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- EMDB-35388: Cryo-EM structure of ATP13A2 in the nominal E1P state -

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Basic information

Entry
Database: EMDB / ID: EMD-35388
TitleCryo-EM structure of ATP13A2 in the nominal E1P state
Map dataCryo-EM structure of ATP13A2 in the nominal E1P state
Sample
  • Complex: Cryo-EM structure of ATP13A2 in the nominal E1P state
    • Protein or peptide: Polyamine-transporting ATPase 13A2
  • Ligand: TETRAFLUOROALUMINATE ION
  • Ligand: MAGNESIUM ION
  • Ligand: SPERMINE
KeywordsCryo-EM structure of ATP13A2 in the nominal E1P state / Membrane protein / TRANSPORT 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: 3.78 Å
AuthorsLiu ZM / Mu JQ / Xue CY
Funding support China, 1 items
OrganizationGrant numberCountry
National Science Foundation (NSF, China) China
CitationJournal: Nat Commun / Year: 2023
Title: Conformational cycle of human polyamine transporter ATP13A2.
Authors: Jianqiang Mu / Chenyang Xue / Lei Fu / Zongjun Yu / Minhan Nie / Mengqi Wu / Xinmeng Chen / Kun Liu / Ruiqian Bu / Ying Huang / Baisheng Yang / Jianming Han / Qianru Jiang / Kevin C Chan / ...Authors: Jianqiang Mu / Chenyang Xue / Lei Fu / Zongjun Yu / Minhan Nie / Mengqi Wu / Xinmeng Chen / Kun Liu / Ruiqian Bu / Ying Huang / Baisheng Yang / Jianming Han / Qianru Jiang / Kevin C Chan / Ruhong Zhou / Huilin Li / Ancheng Huang / Yong Wang / Zhongmin Liu /
Abstract: Dysregulation of polyamine homeostasis strongly associates with human diseases. ATP13A2, which is mutated in juvenile-onset Parkinson's disease and autosomal recessive spastic paraplegia 78, is a ...Dysregulation of polyamine homeostasis strongly associates with human diseases. ATP13A2, which is mutated in juvenile-onset Parkinson's disease and autosomal recessive spastic paraplegia 78, is a transporter with a critical role in balancing the polyamine concentration between the lysosome and the cytosol. Here, to better understand human ATP13A2-mediated polyamine transport, we use single-particle cryo-electron microscopy to solve high-resolution structures of human ATP13A2 in six intermediate states, including the putative E2 structure for the P5 subfamily of the P-type ATPases. These structures comprise a nearly complete conformational cycle spanning the polyamine transport process and capture multiple substrate binding sites distributed along the transmembrane regions, suggesting a potential polyamine transport pathway. Integration of high-resolution structures, biochemical assays, and molecular dynamics simulations allows us to obtain a better understanding of the structural basis of how hATP13A2 transports polyamines, providing a mechanistic framework for ATP13A2-related diseases.
History
DepositionFeb 15, 2023-
Header (metadata) releaseDec 20, 2023-
Map releaseDec 20, 2023-
UpdateDec 20, 2023-
Current statusDec 20, 2023Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_35388.png

Downloads & links

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Map

FileDownload / File: emd_35388.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM structure of ATP13A2 in the nominal E1P state
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.1 Å/pix.
x 288 pix.
= 315.36 Å		1.1 Å/pix.
x 288 pix.
= 315.36 Å		1.1 Å/pix.
x 288 pix.
= 315.36 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.095 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.185
Minimum - Maximum-1.1808763 - 1.7042749
Average (Standard dev.)0.00048810837 (±0.030668112)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 315.36002 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: The half a map of ATP13A2 in the nominal E1P state

Fileemd_35388_half_map_1.map
AnnotationThe half_a map of ATP13A2 in the nominal E1P state
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: The half b map of ATP13A2 in the nominal E1P state

Fileemd_35388_half_map_2.map
AnnotationThe half_b map of ATP13A2 in the nominal E1P state
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Cryo-EM structure of ATP13A2 in the nominal E1P state

EntireName: Cryo-EM structure of ATP13A2 in the nominal E1P state
Components
  • Complex: Cryo-EM structure of ATP13A2 in the nominal E1P state
    • Protein or peptide: Polyamine-transporting ATPase 13A2
  • Ligand: TETRAFLUOROALUMINATE ION
  • Ligand: MAGNESIUM ION
  • Ligand: SPERMINE

