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- EMDB-37086: Cryo-EM structure of human ATG2A-WIPI4 complex -

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Basic information

Entry
Database: EMDB / ID: EMD-37086
TitleCryo-EM structure of human ATG2A-WIPI4 complex
Map dataHalf map A of ATG2A-WIPI4 complex
Sample
  • Complex: ATG2A-WIPI4 complex
    • Protein or peptide: WD repeat domain phosphoinositide-interacting protein 4
    • Protein or peptide: Autophagy-related protein 2 homolog A
KeywordsLipid transport / ATG2A-WIPI4 complex / single particle cryo-EM / Peripheral membrane proteins / LIPID TRANSPORT-MEMBRANE PROTEIN complex
Function / homology
Function and homology information


phagophore / lipid transfer activity / organelle membrane contact site / glycophagy / phosphatidylinositol phosphate binding / nucleophagy / positive regulation of autophagosome assembly / protein localization to phagophore assembly site / phagophore assembly site membrane / autophagy of mitochondrion ...phagophore / lipid transfer activity / organelle membrane contact site / glycophagy / phosphatidylinositol phosphate binding / nucleophagy / positive regulation of autophagosome assembly / protein localization to phagophore assembly site / phagophore assembly site membrane / autophagy of mitochondrion / pexophagy / piecemeal microautophagy of the nucleus / phosphatidylinositol-3-phosphate binding / phagophore assembly site / phosphatidylinositol-3,5-bisphosphate binding / reticulophagy / Macroautophagy / autophagosome assembly / protein-membrane adaptor activity / positive regulation of autophagy / lipid droplet / cellular response to starvation / autophagy / protein-macromolecule adaptor activity / endoplasmic reticulum membrane / protein kinase binding / cytosol
Similarity search - Function
Autophagy-related protein 2/VPS13, C-terminal / Autophagy-related protein 2 / : / Vacuolar protein sorting-associated protein 13-like, N-terminal domain / VPS13-like family N-terminal region / : / 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 / WD repeat domain phosphoinositide-interacting protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.23 Å
AuthorsWang Y / Stjepanovic G
Funding support China, 2 items
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
DepositionAug 4, 2023-
Header (metadata) releaseAug 7, 2024-
Map releaseAug 7, 2024-
UpdateJan 29, 2025-
Current statusJan 29, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_37086.png

Downloads & links

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Map

FileDownload / File: emd_37086.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationHalf map A of ATG2A-WIPI4 complex
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 512 pix.
= 435.2 Å		0.85 Å/pix.
x 512 pix.
= 435.2 Å		0.85 Å/pix.
x 512 pix.
= 435.2 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.85 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.411
Minimum - Maximum-2.212561 - 3.3918488
Average (Standard dev.)0.0002103072 (±0.033116974)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 435.2 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half map B of ATG2A-WIPI4 complex

Fileemd_37086_half_map_1.map
AnnotationHalf map B of ATG2A-WIPI4 complex
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map B of ATG2A-WIPI4 complex

Fileemd_37086_half_map_2.map
AnnotationHalf map B of ATG2A-WIPI4 complex
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : ATG2A-WIPI4 complex

EntireName: ATG2A-WIPI4 complex
Components
  • Complex: ATG2A-WIPI4 complex
    • Protein or peptide: WD repeat domain phosphoinositide-interacting protein 4
    • Protein or peptide: Autophagy-related protein 2 homolog A

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Supramolecule #1: ATG2A-WIPI4 complex

SupramoleculeName: ATG2A-WIPI4 complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 253 KDa

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Macromolecule #1: WD repeat domain phosphoinositide-interacting protein 4

MacromoleculeName: WD repeat domain phosphoinositide-interacting protein 4
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 39.916539 KDa
Recombinant expressionOrganism: Baculovirus expression vector pFastBac1-HM
SequenceString: MTQQPLRGVT SLRFNQDQSC FCCAMETGVR IYNVEPLMEK GHLDHEQVGS MGLVEMLHRS NLLALVGGGS SPKFSEISVL IWDDAREGK DSKEKLVLEF TFTKPVLSVR MRHDKIVIVL KNRIYVYSFP DNPRKLFEFD TRDNPKGLCD LCPSLEKQLL V FPGHKCGS ...String:
MTQQPLRGVT SLRFNQDQSC FCCAMETGVR IYNVEPLMEK GHLDHEQVGS MGLVEMLHRS NLLALVGGGS SPKFSEISVL IWDDAREGK DSKEKLVLEF TFTKPVLSVR MRHDKIVIVL KNRIYVYSFP DNPRKLFEFD TRDNPKGLCD LCPSLEKQLL V FPGHKCGS LQLVDLASTK PGTSSAPFTI NAHQSDIACV SLNQPGTVVA SASQKGTLIR LFDTQSKEKL VELRRGTDPA TL YCINFSH DSSFLCASSD KGTVHIFALK DTRLNRRSAL ARVGKVGPMI GQYVDSQWSL ASFTVPAESA CICAFGRNTS KNV NSVIAI CVDGTFHKYV FTPDGNCNRE AFDVYLDICD DDDF

UniProtKB: WD repeat domain phosphoinositide-interacting protein 4

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Macromolecule #2: Autophagy-related protein 2 homolog A

