- EMDB-12214: human complex II-BATS bound to membrane-attached Rab5a-GTP -
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Basic information
Entry
Database: EMDB / ID: EMD-12214
Title
human complex II-BATS bound to membrane-attached Rab5a-GTP
Map data
Subtomogram averaging reconstruction of human complex II-BATS bound to membrane-attached Rab5a-GTP at 9.8A with the membrane masked out after local-denoising with the LAFTER algorithm
Sample
Complex: human VPS34 complex II (VPS34-VPS15-Beclin1-UVRAG) bound to human Rab5a
Complex: human VPS34 complex II (VPS34-VPS15-Beclin1-UVRAG)
Protein or peptide: UV radiation resistance-associated gene protein
Protein or peptide: Phosphatidylinositol 3-kinase catalytic subunit type 3
Protein or peptide: Phosphoinositide 3-kinase regulatory subunit 4
regulation of protein serine/threonine kinase activity / lytic vacuole / maintenance of Golgi location / regulation of endosome size / nucleus-vacuole junction / cellular response to aluminum ion / cytoplasmic side of early endosome membrane / Toll Like Receptor 9 (TLR9) Cascade / postsynaptic endosome / postsynaptic early endosome ...regulation of protein serine/threonine kinase activity / lytic vacuole / maintenance of Golgi location / regulation of endosome size / nucleus-vacuole junction / cellular response to aluminum ion / cytoplasmic side of early endosome membrane / Toll Like Receptor 9 (TLR9) Cascade / postsynaptic endosome / postsynaptic early 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 / synaptic vesicle recycling / presynaptic endosome / positive regulation of stress granule assembly / response to mitochondrial depolarisation / amyloid-beta clearance by transcytosis / SARS-CoV-2 modulates autophagy / positive regulation by host of viral genome replication / positive regulation of protein lipidation / positive regulation of attachment of mitotic spindle microtubules to kinetochore / negative regulation of lysosome organization / Synthesis of PIPs at the Golgi membrane / phosphatidylinositol kinase activity / modulation by host of viral process / receptor catabolic process / negative regulation of autophagosome assembly / positive regulation of autophagosome assembly / cytoplasmic side of mitochondrial outer membrane / regulation of filopodium assembly / : / protein localization to phagophore assembly site / multivesicular body sorting pathway / protein targeting to vacuole / RAB geranylgeranylation / pexophagy / protein targeting to lysosome / SMAD protein signal transduction / regulation of autophagosome assembly / early endosome to late endosome transport / late endosome to vacuole transport / RAB GEFs exchange GTP for GDP on RABs / double-strand break repair via classical nonhomologous end joining / retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum / early phagosome / phagophore assembly site / Translation of Replicase and Assembly of the Replication Transcription Complex / positive regulation of autophagosome maturation / centrosome cycle / phosphatidylinositol-3-phosphate biosynthetic process / negative regulation of programmed cell death / TBC/RABGAPs / cellular response to nitrogen starvation / response to iron(II) ion / phosphatidylinositol 3-kinase / SNARE complex assembly / spindle organization / lysosome organization / 1-phosphatidylinositol-3-kinase activity / regulation of synaptic vesicle exocytosis / cytoplasmic pattern recognition receptor signaling pathway / mitotic metaphase chromosome alignment / Macroautophagy / positive regulation of cardiac muscle hypertrophy / RSV-host interactions / phosphatidylinositol-mediated signaling / p38MAPK cascade / phosphatidylinositol phosphate biosynthetic process / autolysosome / Synthesis of PIPs at the plasma membrane / positive regulation of exocytosis / Respiratory syncytial virus (RSV) attachment and entry / autophagosome membrane / chromosome, centromeric region / synaptic vesicle endocytosis / autophagosome assembly / PI3K Cascade / axoneme / autophagosome maturation / RHO GTPases Activate NADPH Oxidases / response to vitamin E / negative regulation of reactive oxygen species metabolic process / amyloid-beta metabolic process / regulation of macroautophagy / canonical Wnt signaling pathway / phosphatidylinositol 3-kinase binding / neuron development / cellular defense response / membrane scission GTPase motor activity / phagocytosis / cellular response to glucose starvation / positive regulation of intrinsic apoptotic signaling pathway / mitophagy / phagocytic vesicle / positive regulation of 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 / small GTPase Rab1 family 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 / Ran (Ras-related nuclear proteins) /TC4 subfamily of small GTPases / C2 domain superfamily / Rho (Ras homology) subfamily of Ras-like small GTPases / Ras subfamily of RAS small GTPases / Small GTPase / Ras family / Rab subfamily of small GTPases / Armadillo-like helical / Small GTP-binding protein domain / Armadillo-type fold / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / 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 / P-loop containing nucleoside triphosphate hydrolase Similarity search - Domain/homology
Ras-related protein Rab-5A / Beclin-1 / Phosphatidylinositol 3-kinase catalytic subunit type 3 / Phosphoinositide 3-kinase regulatory subunit 4 / UV radiation resistance-associated gene protein Similarity search - Component