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Supramolecule #1: Cryo-EM structure of ATP13A2 in the nominal E1P state

SupramoleculeName: Cryo-EM structure of ATP13A2 in the nominal E1P state / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
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: 128.914984 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MSADSSPLVG STPTGYGTLT IGTSIDPLSS SVSSVRLSGY CGSPWRVIGY HVVVWMMAGI PLLLFRWKPL WGVRLRLRPC NLAHAETLV IEIRDKEDSS WQLFTVQVQT EAIGEGSLEP SPQSQAEDGR SQAAVGAVPE GAWKDTAQLH KSEEAVSVGQ K RVLRYYLF ...String:
MSADSSPLVG STPTGYGTLT IGTSIDPLSS SVSSVRLSGY CGSPWRVIGY HVVVWMMAGI PLLLFRWKPL WGVRLRLRPC NLAHAETLV IEIRDKEDSS WQLFTVQVQT EAIGEGSLEP SPQSQAEDGR SQAAVGAVPE GAWKDTAQLH KSEEAVSVGQ K RVLRYYLF QGQRYIWIET QQAFYQVSLL DHGRSCDDVH RSRHGLSLQD QMVRKAIYGP NVISIPVKSY PQLLVDEALN PY YGFQAFS IALWLADHYY WYALCIFLIS SISICLSLYK TRKQSQTLRD MVKLSMRVCV CRPGGEEEWV DSSELVPGDC LVL PQEGGL MPCDAALVAG ECMVNESSLT GESIPVLKTA LPEGLGPYCA ETHRRHTLFC GTLILQARAY VGPHVLAVVT RTGF CTAKG GLVSSILHPR PINFKFYKHS MKFVAALSVL ALLGTIYSIF ILYRNRVPLN EIVIRALDLV TVVVPPALPA AMTVC TLYA QSRLRRQGIF CIHPLRINLG GKLQLVCFDK TGTLTEDGLD VMGVVPLKGQ AFLPLVPEPR RLPVGPLLRA LATCHA LSR LQDTPVGDPM DLKMVESTGW VLEEEPAADS AFGTQVLAVM RPPLWEPQLQ AMEEPPVPVS VLHRFPFSSA LQRMSVV VA WPGATQPEAY VKGSPELVAG LCNPETVPTD FAQMLQSYTA AGYRVVALAS KPLPTVPSLE AAQQLTRDTV EGDLSLLG L LVMRNLLKPQ TTPVIQALRR TRIRAVMVTG DNLQTAVTVA RGCGMVAPQE HLIIVHATHP ERGQPASLEF LPMESPTAV NGVKDPDQAA SYTVEPDPRS RHLALSGPTF GIIVKHFPKL LPKVLVQGTV FARMAPEQKT ELVCELQKLQ YCVGMCGDGA NDCGALKAA DVGISLSQAE ASVVSPFTSS MASIECVPMV IREGRCSLDT SFSVFKYMAL YSLTQFISVL ILYTINTNLG D LQFLAIDL VITTTVAVLM SRTGPALVLG RVRPPGALLS VPVLSSLLLQ MVLVTGVQLG GYFLTLAQPW FVPLNRTVAA PD NLPNYEN TVVFSLSSFQ YLILAAAVSK GAPFRRPLYT NVPFLVALAL LSSVLVGLVL VPGLLQGPLA LRNITDTGFK LLL LGLVTL NFVGAFMLES VLDQCLPACL RRLRPKRASK KRFKQLEREL AEQPWPPLPA GPLR

UniProtKB: Polyamine-transporting ATPase 13A2

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Macromolecule #2: TETRAFLUOROALUMINATE ION

MacromoleculeName: TETRAFLUOROALUMINATE ION / type: ligand / ID: 2 / Number of copies: 1 / Formula: ALF
Molecular weightTheoretical: 102.975 Da
Chemical component information

ChemComp-ALF:
TETRAFLUOROALUMINATE ION

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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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Macromolecule #4: SPERMINE

MacromoleculeName: SPERMINE / type: ligand / ID: 4 / Number of copies: 1 / Formula: SPM
Molecular weightTheoretical: 202.34 Da
Chemical component information

ChemComp-SPM:
SPERMINE

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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
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: 50.0 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: 3.78 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 266168
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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