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- PDB-9rx8: Apo VPS34-CII (VPS34/VPS15/BECLIN1/UVRAG) -

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Basic information

Entry
Database: PDB / ID: 9rx8
TitleApo VPS34-CII (VPS34/VPS15/BECLIN1/UVRAG)
Components
  • Beclin-1
  • Phosphatidylinositol 3-kinase catalytic subunit type 3
  • Phosphoinositide 3-kinase regulatory subunit 4
  • UV radiation resistance associated protein
KeywordsENDOCYTOSIS / Lipid kinase / GTPase / kinase / autophagy / endocytic trafficking / SIGNALING PROTEIN
Function / homology
Function and homology information


protein-containing complex organization / nucleus-vacuole junction / cellular response to aluminum ion / positive regulation of protein lipidation / postsynaptic endosome / Toll Like Receptor 9 (TLR9) Cascade / positive regulation of stress granule assembly / Synthesis of PIPs at the late endosome membrane / phosphatidylinositol 3-kinase complex, class III / cellular response to oxygen-glucose deprivation ...protein-containing complex organization / nucleus-vacuole junction / cellular response to aluminum ion / positive regulation of protein lipidation / postsynaptic endosome / Toll Like Receptor 9 (TLR9) Cascade / positive regulation of stress granule assembly / Synthesis of PIPs at the late endosome membrane / 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 / response to mitochondrial depolarisation / presynaptic endosome / positive regulation of attachment of mitotic spindle microtubules to kinetochore / host-mediated activation of viral genome replication / Dengue virus modulates apoptosis / engulfment of apoptotic cell / negative regulation of lysosome organization / phosphatidylinositol kinase activity / SMAD protein signal transduction / positive regulation of autophagosome assembly / Synthesis of PIPs at the Golgi membrane / cytoplasmic side of mitochondrial outer membrane / early endosome to late endosome transport / receptor catabolic process / response to L-leucine / protein targeting to vacuole / late endosome to vacuole transport / protein targeting to lysosome / endosome organization / pexophagy / positive regulation of natural killer cell mediated cytotoxicity / phagophore assembly site / Translation of Replicase and Assembly of the Replication Transcription Complex / cellular response to nitrogen starvation / centrosome cycle / phosphatidylinositol 3-kinase / phosphatidylinositol-3-phosphate biosynthetic process / 1-phosphatidylinositol-3-kinase activity / negative regulation of programmed cell death / response to vitamin E / Macroautophagy / response to iron(II) ion / RSV-host interactions / p38MAPK cascade / cytoplasmic pattern recognition receptor signaling pathway / phosphatidylinositol phosphate biosynthetic process / mitotic metaphase chromosome alignment / phosphatidylinositol-mediated signaling / autolysosome / PI3K Cascade / chromosome, centromeric region / RHO GTPases Activate NADPH Oxidases / regulation of macroautophagy / autophagosome maturation / axoneme / synaptic vesicle endocytosis / cellular defense response / autophagosome assembly / phosphatidylinositol 3-kinase binding / cellular response to glucose starvation / intercellular bridge / mitophagy / JNK cascade / phagocytic vesicle / positive regulation of intrinsic apoptotic signaling pathway / vesicle-mediated transport / positive regulation of autophagy / autophagosome / cellular response to epidermal growth factor stimulus / cellular response to copper ion / cellular response to amino acid starvation / regulation of autophagy / regulation of cytokinesis / macroautophagy / Antigen Presentation: Folding, assembly and peptide loading of class I MHC / phosphatidylinositol 3-kinase/protein kinase B signal transduction / trans-Golgi network / circadian rhythm / protein processing / response to lead ion / autophagy / GABA-ergic synapse / ISG15 antiviral mechanism / phagocytic vesicle membrane / cellular response to hydrogen peroxide / endocytosis / late endosome / peroxisome / microtubule cytoskeleton / protein-containing complex assembly / GTPase binding / Translation of Replicase and Assembly of the Replication Transcription Complex / midbody / defense response to virus / molecular adaptor activity / protein phosphorylation / response to hypoxia
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 / 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 ...UV radiation resistance protein/autophagy-related protein 14 / Vacuolar sorting 38 and autophagy-related subunit 14 / Serine/threonine-protein kinase Vps15-like / 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 / : / : / PIK3R4-like, middle domain / HEAT, type 2 / HEAT repeat profile. / 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. / Protein kinase C conserved region 2 (CalB) / C2 domain / C2 domain / C2 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 / WD domain, G-beta repeat / Armadillo-type fold / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Trp-Asp (WD) repeats signature. / Protein kinase domain / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / Serine/Threonine protein kinases, catalytic domain / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
GUANOSINE-5'-DIPHOSPHATE / MYRISTIC ACID / Beclin-1 / UV radiation resistance associated protein / 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: 3.87 Å
AuthorsSpokaite, S. / Ohashi, Y. / Dessus, A.N. / Bourguet, M. / Williams, R.L.
Funding support United Kingdom, 2items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MC_U105184308 United Kingdom
Cancer Research UKDRCPGM 100014 United Kingdom
Citation
Journal: Elife / Year: 2026
Title: A novel RAB5 binding site in human VPS34-CII that is likely the primordial site in eukaryotic evolution.
Authors: Saule Spokaite / Yohei Ohashi / Maxime Bourguet / Antoine Nicolas Dessus / Roger L Williams /
Abstract: RAB5-GTP activation of the multiprotein VPS34 complex II (VPS34-CII) is critical for endosomal sorting and maturation, phagocytosis, and receptor downregulation. RAB5-GTP activates VPS34-CII by ...RAB5-GTP activation of the multiprotein VPS34 complex II (VPS34-CII) is critical for endosomal sorting and maturation, phagocytosis, and receptor downregulation. RAB5-GTP activates VPS34-CII by binding to a helical insertion in the C2 domain of VPS34 on the BECLIN1/UVRAG-containing adaptor arm of the complex. The autophagy complex, VPS34 complex I (VPS34-CI), features a unique ATG14L subunit in place of the VPS34-CII UVRAG subunit, and we found that this distorts the adaptor arm to alter the VPS34 RAB-GTPase binding pocket so that it preferentially binds RAB1-GTP. Surprisingly, our higher-resolution single-particle cryo-EM structure of VPS34-CII showed a second RAB5-GTP binding site on the VPS15 solenoid region. This site (VPS15-RAB5-site) appears to be the primordial RAB5-binding region. A mutant in the helical insertion of the C2 domain of human VPS34 that mimics the sequence abolishes RAB5 binding to VPS34. Mutation of the VPS15-RAB5-site ortholog in VPS15 resulted in defective CPY sorting, loss of colocalisation with the RAB5 ortholog Vps21, and loss of binding to Vps21 in vitro. Evolutionary expansion from one to two RAB5-orthologue binding sites may have increased membrane binding and VPS34-CII activity to adapt to more complex endocytic systems.
#1: Journal: Elife / Year: 2026
Title: A novel RAB5 binding site in human VPS34-CII that is likely the primordial site in eukaryotic evolution
Authors: Spokaite, S. / Ohashi, Y. / Bourguet, M. / Dessus, A.N. / Williams, R.L.
History
DepositionJul 10, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 3, 2026Provider: repository / Type: Initial release
Revision 1.0Jun 3, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jun 3, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Jun 3, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jun 3, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jun 3, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jun 3, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Jun 10, 2026Group: Data collection / Database references / Category: citation / citation_author / em_admin / Item: _em_admin.last_update
Revision 1.1Jun 10, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / Category: citation / citation_author / em_admin / Data content type: EM metadata / 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: Phosphatidylinositol 3-kinase catalytic subunit type 3
B: Phosphoinositide 3-kinase regulatory subunit 4
C: Beclin-1
D: UV radiation resistance associated protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)387,3448
Polymers386,5824
Non-polymers7614
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

