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- PDB-8sor: Structure of human PI3KC3-C1 complex -

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Basic information

Entry
Database: PDB / ID: 8sor
TitleStructure of human PI3KC3-C1 complex
Components
  • Beclin 1-associated autophagy-related key regulator
  • Beclin-1
  • Phosphatidylinositol 3-kinase catalytic subunit type 3
  • Phosphoinositide 3-kinase regulatory subunit 4
KeywordsIMMUNE SYSTEM / Autophagy / Lipid kinase / Complex
Function / homology
Function and homology information


extrinsic component of omegasome membrane / phosphatidylinositol 3-kinase inhibitor activity / regulation of triglyceride metabolic process / extrinsic component of phagophore assembly site membrane / nucleus-vacuole junction / cellular response to aluminum ion / positive regulation of protein lipidation / postsynaptic endosome / Toll Like Receptor 9 (TLR9) Cascade / Synthesis of PIPs at the late endosome membrane ...extrinsic component of omegasome membrane / phosphatidylinositol 3-kinase inhibitor activity / regulation of triglyceride metabolic process / extrinsic component of phagophore assembly site membrane / nucleus-vacuole junction / cellular response to aluminum ion / positive regulation of protein lipidation / postsynaptic endosome / Toll Like Receptor 9 (TLR9) Cascade / Synthesis of PIPs at the late endosome membrane / positive regulation of stress granule assembly / phosphatidylinositol 3-kinase complex, class III / cellular response to oxygen-glucose deprivation / Synthesis of PIPs at the early endosome membrane / phosphatidylinositol 3-kinase complex, class III, type II / phosphatidylinositol 3-kinase complex, class III, type I / host-mediated activation of viral genome replication / response to mitochondrial depolarisation / presynaptic endosome / positive regulation of attachment of mitotic spindle microtubules to kinetochore / mitochondria-associated endoplasmic reticulum membrane contact site / negative regulation of lysosome organization / engulfment of apoptotic cell / Synthesis of PIPs at the Golgi membrane / phosphatidylinositol kinase activity / regulation of protein complex stability / positive regulation of autophagosome assembly / early endosome to late endosome transport / response to L-leucine / cytoplasmic side of mitochondrial outer membrane / negative regulation of autophagosome assembly / protein localization to phagophore assembly site / phosphatidylinositol 3-kinase regulator activity / receptor catabolic process / phagophore assembly site membrane / protein targeting to vacuole / protein targeting to lysosome / SMAD protein signal transduction / late endosome to vacuole transport / endosome organization / pexophagy / phagophore assembly site / Translation of Replicase and Assembly of the Replication Transcription Complex / phosphatidylinositol-3-phosphate biosynthetic process / cellular response to nitrogen starvation / negative regulation of programmed cell death / phosphatidylinositol 3-kinase / 1-phosphatidylinositol-3-kinase activity / lysosome organization / response to vitamin E / post-transcriptional regulation of gene expression / mitotic metaphase chromosome alignment / cytoplasmic pattern recognition receptor signaling pathway / response to iron(II) ion / endosome to lysosome transport / positive regulation of cardiac muscle hypertrophy / Macroautophagy / phosphatidylinositol-mediated signaling / autophagosome membrane docking / RSV-host interactions / p38MAPK cascade / phosphatidylinositol phosphate biosynthetic process / negative regulation of protein phosphorylation / autolysosome / autophagosome membrane / PI3K Cascade / axoneme / autophagosome assembly / synaptic vesicle endocytosis / RHO GTPases Activate NADPH Oxidases / amyloid-beta metabolic process / autophagosome maturation / regulation of macroautophagy / cellular defense response / neuron development / cellular response to glucose starvation / phosphatidylinositol 3-kinase binding / mitophagy / intercellular bridge / positive regulation of intrinsic apoptotic signaling pathway / phagocytic vesicle / JNK cascade / protein-membrane adaptor activity / positive regulation of autophagy / cellular response to amino acid starvation / autophagosome / cellular response to copper ion / cellular response to epidermal growth factor stimulus / cellular response to starvation / regulation of cytokinesis / Antigen Presentation: Folding, assembly and peptide loading of class I MHC / macroautophagy / phosphatidylinositol 3-kinase/protein kinase B signal transduction / trans-Golgi network / circadian rhythm / GABA-ergic synapse / protein processing / response to lead ion / ISG15 antiviral mechanism / autophagy
Similarity search - Function
UV radiation resistance protein/autophagy-related protein 14 / Vacuolar sorting 38 and autophagy-related subunit 14 / Serine/threonine-protein kinase Vps15-like / : / VPS15-like, helical domain / Beclin-1, BH3 domain / Beclin-1 BH3 domain, Bcl-2-interacting / Atg6/Beclin / Atg6/Beclin C-terminal domain superfamily / Atg6, BARA domain ...UV radiation resistance protein/autophagy-related protein 14 / Vacuolar sorting 38 and autophagy-related subunit 14 / Serine/threonine-protein kinase Vps15-like / : / VPS15-like, helical domain / Beclin-1, BH3 domain / Beclin-1 BH3 domain, Bcl-2-interacting / Atg6/Beclin / Atg6/Beclin C-terminal domain superfamily / Atg6, BARA domain / Atg6/beclin, coiled-coil domain / Apg6 BARA domain / Apg6 coiled-coil region / Phosphatidylinositol 3-kinase, Vps34 type / HEAT repeat profile. / HEAT, type 2 / C2 phosphatidylinositol 3-kinase-type domain / Phosphoinositide 3-kinase C2 / C2 phosphatidylinositol 3-kinase (PI3K)-type domain profile. / Phosphoinositide 3-kinase, region postulated to contain C2 domain / Phosphoinositide 3-kinase family, accessory domain (PIK domain) / Phosphoinositide 3-kinase family, accessory domain (PIK domain) / Phosphoinositide 3-kinase, accessory (PIK) domain superfamily / Phosphoinositide 3-kinase, accessory (PIK) domain / Phosphatidylinositol kinase / PIK helical domain profile. / Leucine-rich Repeat Variant / Leucine-rich Repeat Variant / 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 / C2 domain superfamily / Armadillo-like helical / Alpha Horseshoe / WD domain, G-beta repeat / Armadillo-type fold / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / Protein kinase domain / WD40-repeat-containing domain superfamily / Serine/Threonine protein kinases, catalytic domain / WD40/YVTN repeat-like-containing domain superfamily / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / Mainly Alpha
Similarity search - Domain/homology
ADENOSINE-5'-DIPHOSPHATE / Beclin-1 / Beclin 1-associated autophagy-related key regulator / Phosphatidylinositol 3-kinase catalytic subunit type 3 / Phosphoinositide 3-kinase regulatory subunit 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.96 Å
AuthorsChen, M. / Hurley, J.H.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM111730 United States
Michael J. Fox FoundationASAP-000350 United States
CitationJournal: bioRxiv / Year: 2023
Title: Structure and activation of the human autophagy-initiating ULK1C:PI3KC3-C1 supercomplex
Authors: Chen, M. / Ren, X. / Cook, A. / Hurley, J.H.
History
DepositionApr 29, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 21, 2023Provider: repository / Type: Initial release
Revision 1.1Jun 28, 2023Group: Database references / Category: citation / pdbx_database_related / Item: _citation.year
Revision 1.2Oct 9, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: Phosphatidylinositol 3-kinase catalytic subunit type 3
C: Beclin 1-associated autophagy-related key regulator
D: Beclin-1
A: Phosphoinositide 3-kinase regulatory subunit 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)362,7425
Polymers362,3144
Non-polymers4271
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Phosphatidylinositol 3-kinase catalytic subunit type 3 / PI3-kinase type 3 / PI3K type 3 / PtdIns-3-kinase type 3 / Phosphatidylinositol 3-kinase p100 ...PI3-kinase type 3 / PI3K type 3 / PtdIns-3-kinase type 3 / Phosphatidylinositol 3-kinase p100 subunit / Phosphoinositide-3-kinase class 3 / hVps34


