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- EMDB-23685: Transport protein in inhibited state 2 -

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Basic information

Entry
Database: EMDB / ID: EMD-23685
TitleTransport protein in inhibited state 2
Map data
Sample
  • Complex: Transport protein in inhibited state 2 monomer
    • Protein or peptide: x 1 types
  • Ligand: x 12 types
Keywordsion transport inhibited state / MEMBRANE PROTEIN / TRANSPORT PROTEIN
Function / homology
Function and homology information


polyamine transmembrane transporter activity / polyamine transmembrane transport / spermine transmembrane transport / : / ABC-type polyamine transporter activity / regulation of autophagosome size / extracellular exosome biogenesis / regulation of chaperone-mediated autophagy / negative regulation of lysosomal protein catabolic process / regulation of autophagy of mitochondrion ...polyamine transmembrane transporter activity / polyamine transmembrane transport / spermine transmembrane transport / : / ABC-type polyamine transporter activity / regulation of autophagosome size / extracellular exosome biogenesis / regulation of chaperone-mediated autophagy / negative regulation of lysosomal protein catabolic process / regulation of autophagy of mitochondrion / P-type ion transporter activity / regulation of lysosomal protein catabolic process / intracellular monoatomic cation homeostasis / autophagosome-lysosome fusion / protein localization to lysosome / autophagosome organization / phosphatidic acid binding / positive regulation of exosomal secretion / multivesicular body membrane / ATPase-coupled monoatomic cation transmembrane transporter activity / regulation of protein localization to nucleus / intracellular zinc ion homeostasis / cupric ion binding / phosphatidylinositol-3,5-bisphosphate binding / regulation of mitochondrion organization / Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate / cellular response to zinc ion / lysosomal transport / regulation of intracellular protein transport / lipid homeostasis / Ion transport by P-type ATPases / autophagosome membrane / cellular response to manganese ion / regulation of macroautophagy / transport vesicle / regulation of neuron apoptotic process / multivesicular body / lysosomal lumen / autophagosome / positive regulation of protein secretion / autophagy / intracellular calcium ion homeostasis / late endosome membrane / late endosome / manganese ion binding / cellular response to oxidative stress / monoatomic ion transmembrane transport / vesicle / intracellular iron ion homeostasis / 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: 3.0 Å
AuthorsLee KPK
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Mol Cell / Year: 2021
Title: Structural mechanisms for gating and ion selectivity of the human polyamine transporter ATP13A2.
Authors: Jordan Tillinghast / Sydney Drury / Darren Bowser / Alana Benn / Kenneth Pak Kin Lee /
Abstract: Mutations in ATP13A2, also known as PARK9, cause a rare monogenic form of juvenile-onset Parkinson's disease named Kufor-Rakeb syndrome and other neurodegenerative diseases. ATP13A2 encodes a ...Mutations in ATP13A2, also known as PARK9, cause a rare monogenic form of juvenile-onset Parkinson's disease named Kufor-Rakeb syndrome and other neurodegenerative diseases. ATP13A2 encodes a neuroprotective P5B P-type ATPase highly enriched in the brain that mediates selective import of spermine ions from lysosomes into the cytosol via an unknown mechanism. Here we present three structures of human ATP13A2 bound to an ATP analog or to spermine in the presence of phosphomimetics determined by cryoelectron microscopy. ATP13A2 autophosphorylation opens a lysosome luminal gate to reveal a narrow lumen access channel that holds a spermine ion in its entrance. ATP13A2's architecture suggests physical principles underlying selective polyamine transport and anticipates a "pump-channel" intermediate that could function as a counter-cation conduit to facilitate lysosome acidification. Our findings establish a firm foundation to understand ATP13A2 mutations associated with disease and bring us closer to realizing ATP13A2's potential in neuroprotective therapy.
History
DepositionMar 25, 2021-
Header (metadata) releaseMar 30, 2022-
Map releaseMar 30, 2022-
UpdateNov 13, 2024-
Current statusNov 13, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_23685.png

Downloads & links

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Map

FileDownload / File: emd_23685.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 384 pix.
= 318.72 Å		0.83 Å/pix.
x 384 pix.
= 318.72 Å		0.83 Å/pix.
x 384 pix.
= 318.72 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.83 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.2
Minimum - Maximum-0.17041005 - 0.8101156
Average (Standard dev.)0.0016169857 (±0.023378098)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 318.72 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : Transport protein in inhibited state 2 monomer