Biological species
Homo sapiens (human)
Method
subtomogram averaging / cryo EM / Resolution: 9.8 Å
Journal: Nat Commun / Year: 2021 Title: Structural basis for VPS34 kinase activation by Rab1 and Rab5 on membranes. Authors: Shirley Tremel / Yohei Ohashi / Dustin R Morado / Jessie Bertram / Olga Perisic / Laura T L Brandt / Marie-Kristin von Wrisberg / Zhuo A Chen / Sarah L Maslen / Oleksiy Kovtun / Mark Skehel ...Authors: Shirley Tremel / Yohei Ohashi / Dustin R Morado / Jessie Bertram / Olga Perisic / Laura T L Brandt / Marie-Kristin von Wrisberg / Zhuo A Chen / Sarah L Maslen / Oleksiy Kovtun / Mark Skehel / Juri Rappsilber / Kathrin Lang / Sean Munro / John A G Briggs / Roger L Williams / Abstract: The lipid phosphatidylinositol-3-phosphate (PI3P) is a regulator of two fundamental but distinct cellular processes, endocytosis and autophagy, so its generation needs to be under precise temporal ...The lipid phosphatidylinositol-3-phosphate (PI3P) is a regulator of two fundamental but distinct cellular processes, endocytosis and autophagy, so its generation needs to be under precise temporal and spatial control. PI3P is generated by two complexes that both contain the lipid kinase VPS34: complex II on endosomes (VPS34/VPS15/Beclin 1/UVRAG), and complex I on autophagosomes (VPS34/VPS15/Beclin 1/ATG14L). The endosomal GTPase Rab5 binds complex II, but the mechanism of VPS34 activation by Rab5 has remained elusive, and no GTPase is known to bind complex I. Here we show that Rab5a-GTP recruits endocytic complex II to membranes and activates it by binding between the VPS34 C2 and VPS15 WD40 domains. Electron cryotomography of complex II on Rab5a-decorated vesicles shows that the VPS34 kinase domain is released from inhibition by VPS15 and hovers over the lipid bilayer, poised for catalysis. We also show that the GTPase Rab1a, which is known to be involved in autophagy, recruits and activates the autophagy-specific complex I, but not complex II. Both Rabs bind to the same VPS34 interface but in a manner unique for each. These findings reveal how VPS34 complexes are activated on membranes by specific Rab GTPases and how they are recruited to unique cellular locations.
History
Deposition
Jan 17, 2021
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Header (metadata) release
Mar 3, 2021
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Map release
Mar 3, 2021
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Update
May 1, 2024
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Current status
May 1, 2024
Processing site: PDBe / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
Download / File: emd_12214.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotation
Subtomogram averaging reconstruction of human complex II-BATS bound to membrane-attached Rab5a-GTP at 9.8A with the membrane masked out after local-denoising with the LAFTER algorithm
Entire : human VPS34 complex II (VPS34-VPS15-Beclin1-UVRAG) bound to human...
Entire
Name: human VPS34 complex II (VPS34-VPS15-Beclin1-UVRAG) bound to human Rab5a
Components
Complex: human VPS34 complex II (VPS34-VPS15-Beclin1-UVRAG) bound to human Rab5a
Complex: human VPS34 complex II (VPS34-VPS15-Beclin1-UVRAG)
Protein or peptide: UV radiation resistance-associated gene protein
Protein or peptide: Phosphatidylinositol 3-kinase catalytic subunit type 3
Protein or peptide: Phosphoinositide 3-kinase regulatory subunit 4
Protein or peptide: Beclin-1
Protein or peptide: unknown peptide
Complex: Ras-related protein Rab-5A
Protein or peptide: Ras-related protein Rab-5A
Ligand: GUANOSINE-5'-TRIPHOSPHATE
Ligand: MAGNESIUM ION
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Supramolecule #1: human VPS34 complex II (VPS34-VPS15-Beclin1-UVRAG) bound to human...
Supramolecule
Name: human VPS34 complex II (VPS34-VPS15-Beclin1-UVRAG) bound to human Rab5a type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#6 Details: The subunits were expressed using transient transfection in HEK293T cells. Cells were transfected with three plasmids: pYO1025 (encoding VPS34 and VPS15 in a pCAG backbone), pYO1124 ...Details: The subunits were expressed using transient transfection in HEK293T cells. Cells were transfected with three plasmids: pYO1025 (encoding VPS34 and VPS15 in a pCAG backbone), pYO1124 (encoding UVGRAG 1-464 fused to the BATS of ATG14, residues 413-492 in pVAG) and pYO1006 (Beclin1 in pCAG)
Molecular weight
Theoretical: 392615 kDa/nm
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Supramolecule #2: human VPS34 complex II (VPS34-VPS15-Beclin1-UVRAG)
Supramolecule
Name: human VPS34 complex II (VPS34-VPS15-Beclin1-UVRAG) / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1-#5
chain_id: A, source_name: PDB, initial_model_type: experimental model
Details
An initial model was build with SWISSMODEL. using 5DFZ, 4DDP and 3IHY. This was then fit manually to density while running restrained MD with ISOLDE. The model was refined in REFMAC with self-restraints (4.3) and restraints to 3MJH, 4DDP and 3IHY.
Refinement
Space: REAL / Protocol: FLEXIBLE FIT / Overall B value: 320 / Target criteria: correlation
Output model
PDB-7bl1: human complex II-BATS bound to membrane-attached Rab5a-GTP
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