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- EMDB-32066: Cryo-EM structure of the human ATP13A2 (E1-ATP state) -

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Basic information

Entry
Database: EMDB / ID: EMD-32066
TitleCryo-EM structure of the human ATP13A2 (E1-ATP state)
Map datapostprocess_masked.mrc from Relion
Sample
  • Complex: ATP13A2
    • Protein or peptide: Polyamine-transporting ATPase 13A2
  • Ligand: PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER
  • Ligand: MAGNESIUM ION
KeywordsATP13A2 / PARK9 / P-type ATPase / MEMBRANE PROTEIN
Function / homology
Function and homology information


polyamine transmembrane transporter activity / polyamine transmembrane transport / spermine transmembrane transport / peptidyl-aspartic acid autophosphorylation / regulation of ubiquitin-specific protease activity / ABC-type polyamine transporter activity / regulation of autophagosome size / extracellular exosome biogenesis / P-type ion transporter activity / regulation of chaperone-mediated autophagy ...polyamine transmembrane transporter activity / polyamine transmembrane transport / spermine transmembrane transport / peptidyl-aspartic acid autophosphorylation / regulation of ubiquitin-specific protease activity / ABC-type polyamine transporter activity / regulation of autophagosome size / extracellular exosome biogenesis / P-type ion transporter activity / regulation of chaperone-mediated autophagy / negative regulation of lysosomal protein catabolic process / regulation of autophagy of mitochondrion / regulation of lysosomal protein catabolic process / intracellular monoatomic cation homeostasis / autophagosome-lysosome fusion / autophagosome organization / protein localization to lysosome / phosphatidic acid binding / positive regulation of exosomal secretion / multivesicular body membrane / ATPase-coupled monoatomic cation transmembrane transporter activity / intracellular zinc ion homeostasis / regulation of protein localization to nucleus / Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate / cupric ion binding / regulation of mitochondrion organization / regulation of endopeptidase activity / lysosomal transport / phosphatidylinositol-3,5-bisphosphate binding / cellular response to zinc ion / regulation of intracellular protein transport / lipid homeostasis / Ion transport by P-type ATPases / autophagosome membrane / cellular response to manganese ion / regulation of macroautophagy / regulation of neuron apoptotic process / transport vesicle / autophagosome / multivesicular body / lysosomal lumen / positive regulation of protein secretion / transmembrane transport / autophagy / intracellular calcium ion homeostasis / late endosome / late endosome membrane / manganese ion binding / cellular response to oxidative stress / monoatomic ion transmembrane transport / intracellular iron ion homeostasis / vesicle / protein autophosphorylation / lysosome / neuron projection / lysosomal membrane / neuronal cell body / positive regulation of gene expression / ATP hydrolysis activity / zinc ion binding / ATP binding / membrane
Similarity search - Function
: / : / P5-type ATPase cation transporter / P-type ATPase, subfamily V / E1-E2 ATPase / P-type ATPase, haloacid dehalogenase domain / P-type ATPase, phosphorylation site / P-type ATPase, cytoplasmic domain N / E1-E2 ATPases phosphorylation site. / P-type ATPase, A domain superfamily ...: / : / P5-type ATPase cation transporter / P-type ATPase, subfamily V / E1-E2 ATPase / P-type ATPase, haloacid dehalogenase domain / P-type ATPase, phosphorylation site / P-type ATPase, cytoplasmic domain N / E1-E2 ATPases phosphorylation site. / P-type ATPase, A domain superfamily / P-type ATPase / P-type ATPase, transmembrane domain superfamily / HAD superfamily / HAD-like superfamily
Similarity search - Domain/homology
Polyamine-transporting ATPase 13A2
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsTomita A / Yamashita K / Nishizawa T / Nureki O
Funding support Japan, 3 items
OrganizationGrant numberCountry
Japan Society for the Promotion of Science (JSPS)16H06294 Japan
Japan Society for the Promotion of Science (JSPS)20H03216 Japan
Japan Agency for Medical Research and Development (AMED)JP19am01011115 Japan
CitationJournal: Mol Cell / Year: 2021
Title: Cryo-EM reveals mechanistic insights into lipid-facilitated polyamine export by human ATP13A2.
Authors: Atsuhiro Tomita / Takashi Daiho / Tsukasa Kusakizako / Keitaro Yamashita / Satoshi Ogasawara / Takeshi Murata / Tomohiro Nishizawa / Osamu Nureki /
Abstract: The cytoplasmic polyamine maintains cellular homeostasis by chelating toxic metal cations, regulating transcriptional activity, and protecting DNA. ATP13A2 was identified as a lysosomal polyamine ...The cytoplasmic polyamine maintains cellular homeostasis by chelating toxic metal cations, regulating transcriptional activity, and protecting DNA. ATP13A2 was identified as a lysosomal polyamine exporter responsible for polyamine release into the cytosol, and its dysfunction is associated with Alzheimer's disease and other neural degradation diseases. ATP13A2 belongs to the P5 subfamily of the P-type ATPase family, but its mechanisms remain unknown. Here, we report the cryoelectron microscopy (cryo-EM) structures of human ATP13A2 under four different conditions, revealing the structural coupling between the polyamine binding and the dephosphorylation. Polyamine is bound at the luminal tunnel and recognized through numerous electrostatic and π-cation interactions, explaining its broad specificity. The unique N-terminal domain is anchored to the lipid membrane to stabilize the E2P conformation, thereby accelerating the E1P-to-E2P transition. These findings reveal the distinct mechanism of P5B ATPases, thereby paving the way for neuroprotective therapy by activating ATP13A2.
History
DepositionOct 17, 2021-
Header (metadata) releaseDec 29, 2021-
Map releaseDec 29, 2021-
UpdateJun 19, 2024-
Current statusJun 19, 2024Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.0359
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.0359
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7vpi
  • Surface level: 0.0359
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_32066.png