MacromoleculeName: Autophagy-related protein 2 homolog A / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 213.100281 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MSRWLWPWSN CVKERVCRYL LHHYLGHFFQ EHLSLDQLSL DLYKGSVALR DIHLEIWSVN EVLESMESPL ELVEGFVGSI EVAVPWAAL LTDHCTVRVS GLQLTLQPRR GPAPGAADSQ SWASCMTTSL QLAQECLRDG LPEPSEPPQP LEGLEMFAQT I ETVLRRIK ...String:
MSRWLWPWSN CVKERVCRYL LHHYLGHFFQ EHLSLDQLSL DLYKGSVALR DIHLEIWSVN EVLESMESPL ELVEGFVGSI EVAVPWAAL LTDHCTVRVS GLQLTLQPRR GPAPGAADSQ SWASCMTTSL QLAQECLRDG LPEPSEPPQP LEGLEMFAQT I ETVLRRIK VTFLDTVVRV EHSPGDGERG VAVEVRVQRL EYCDEAVRDP SQAPPVDVHQ PPAFLHKLLQ LAGVRLHYEE LP AQEEPPE PPLQIGSCSG YMELMVKLKQ NEAFPGPKLE VAGQLGSLHL LLTPRQLQQL QELLSAVSLT DHEGLADKLN KSR PLGAED LWLIEQDLNQ QLQAGAVAEP LSPDPLTNPL LNLDNTDLFF SMAGLTSSVA SALSELSLSD VDLASSVRSD MASR RLSAQ AHPAGKMAPN PLLDTMRPDS LLKMTLGGVT LTLLQTSAPS SGPPDLATHF FTEFDATKDG PFGSRDFHHL RPRFQ RACP CSHVRLTGTA VQLSWELRTG SRGRRTTSME VHFGQLEVLE CLWPRGTSEP EYTEILTFPG TLGSQASARP CAHLRH TQI LRRVPKSRPR RSVACHCHSE LALDLANFQA DVELGALDRL AALLRLATVP AEPPAGLLTE PLPAMEQQTV FRLSAPR AT LRLRFPIADL RPEPDPWAGQ AVRAEQLRLE LSEPQFRSEL SSGPGPPVPT HLELTCSDLH GIYEDGGKPP VPCLRVSK A LDPKSTGRKY FLPQVVVTVN PQSSSTQWEV APEKGEELEL SVESPCELRE PEPSPFSSKR TMYETEEMVI PGDPEEMRT FQSRTLALSR CSLEVILPSV HIFLPSKEVY ESIYNRINND LLMWEPADLL PTPDPAAQPS GFPGPSGFWH DSFKMCKSAF KLANCFDLT PDSDSDDEDA HFFSVGASGG PQAAAPEAPS LHLQSTFSTL VTVLKGRITA LCETKDEGGK RLEAVHGELV L DMEHGTLF SVSQYCGQPG LGYFCLEAEK ATLYHRAAVD DYPLPSHLDL PSFAPPAQLA PTIYPSEEGV TERGASGRKG QG RGPHMLS TAVRIHLDPH KNVKEFLVTL RLHKATLRHY MALPEQSWHS QLLEFLDVLD DPVLGYLPPT VITILHTHLF SCS VDYRPL YLPVRVLITA ETFTLSSNII MDTSTFLLRF ILDDSALYLS DKCEVETLDL RRDYVCVLDV DLLELVIKTW KGST EGKLS QPLFELRCSN NVVHVHSCAD SCALLVNLLQ YVMSTGDLHP PPRPPSPTEI AGQKLSESPA SLPSCPPVET ALINQ RDLA DALLDTERSL RELAQPSGGH LPQASPISVY LFPGERSGAP PPSPPVGGPA GSLGSCSEEK EDEREEEGDG DTLDSD EFC ILDAPGLGIP PRDGEPVVTQ LHPGPIVVRD GYFSRPIGST DLLRAPAHFP VPSTRVVLRE VSLVWHLYGG RDFGPHP GH RARTGLSGPR SSPSRCSGPN RPQNSWRTQG GSGRQHHVLM EIQLSKVSFQ HEVYPAEPAT GPAAPSQELE ERPLSRQV F IVQELEVRDR LASSQINKFL YLHTSERMPR RAHSNMLTIK ALHVAPTTNL GGPECCLRVS LMPLRLNVDQ DALFFLKDF FTSLVAGINP VVPGETSAEA RPETRAQPSS PLEGQAEGVE TTGSQEAPGG GHSPSPPDQQ PIYFREFRFT SEVPIWLDYH GKHVTMDQV GTFAGLLIGL AQLNCSELKL KRLCCRHGLL GVDKVLGYAL NEWLQDIRKN QLPGLLGGVG PMHSVVQLFQ G FRDLLWLP IEQYRKDGRL MRGLQRGAAS FGSSTASAAL ELSNRLVQAI QATAETVYDI LSPAAPVSRS LQDKRSARRL RR GQQPADL REGVAKAYDT VREGILDTAQ TICDVASRGH EQKGLTGAVG GVIRQLPPTV VKPLILATEA TSSLLGGMRN QIV PDAHKD HALKWRSDSA QD

UniProtKB: Autophagy-related protein 2 homolog A

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 61.65 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 100.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.2 µm / Nominal magnification: 105000
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.23 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 294088
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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