Mass: 101680.328 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3C3, VPS34 / Production host: Homo sapiens (human) / References: UniProt: Q8NEB9, phosphatidylinositol 3-kinase
#2: Protein Beclin 1-associated autophagy-related key regulator


Mass: 55387.266 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ATG14 / Production host: Homo sapiens (human) / References: UniProt: Q6ZNE5
#3: Protein Beclin-1 / Coiled-coil myosin-like BCL2-interacting protein / Protein GT197


Mass: 51953.102 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BECN1, GT197 / Production host: Homo sapiens (human) / References: UniProt: Q14457
#4: Protein Phosphoinositide 3-kinase regulatory subunit 4 / PI3-kinase regulatory subunit 4 / PI3-kinase p150 subunit / Phosphoinositide 3-kinase adaptor protein


Mass: 153293.797 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3R4, VPS15 / Production host: Homo sapiens (human)
References: UniProt: Q99570, non-specific serine/threonine protein kinase
#5: Chemical ChemComp-ADP / ADENOSINE-5'-DIPHOSPHATE


Mass: 427.201 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: ADP, energy-carrying molecule*YM
Has ligand of interestY
Has protein modificationY

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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: Human autophagy initiation PI3KC3-C1 complex / Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT
Molecular weightValue: 0.362 MDa / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Cell: HEK GnTi-
Buffer solutionpH: 7.4
Buffer component
IDConc.NameFormulaBuffer-ID
125 mMHEPESC8H18N2O4S1
2300 mMsodium chlorideNaCl1
31 mMmagnesium chlorideMgCl21
425 mMTCEPC9H15O6P1
SpecimenConc.: 0.25 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: 25 mA / Grid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 36000 X / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm
Specimen holderCryogen: NITROGEN
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 2243

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Processing

EM software
IDNameVersionCategory
1Topaz0.2.5aparticle selection
2SerialEM3.8image acquisition
4cryoSPARC3.3.1CTF correction
7ISOLDE1.5model fitting
8Coot0.9.8model fitting
10PHENIX1.20.1model refinement
11cryoSPARC3.3.1initial Euler assignment
12cryoSPARC3.3.1final Euler assignment
13cryoSPARC3.3.1classification
14cryoSPARC3.3.13D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 1229932
3D reconstructionResolution: 3.96 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 266147 / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingProtocol: AB INITIO MODEL / Space: REAL
Atomic model buildingSource name: AlphaFold / Type: in silico model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00416380
ELECTRON MICROSCOPYf_angle_d0.56522136
ELECTRON MICROSCOPYf_dihedral_angle_d5.7232155
ELECTRON MICROSCOPYf_chiral_restr0.042455
ELECTRON MICROSCOPYf_plane_restr0.0032826

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