Downloads & links

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Map

FileDownload / File: emd_32066.map.gz / Format: CCP4 / Size: 6.3 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationpostprocess_masked.mrc from Relion
Projections & slices

Image control

Size
Brightness
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.52 Å/pix.
x 118 pix.
= 179.09 Å		1.52 Å/pix.
x 118 pix.
= 179.09 Å		1.52 Å/pix.
x 118 pix.
= 179.09 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.51771 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0359 / Movie #1: 0.0359
Minimum - Maximum-0.4135384 - 0.5884178
Average (Standard dev.)0.00068172015 (±0.0128142685)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions118118118
Spacing118118118
CellA=B=C: 179.08978 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.51771186440681.51771186440681.5177118644068
M x/y/z118118118
origin x/y/z0.0000.0000.000
length x/y/z179.090179.090179.090
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ480480480
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS118118118
D min/max/mean-0.4140.5880.001

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Supplemental data

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Mask #1

Fileemd_32066_msk_1.map
Projections & Slices
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Half map: run half1 class001.mrc

Fileemd_32066_half_map_1.map
Annotationrun_half1_class001.mrc
Projections & Slices
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Histogram (log scale)

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Half map: run half2 class001.mrc

Fileemd_32066_half_map_2.map
Annotationrun_half2_class001.mrc
Projections & Slices
AxesZYX

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Sample components

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Entire : ATP13A2

EntireName: ATP13A2
Components
  • Complex: ATP13A2
    • Protein or peptide: Polyamine-transporting ATPase 13A2
  • Ligand: PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER
  • Ligand: MAGNESIUM ION

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Supramolecule #1: ATP13A2

SupramoleculeName: ATP13A2 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 / Details: Human ATP13A2 in complex with AMPPCP
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Polyamine-transporting ATPase 13A2

