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- EMDB-38839: Cryo-EM structure of human N-terminally bound ATG9A-ATG2A-WIPI4 c... -

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Basic information

Entry
Database: EMDB / ID: EMD-38839
TitleCryo-EM structure of human N-terminally bound ATG9A-ATG2A-WIPI4 complex
Map dataThe cryo-EM map of N-terminally bound ATG9A-ATG2A-WIPI4 complex.
Sample
  • Complex: N-terminally bound ATG9A-ATG2A-WIPI4 complex
    • Protein or peptide: Autophagy-related protein 9A
    • Protein or peptide: WD repeat domain phosphoinositide-interacting protein 4
    • Protein or peptide: Autophagy-related protein 2 homolog A
KeywordsLipid transfer / ATG9A-ATG2A-WIPI4 complex / single particle cryo-EM / autophagy / LIPID TRANSPORT/MEMBRANE PROTEIN / LIPID TRANSPORT-MEMBRANE PROTEIN complex / LIPID TRANSPORT
Function / homology
Function and homology information


phagophore / lipid transfer activity / organelle membrane contact site / phosphatidylinositol phosphate binding / phospholipid scramblase activity / glycophagy / nucleophagy / programmed necrotic cell death / positive regulation of autophagosome assembly / protein localization to phagophore assembly site ...phagophore / lipid transfer activity / organelle membrane contact site / phosphatidylinositol phosphate binding / phospholipid scramblase activity / glycophagy / nucleophagy / programmed necrotic cell death / positive regulation of autophagosome assembly / protein localization to phagophore assembly site / phagophore assembly site membrane / piecemeal microautophagy of the nucleus / phosphatidylinositol-3-phosphate binding / phagophore assembly site / bone morphogenesis / phosphatidylinositol-3,5-bisphosphate binding / reticulophagy / extrinsic component of membrane / autophagy of mitochondrion / Macroautophagy / autophagosome assembly / protein-membrane adaptor activity / cellular response to starvation / lipid droplet / autophagosome / PINK1-PRKN Mediated Mitophagy / mitochondrial membrane / trans-Golgi network / recycling endosome / autophagy / recycling endosome membrane / late endosome membrane / late endosome / endosome / Golgi membrane / intracellular membrane-bounded organelle / endoplasmic reticulum membrane / protein kinase binding / Golgi apparatus / mitochondrion / membrane / 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 / Autophagy-related protein 9 / Autophagy protein ATG9 / : / PROPPIN / WD40 repeats ...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 / 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)
Methodsingle particle reconstruction / cryo EM / Resolution: 7.05 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
DepositionJan 25, 2024-
Header (metadata) releaseSep 4, 2024-
Map releaseSep 4, 2024-
UpdateFeb 5, 2025-
Current statusFeb 5, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_38839.png

Downloads & links

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Map

FileDownload / File: emd_38839.map.gz / Format: CCP4 / Size: 1.9 GB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationThe cryo-EM map of N-terminally bound ATG9A-ATG2A-WIPI4 complex.
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 800 pix.
= 680. Å		0.85 Å/pix.
x 800 pix.
= 680. Å		0.85 Å/pix.
x 800 pix.
= 680. 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: 0.18
Minimum - Maximum-0.6983396 - 1.5643307
Average (Standard dev.)-0.00021839672 (±0.013758918)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions800800800
Spacing800800800
CellA=B=C: 680.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : N-terminally bound ATG9A-ATG2A-WIPI4 complex

EntireName: N-terminally bound ATG9A-ATG2A-WIPI4 complex
Components
  • Complex: N-terminally bound ATG9A-ATG2A-WIPI4 complex
    • Protein or peptide: Autophagy-related protein 9A
    • 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: N-terminally bound ATG9A-ATG2A-WIPI4 complex

SupramoleculeName: N-terminally bound ATG9A-ATG2A-WIPI4 complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 536 KDa

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Macromolecule #1: Autophagy-related protein 9A

MacromoleculeName: Autophagy-related protein 9A / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 94.551031 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAQFDTEYQR LEASYSDSPP GEEDLLVHVA EGSKSPWHHI ENLDLFFSRV YNLHQKNGFT CMLIGEIFEL MQFLFVVAFT TFLVSCVDY DILFANKMVN HSLHPTEPVK VTLPDAFLPA QVCSARIQEN GSLITILVIA GVFWIHRLIK FIYNICCYWE I HSFYLHAL ...String:
MAQFDTEYQR LEASYSDSPP GEEDLLVHVA EGSKSPWHHI ENLDLFFSRV YNLHQKNGFT CMLIGEIFEL MQFLFVVAFT TFLVSCVDY DILFANKMVN HSLHPTEPVK VTLPDAFLPA QVCSARIQEN GSLITILVIA GVFWIHRLIK FIYNICCYWE I HSFYLHAL RIPMSALPYC TWQEVQARIV QTQKEHQICI HKRELTELDI YHRILRFQNY MVALVNKSLL PLRFRLPGLG EA VFFTRGL KYNFELILFW GPGSLFLNEW SLKAEYKRGG QRLELAQRLS NRILWIGIAN FLLCPLILIW QILYAFFSYA EVL KREPGA LGARCWSLYG RCYLRHFNEL EHELQSRLNR GYKPASKYMN CFLSPLLTLL AKNGAFFAGS ILAVLIALTI YDED VLAVE HVLTTVTLLG VTVTVCRSFI PDQHMVFCPE QLLRVILAHI HYMPDHWQGN AHRSQTRDEF AQLFQYKAVF ILEEL LSPI VTPLILIFCL RPRALEIIDF FRNFTVEVVG VGDTCSFAQM DVRQHGHPQW LSAGQTEASV YQQAEDGKTE LSLMHF AIT NPGWQPPRES TAFLGFLKEQ VQRDGAAASL AQGGLLPENA LFTSIQSLQS ESEPLSLIAN VVAGSSCRGP PLPRDLQ GS RHRAEVASAL RSFSPLQPGQ APTGRAHSTM TGSGVDARTA SSGSSVWEGQ LQSLVLSEYA STEMSLHALY MHQLHKQQ A QAEPERHVWH RRESDESGES APDEGGEGAR APQSIPRSAS YPCAAPRPGA PETTALHGGF QRRYGGITDP GTVPRVPSH FSRLPLGGWA EDGQSASRHP EPVPEEGSED ELPPQVHKV

UniProtKB: Autophagy-related protein 9A

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Macromolecule #2: WD repeat domain phosphoinositide-interacting protein 4

MacromoleculeName: WD repeat domain phosphoinositide-interacting protein 4
type: protein_or_peptide / ID: 2 / 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 #3: Autophagy-related protein 2 homolog A

MacromoleculeName: Autophagy-related protein 2 homolog A / type: protein_or_peptide / ID: 3 / 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: 8
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: 51.46 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 µm / Nominal defocus min: 1.2 µm
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: 7.05 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 232894
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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