1/Avo1 / SAPK-interacting protein 1, Pleckstrin-homology domain / Sin1, middle CRIM domain / SAPK-interacting protein 1 (Sin1), middle CRIM domain / SAPK-interacting protein 1 (Sin1), Pleckstrin-homology / 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 / 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 / PH-like domain superfamily / WD domain, G-beta repeat / Armadillo-type fold / G-protein beta WD-40 repeat / Winged helix DNA-binding domain superfamily / 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/YVTN repeat-like-containing domain superfamily / Protein kinase-like domain superfamily
Similarity search - Domain/homology
ACETYL GROUP / INOSITOL HEXAKISPHOSPHATE / Serine/threonine-protein kinase mTOR / Rapamycin-insensitive companion of mTOR / DEP domain-containing mTOR-interacting protein / Target of rapamycin complex 2 subunit MAPKAP1 / Target of rapamycin complex subunit LST8
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 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
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

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Structure visualization

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Assembly

Deposited unit
A: Serine/threonine-protein kinase mTOR
C: Target of rapamycin complex subunit LST8
E: Rapamycin-insensitive companion of mTOR
G: Target of rapamycin complex 2 subunit MAPKAP1
I: DEP domain-containing mTOR-interacting protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)626,0478
Polymers625,2785
Non-polymers7693
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area18500 Å2
ΔGint-94 kcal/mol
Surface area171270 Å2
MethodPISA

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Components

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Protein , 3 types, 3 molecules AEI

#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: 291321.938 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
#3: Protein Rapamycin-insensitive companion of mTOR / AVO3 homolog / hAVO3


Mass: 192472.922 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RICTOR, KIAA1999 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q6R327
#5: 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

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Target of rapamycin complex ... , 2 types, 2 molecules CG

#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
#4: Protein Target of rapamycin complex 2 subunit MAPKAP1 / TORC2 subunit MAPKAP1 / Mitogen-activated protein kinase 2-associated protein 1 / Stress-activated ...TORC2 subunit MAPKAP1 / Mitogen-activated protein kinase 2-associated protein 1 / Stress-activated map kinase-interacting protein 1 / mSIN1


Mass: 59206.738 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAPKAP1, MIP1, SIN1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9BPZ7

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Non-polymers , 3 types, 3 molecules

#6: 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
#7: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#8: Chemical ChemComp-ACE / ACETYL GROUP


Mass: 44.053 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H4O

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Details

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: mTORC2 in complex with its regulator DEPTOR / Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT
Molecular weightValue: 1.24 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
SpecimenConc.: 1.2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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
Image recordingElectron dose: 50 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

Software
NameVersionClassification
phenix.real_space_refine1.19_4092refinement
PHENIX1.19_4092refinement
EM software
IDNameVersionCategory
4RELION3.1CTF correction
10cryoSPARC3.2.0initial Euler assignment
11cryoSPARC3.2.0final Euler assignment
13cryoSPARC3.2.03D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 750254 / Symmetry type: POINT
RefinementHighest resolution: 3.2 Å / Cross valid method: NONE
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.001329834
ELECTRON MICROSCOPYf_angle_d0.368240503
ELECTRON MICROSCOPYf_chiral_restr0.03644695
ELECTRON MICROSCOPYf_plane_restr0.00295196
ELECTRON MICROSCOPYf_dihedral_angle_d8.67810714

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