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- PDB-9c82: Structure of human ULK1C:PI3KC3-C1 supercomplex -

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Basic information

Entry
Database: PDB / ID: 9c82
TitleStructure of human ULK1C:PI3KC3-C1 supercomplex
Components
  • Beclin 1-associated autophagy-related key regulator
  • Beclin-1
  • Phosphatidylinositol 3-kinase catalytic subunit type 3
  • Phosphoinositide 3-kinase regulatory subunit 4
  • RB1-inducible coiled-coil protein 1
KeywordsIMMUNE SYSTEM / Autophagy / Protein kinase / Lipid kinase / Supercomplex
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 / Toll Like Receptor 9 (TLR9) Cascade / postsynaptic endosome / Synthesis of PIPs at the late endosome membrane / phosphatidylinositol 3-kinase complex, class III ...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 / Toll Like Receptor 9 (TLR9) Cascade / postsynaptic endosome / Synthesis of PIPs at the late endosome membrane / phosphatidylinositol 3-kinase complex, class III / engulfment of apoptotic cell / 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 / Atg1/ULK1 kinase complex / presynaptic endosome / positive regulation of stress granule assembly / ribophagy / glycophagy / response to mitochondrial depolarisation / positive regulation of protein lipidation / positive regulation by host of viral genome replication / positive regulation of attachment of mitotic spindle microtubules to kinetochore / mitochondria-associated endoplasmic reticulum membrane contact site / negative regulation of lysosome organization / Synthesis of PIPs at the Golgi membrane / phosphatidylinositol kinase activity / regulation of protein complex stability / positive regulation of autophagosome assembly / phosphatidylinositol 3-kinase regulator activity / negative regulation of autophagosome assembly / cytoplasmic side of mitochondrial outer membrane / protein localization to phagophore assembly site / receptor catabolic process / phagophore assembly site membrane / protein targeting to vacuole / SMAD protein signal transduction / protein targeting to lysosome / early endosome to late endosome transport / late endosome to vacuole transport / autophagy of mitochondrion / pexophagy / piecemeal microautophagy of the nucleus / 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 / reticulophagy / response to iron(II) ion / phosphatidylinositol 3-kinase / lysosome organization / 1-phosphatidylinositol-3-kinase activity / mitotic metaphase chromosome alignment / post-transcriptional regulation of gene expression / cytoplasmic pattern recognition receptor signaling pathway / autophagosome membrane docking / endosome to lysosome transport / Macroautophagy / phosphatidylinositol-mediated signaling / positive regulation of cardiac muscle hypertrophy / RSV-host interactions / p38MAPK cascade / phosphatidylinositol phosphate biosynthetic process / autolysosome / regulation of protein phosphorylation / autophagosome membrane / negative regulation of protein phosphorylation / synaptic vesicle endocytosis / PI3K Cascade / axoneme / autophagosome assembly / RHO GTPases Activate NADPH Oxidases / response to vitamin E / autophagosome maturation / positive regulation of cell size / amyloid-beta metabolic process / regulation of macroautophagy / neuron development / phosphatidylinositol 3-kinase binding / cellular defense response / cellular response to glucose starvation / mitophagy / positive regulation of intrinsic apoptotic signaling pathway / protein-membrane adaptor activity / phagocytic vesicle / extrinsic apoptotic signaling pathway / JNK cascade / cellular response to copper ion / positive regulation of autophagy / cellular response to epidermal growth factor stimulus / cellular response to amino acid starvation / autophagosome / liver development / cellular response to starvation / regulation of cytokinesis / GABA-ergic synapse / negative regulation of extrinsic apoptotic signaling pathway / Antigen Presentation: Folding, assembly and peptide loading of class I MHC
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 / Autophagy-related protein 11, C-terminal / Autophagy-related protein 11 / Autophagy-related protein 11 / Beclin-1, BH3 domain / Beclin-1 BH3 domain, Bcl-2-interacting ...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 / Autophagy-related protein 11, C-terminal / Autophagy-related protein 11 / Autophagy-related protein 11 / 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. / 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 / Armadillo-type fold / Trp-Asp (WD) repeats signature. / WD domain, G-beta repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / WD40 repeat / WD40-repeat-containing domain superfamily / Protein kinase domain / 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
Similarity search - Domain/homology
Beclin-1 / Beclin 1-associated autophagy-related key regulator / Phosphatidylinositol 3-kinase catalytic subunit type 3 / RB1-inducible coiled-coil protein 1 / Phosphoinositide 3-kinase regulatory subunit 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 6.84 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
Citation
Journal: Nat Struct Mol Biol / Year: 2025
Title: Structure and activation of the human autophagy-initiating ULK1C:PI3KC3-C1 supercomplex.
Authors: Minghao Chen / Thanh N Nguyen / Xuefeng Ren / Grace Khuu / Annan S I Cook / Yuanchang Zhao / Ahmet Yildiz / Michael Lazarou / James H Hurley /
Abstract: The Unc-51-like kinase protein kinase complex (ULK1C) is the most upstream and central player in the initiation of macroautophagy in mammals. Here, we determined the cryo-electron microscopy ...The Unc-51-like kinase protein kinase complex (ULK1C) is the most upstream and central player in the initiation of macroautophagy in mammals. Here, we determined the cryo-electron microscopy structure of the human ULK1C core at amino-acid-level resolution. We also determined a moderate-resolution structure of the ULK1C core in complex with another autophagy core complex, the class III phosphatidylinositol 3-OH kinase complex I (PI3KC3-C1). We show that the two complexes coassemble through extensive contacts between the FIP200 scaffold subunit of ULK1C and the VPS15, ATG14 and BECN1 subunits of PI3KC3-C1. The FIP200:ATG13:ULK1 core of ULK1C undergoes a rearrangement from 2:1:1 to 2:2:2 stoichiometry in the presence of PI3KC3-C1. This suggests a structural mechanism for the initiation of autophagy through formation of a ULK1C:PI3KC3-C1 supercomplex and dimerization of ULK1 on the FIP200 scaffold.
#1: Journal: 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
DepositionJun 11, 2024Deposition site: RCSB / Processing site: RCSB
SupersessionJul 3, 2024ID: 8SRQ
Revision 1.0Jul 3, 2024Provider: repository / Type: Initial release
Revision 1.1Jun 18, 2025Group: Data collection / Database references / Structure summary
Category: citation / citation_author ...citation / citation_author / em_admin / pdbx_entry_details
Item: _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Phosphoinositide 3-kinase regulatory subunit 4
B: Phosphatidylinositol 3-kinase catalytic subunit type 3
C: Beclin 1-associated autophagy-related key regulator
D: Beclin-1
F: RB1-inducible coiled-coil protein 1