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Protein , 4 types, 4 molecules ABCD

#1: Protein Phosphatidylinositol 3-kinase catalytic subunit type 3 / PtdIns-3-kinase type 3 / Phosphatidylinositol 3-kinase p100 subunit / Phosphoinositide-3-kinase ...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 / Cell line (production host): Expi293 / Production host: Homo sapiens (human) / References: UniProt: Q8NEB9, phosphatidylinositol 3-kinase
#2: Protein Phosphoinositide 3-kinase regulatory subunit 4 / PI3-kinase regulatory subunit 4 / PI3-kinase p150 subunit / Phosphoinositide 3-kinase adaptor protein


Mass: 154659.188 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Full length VPS15 with 13 extra residues left after TEV cleavage (VPS15-SRPTTASENLYFQ)
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3R4, VPS15 / Cell line (production host): Expi293F / Production host: Homo sapiens (human)
References: UniProt: Q99570, non-specific serine/threonine protein kinase
#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 UV radiation resistance associated protein


Mass: 78289.852 Da / Num. of mol.: 1 / Mutation: P10Q
Source method: isolated from a genetically manipulated source
Details: Full length UVRAG with a P10Q mutation / Source: (gene. exp.) Homo sapiens (human) / Gene: UVRAG / Production host: Homo sapiens (human) / References: UniProt: Q6P1X0

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Non-polymers , 4 types, 4 molecules

#5: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: GDP, energy-carrying molecule*YM
#6: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
#7: Chemical ChemComp-MYR / MYRISTIC ACID


Mass: 228.371 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H28O2 / Feature type: SUBJECT OF INVESTIGATION
#8: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION

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Details

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 VPS34-CII (VPS34/VPS15/BECLIN1/UVRAG) incubated with 22-fold molar excess of RAB5A-GTP (C19S, C63S, Q79L)
Type: COMPLEX
Details: No RAB5A molecules were bound to VPS34-CII in this class
Entity ID: #1, #4, #3 / Source: RECOMBINANT
Molecular weightValue: 0.432 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
Buffer component
IDConc.NameFormulaBuffer-ID
150 mMHEPESC8H18N2O4S1
2200 mMSodium chlorideNaCl1
31 mMTCEPC9H15O6P1
45 mMMagnesium chlorideMgCl21
51 mMAMPPNPC10H17N6O12P31
64 mMCHAPSOC32H58N2O8S1
70.005 % v/vNonidet P40 substitute(C2H4O)nC14H22O1
SpecimenConc.: 1.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: Sample was crosslinked with 20 uM BS3 for 20 minutes on ice, then quenched with 100 mM TRIS pH 8.0 prior to vitrification
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK III / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 287 K
Details: 3.5 uL sample, 0 second wait, 4 second blot, blot force +8

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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: 105000 X / Nominal defocus max: 2200 nm / Nominal defocus min: 800 nm / C2 aperture diameter: 50 µm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 40 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 2 / Num. of real images: 19844
EM imaging opticsEnergyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV

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Processing

EM software
IDNameVersionCategory
1crYOLO1.7.5particle selection
2PHENIX1.21rc1_5156:model refinement
13cryoSPARC3D reconstruction
CTF correctionType: NONE
Particle selectionNum. of particles selected: 717560
3D reconstructionResolution: 3.87 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 66323 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00323178
ELECTRON MICROSCOPYf_angle_d0.65331334
ELECTRON MICROSCOPYf_dihedral_angle_d6.5953080
ELECTRON MICROSCOPYf_chiral_restr0.0443477
ELECTRON MICROSCOPYf_plane_restr0.0064028

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