EntireName: Transport protein in inhibited state 2 monomer
Components
  • Complex: Transport protein in inhibited state 2 monomer
    • Protein or peptide: Polyamine-transporting ATPase 13A2
  • Ligand: MAGNESIUM ION
  • Ligand: TETRAFLUOROMAGNESATE(2-)
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: DODECYL-BETA-D-MALTOSIDE
  • Ligand: CHOLESTEROL
  • Ligand: DECANE
  • Ligand: TETRADECANE
  • Ligand: DODECANE
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: SPERMINE (FULLY PROTONATED FORM)
  • Ligand: (2R)-3-{[(S)-hydroxy{[(1S,2R,3R,4S,5S,6R)-2,4,6-trihydroxy-3,5-bis(phosphonooxy)cyclohexyl]oxy}phosphoryl]oxy}propane-1,2-diyl dioctanoate
  • Ligand: water

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Supramolecule #1: Transport protein in inhibited state 2 monomer

SupramoleculeName: Transport protein in inhibited state 2 monomer / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 130 KDa

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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: 129.933102 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 GPLRSNSLEV LFQ

UniProtKB: Polyamine-transporting ATPase 13A2

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Macromolecule #2: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 2 / Number of copies: 1 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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Macromolecule #3: TETRAFLUOROMAGNESATE(2-)

MacromoleculeName: TETRAFLUOROMAGNESATE(2-) / type: ligand / ID: 3 / Number of copies: 1 / Formula: MF4
Molecular weightTheoretical: 100.299 Da
Chemical component information

ChemComp-MF4:
TETRAFLUOROMAGNESATE(2-)

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Macromolecule #4: CHOLESTEROL HEMISUCCINATE

MacromoleculeName: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 4 / Number of copies: 3 / Formula: Y01
Molecular weightTheoretical: 486.726 Da
Chemical component information

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

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Macromolecule #5: DODECYL-BETA-D-MALTOSIDE

MacromoleculeName: DODECYL-BETA-D-MALTOSIDE / type: ligand / ID: 5 / Number of copies: 1 / Formula: LMT
Molecular weightTheoretical: 510.615 Da
Chemical component information

ChemComp-LMT:
DODECYL-BETA-D-MALTOSIDE / detergent*YM

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Macromolecule #6: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 6 / Number of copies: 4 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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Macromolecule #7: DECANE

MacromoleculeName: DECANE / type: ligand / ID: 7 / Number of copies: 9 / Formula: D10
Molecular weightTheoretical: 142.282 Da
Chemical component information

ChemComp-D10:
DECANE

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Macromolecule #8: TETRADECANE

MacromoleculeName: TETRADECANE / type: ligand / ID: 8 / Number of copies: 1 / Formula: C14
Molecular weightTheoretical: 198.388 Da
Chemical component information

ChemComp-C14:
TETRADECANE

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Macromolecule #9: DODECANE

MacromoleculeName: DODECANE / type: ligand / ID: 9 / Number of copies: 1 / Formula: D12
Molecular weightTheoretical: 170.335 Da
Chemical component information

ChemComp-D12:
DODECANE

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Macromolecule #10: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 10 / Number of copies: 1 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Macromolecule #11: SPERMINE (FULLY PROTONATED FORM)

MacromoleculeName: SPERMINE (FULLY PROTONATED FORM) / type: ligand / ID: 11 / Number of copies: 1 / Formula: SPK
Molecular weightTheoretical: 206.372 Da
Chemical component information

ChemComp-SPK:
SPERMINE (FULLY PROTONATED FORM)

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Macromolecule #12: (2R)-3-{[(S)-hydroxy{[(1S,2R,3R,4S,5S,6R)-2,4,6-trihydroxy-3,5-bi...

MacromoleculeName: (2R)-3-{[(S)-hydroxy{[(1S,2R,3R,4S,5S,6R)-2,4,6-trihydroxy-3,5-bis(phosphonooxy)cyclohexyl]oxy}phosphoryl]oxy}propane-1,2-diyl dioctanoate
type: ligand / ID: 12 / Number of copies: 1 / Formula: EUJ
Molecular weightTheoretical: 746.566 Da
Chemical component information

ChemComp-EUJ:
(2R)-3-{[(S)-hydroxy{[(1S,2R,3R,4S,5S,6R)-2,4,6-trihydroxy-3,5-bis(phosphonooxy)cyclohexyl]oxy}phosphoryl]oxy}propane-1,2-diyl dioctanoate

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Macromolecule #13: water

MacromoleculeName: water / type: ligand / ID: 13 / Number of copies: 8 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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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 BIOQUANTUM (6k x 4k) / Average electron dose: 65.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.5 µm
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) / Resolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 285797
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER

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