Theoretical massNumber of molelcules
Total (without water)435,6405
Polymers435,6405
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, assay for oligomerization, The complex formation was confirmed by strep pulldown
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: 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
#2: 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
#3: 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
#4: 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
#5: Protein RB1-inducible coiled-coil protein 1 / FAK family kinase-interacting protein of 200 kDa / FIP200


Mass: 73325.633 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RB1CC1, KIAA0203, RBICC / Production host: Homo sapiens (human) / References: UniProt: Q8TDY2
Has protein modificationN

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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: Supercomplex composed of ULK1 complex and PI3KC3-C1 complex
Type: COMPLEX
Details: Individually expressed the ULK1 complex core (consists of two molecules of FIP200 (1-640), ULK1 (828-1050), and ATG13 (363-517)) and the full-length PI3KC3-C1 (consists of VPS34, VPS15, ...Details: Individually expressed the ULK1 complex core (consists of two molecules of FIP200 (1-640), ULK1 (828-1050), and ATG13 (363-517)) and the full-length PI3KC3-C1 (consists of VPS34, VPS15, BECN1, and ATG14). Mixed the above two complexes in a molecular ratio of 1.5:1 and purified the supercomplex by strep pulldown of the TSF-tagged VPS15.
Entity ID: all / Source: RECOMBINANT
Molecular weight
IDEntity assembly-IDValue (°)Experimental value
110.55 MDaNO
210.55 MDaNO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
Buffer component
IDConc.NameFormulaBuffer-ID
125 mMHEPESC8H18N2O4S1
2200 mMNaClNaCl1
31 mMMgCl2MgCl21
410 mMTCEPC9H15O6P1
54 mMd-DesthiobiotinC10H18N2O31
SpecimenConc.: 0.15 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: This sample was purified by strep pulldown.
Specimen supportDetails: 25 mA / Grid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R2/1
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K
Details: added 0.05% (w/v) octylglucopyranoside as surfactant

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 81000 X / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1Topaz0.2.5aparticle selection
2SerialEMimage acquisition
4cryoSPARC4.3.0CTF correction
7UCSF ChimeraX1.7model fitting
9PHENIX1.21.1model refinement
10cryoSPARC4.3.0initial Euler assignment
11cryoSPARC4.3.0final Euler assignment
12cryoSPARC4.3.0classification
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 4473551
3D reconstructionResolution: 6.84 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 21937 / Symmetry type: POINT
Atomic model buildingProtocol: AB INITIO MODEL / Space: REAL

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