MacromoleculeName: Polyamine-transporting ATPase 13A2 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
EC number: Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 129.313391 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: GPSRMSADSS PLVGSTPTGY GTLTIGTSID PLSSSVSSVR LSGYCGSPWR VIGYHVVVWM MAGIPLLLFR WKPLWGVRLR LRPCNLAHA ETLVIEIRDK EDSSWQLFTV QVQTEAIGEG SLEPSPQSQA EDGRSQAAVG AVPEGAWKDT AQLHKSEEAV S VGQKRVLR ...String:
GPSRMSADSS PLVGSTPTGY GTLTIGTSID PLSSSVSSVR LSGYCGSPWR VIGYHVVVWM MAGIPLLLFR WKPLWGVRLR LRPCNLAHA ETLVIEIRDK EDSSWQLFTV QVQTEAIGEG SLEPSPQSQA EDGRSQAAVG AVPEGAWKDT AQLHKSEEAV S VGQKRVLR YYLFQGQRYI WIETQQAFYQ VSLLDHGRSC DDVHRSRHGL SLQDQMVRKA IYGPNVISIP VKSYPQLLVD EA LNPYYGF QAFSIALWLA DHYYWYALCI FLISSISICL SLYKTRKQSQ TLRDMVKLSM RVCVCRPGGE EEWVDSSELV PGD CLVLPQ EGGLMPCDAA LVAGECMVNE SSLTGESIPV LKTALPEGLG PYCAETHRRH TLFCGTLILQ ARAYVGPHVL AVVT RTGFC TAKGGLVSSI LHPRPINFKF YKHSMKFVAA LSVLALLGTI YSIFILYRNR VPLNEIVIRA LDLVTVVVPP ALPAA MTVC TLYAQSRLRR QGIFCIHPLR INLGGKLQLV CFDKTGTLTE DGLDVMGVVP LKGQAFLPLV PEPRRLPVGP LLRALA TCH ALSRLQDTPV GDPMDLKMVE STGWVLEEEP AADSAFGTQV LAVMRPPLWE PQLQAMEEPP VPVSVLHRFP FSSALQR MS VVVAWPGATQ PEAYVKGSPE LVAGLCNPET VPTDFAQMLQ SYTAAGYRVV ALASKPLPTV PSLEAAQQLT RDTVEGDL S LLGLLVMRNL LKPQTTPVIQ ALRRTRIRAV MVTGDNLQTA VTVARGCGMV APQEHLIIVH ATHPERGQPA SLEFLPMES PTAVNGVKDP DQAASYTVEP DPRSRHLALS GPTFGIIVKH FPKLLPKVLV QGTVFARMAP EQKTELVCEL QKLQYCVGMC GDGANDCGA LKAADVGISL SQAEASVVSP FTSSMASIEC VPMVIREGRC SLDTSFSVFK YMALYSLTQF ISVLILYTIN T NLGDLQFL AIDLVITTTV AVLMSRTGPA LVLGRVRPPG ALLSVPVLSS LLLQMVLVTG VQLGGYFLTL AQPWFVPLNR TV AAPDNLP NYENTVVFSL SSFQYLILAA AVSKGAPFRR PLYTNVPFLV ALALLSSVLV GLVLVPGLLQ GPLALRNITD TGF KLLLLG LVTLNFVGAF MLESVLDQCL PACLRRLRPK RASKKRFKQL ERELAEQPWP PLPAGPLR

UniProtKB: Polyamine-transporting ATPase 13A2

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Macromolecule #2: PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER

MacromoleculeName: PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER / type: ligand / ID: 2 / Number of copies: 1 / Formula: ACP
Molecular weightTheoretical: 505.208 Da
Chemical component information

ChemComp-ACP:
PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER / AMP-PCP, energy-carrying molecule analogue*YM

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Macromolecule #3: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 3 / Number of copies: 1 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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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

Concentration10 mg/mL
BufferpH: 8
GridModel: Quantifoil R1.2/1.3 / Material: COPPER/RHODIUM / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY ARRAY
VitrificationCryogen name: ETHANE / Chamber humidity: 100 %

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.1) / Number images used: 3114
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.1)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.1)
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: RECIPROCAL / Protocol: AB INITIO MODEL
Output model

PDB-7vpi:
Cryo-EM structure of the human ATP13A2 (E1-ATP state)

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