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- PDB-8y1l: Cryo-EM structure of human N-terminally bound ATG9A-ATG2A-WIPI4 c... -

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Basic information

Entry
Database: PDB / ID: 8y1l
TitleCryo-EM structure of human N-terminally bound ATG9A-ATG2A-WIPI4 complex
Components
  • Autophagy-related protein 2 homolog A
  • Autophagy-related protein 9A
  • WD repeat domain phosphoinositide-interacting protein 4
KeywordsLIPID TRANSPORT / Lipid transfer / ATG9A-ATG2A-WIPI4 complex / single particle cryo-EM / autophagy / LIPID TRANSPORT/MEMBRANE PROTEIN / LIPID TRANSPORT-MEMBRANE PROTEIN complex
Function / homology
Function and homology information


phagophore / lipid transfer activity / organelle membrane contact site / phosphatidylinositol phosphate binding / glycophagy / negative regulation of macrophage cytokine production / phospholipid scramblase activity / nucleophagy / protein localization to Golgi apparatus / programmed necrotic cell death ...phagophore / lipid transfer activity / organelle membrane contact site / phosphatidylinositol phosphate binding / glycophagy / negative regulation of macrophage cytokine production / phospholipid scramblase activity / nucleophagy / protein localization to Golgi apparatus / programmed necrotic cell death / positive regulation of autophagosome assembly / protein localization to phagophore assembly site / phagophore assembly site membrane / pexophagy / autophagy of mitochondrion / piecemeal microautophagy of the nucleus / negative regulation of interferon-beta production / phosphatidylinositol-3-phosphate binding / bone morphogenesis / phagophore assembly site / phosphatidylinositol-3,5-bisphosphate binding / reticulophagy / Macroautophagy / autophagosome assembly / mitophagy / protein-membrane adaptor activity / lipid droplet / positive regulation of autophagy / autophagosome / synaptic membrane / cellular response to starvation / PINK1-PRKN Mediated Mitophagy / trans-Golgi network / recycling endosome / mitochondrial membrane / autophagy / recycling endosome membrane / late endosome membrane / late endosome / protein-macromolecule adaptor activity / endosome / Golgi membrane / innate immune response / intracellular membrane-bounded organelle / endoplasmic reticulum membrane / protein kinase binding / Golgi apparatus / mitochondrion / membrane / cytosol
Similarity search - Function
Autophagy-related protein 2 / Autophagy-related protein 2 / Autophagy-related protein 9 / Autophagy protein ATG9 / : / PROPPIN / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
Autophagy-related protein 2 homolog A / Autophagy-related protein 9A / WD repeat domain phosphoinositide-interacting protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 7.05 Å
AuthorsWang, Y. / Stjepanovic, G.
Funding support China, 2items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)31950410540 China
Ministry of Science and Technology (MoST, China)QN2021032004L China
CitationJournal: Nat Struct Mol Biol / Year: 2025
Title: Structural basis for lipid transfer by the ATG2A-ATG9A complex.
Authors: Yang Wang / Selma Dahmane / Rujuan Ti / Xinyi Mai / Lizhe Zhu / Lars-Anders Carlson / Goran Stjepanovic /
Abstract: Autophagy is characterized by the formation of double-membrane vesicles called autophagosomes. Autophagy-related proteins (ATGs) 2A and 9A have an essential role in autophagy by mediating lipid ...Autophagy is characterized by the formation of double-membrane vesicles called autophagosomes. Autophagy-related proteins (ATGs) 2A and 9A have an essential role in autophagy by mediating lipid transfer and re-equilibration between membranes for autophagosome formation. Here we report the cryo-electron microscopy structures of human ATG2A in complex with WD-repeat protein interacting with phosphoinositides 4 (WIPI4) at 3.2 Å and the ATG2A-WIPI4-ATG9A complex at 7 Å global resolution. On the basis of molecular dynamics simulations, we propose a mechanism of lipid extraction from the donor membranes. Our analysis revealed 3:1 stoichiometry of the ATG9A-ATG2A complex, directly aligning the ATG9A lateral pore with ATG2A lipid transfer cavity, and an interaction of the ATG9A trimer with both the N-terminal and the C-terminal tip of rod-shaped ATG2A. Cryo-electron tomography of ATG2A liposome-binding states showed that ATG2A tethers lipid vesicles at different orientations. In summary, this study provides a molecular basis for the growth of the phagophore membrane and lends structural insights into spatially coupled lipid transport and re-equilibration during autophagosome formation.
History
DepositionJan 25, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Sep 4, 2024Provider: repository / Type: Initial release
Revision 1.1Feb 5, 2025Group: Data collection / Database references / Structure summary
Category: citation / citation_author ...citation / citation_author / em_admin / pdbx_entry_details
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
C: Autophagy-related protein 9A
D: Autophagy-related protein 9A
E: Autophagy-related protein 9A
A: WD repeat domain phosphoinositide-interacting protein 4
B: Autophagy-related protein 2 homolog A


Theoretical massNumber of molelcules
Total (without water)536,6705
Polymers536,6705
Non-polymers00
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

#1: Protein Autophagy-related protein 9A / APG9-like 1 / mATG9


Mass: 94551.031 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ATG9A, APG9L1 / Production host: Homo sapiens (human) / References: UniProt: Q7Z3C6
#2: Protein WD repeat domain phosphoinositide-interacting protein 4 / WIPI-4 / WD repeat-containing protein 45


Mass: 39916.539 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: WDR45, WDRX1, WDRXI4, WIPI4, JM5 / Production host: Baculovirus expression vector pFastBac1-HM / References: UniProt: Q9Y484
#3: Protein Autophagy-related protein 2 homolog A


Mass: 213100.281 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ATG2A, KIAA0404 / Production host: Homo sapiens (human) / References: UniProt: Q2TAZ0
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: N-terminally bound ATG9A-ATG2A-WIPI4 complex / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 0.536 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
SpecimenEmbedding 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 / Nominal defocus max: 1800 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 51.46 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 7.05 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 232894 / Symmetry type: POINT

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