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

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Basic information

Entry
Database: PDB / ID: 7vpi
TitleCryo-EM structure of the human ATP13A2 (E1-ATP state)
ComponentsPolyamine-transporting ATPase 13A2
KeywordsMEMBRANE PROTEIN / ATP13A2 / PARK9 / P-type ATPase
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 / P-type ion transporter activity ...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 / P-type ion transporter activity / regulation of autophagy of mitochondrion / regulation of lysosomal protein catabolic process / intracellular monoatomic cation homeostasis / autophagosome-lysosome fusion / autophagosome organization / protein localization to lysosome / positive regulation of exosomal secretion / phosphatidic acid binding / ATPase-coupled monoatomic cation transmembrane transporter activity / multivesicular body membrane / intracellular zinc ion homeostasis / cupric ion binding / regulation of protein localization to nucleus / regulation of mitochondrion organization / Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate / phosphatidylinositol-3,5-bisphosphate binding / lysosomal transport / regulation of intracellular protein transport / cellular response to zinc ion / lipid homeostasis / Ion transport by P-type ATPases / autophagosome membrane / regulation of macroautophagy / transport vesicle / regulation of neuron apoptotic process / cellular response to manganese ion / 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 / P-type ATPase actuator domain / HAD superfamily/HAD-like / P-type ATPase, haloacid dehalogenase domain / P-type ATPase, phosphorylation site / P-type ATPase, cytoplasmic domain N / E1-E2 ATPases phosphorylation site. ...: / : / P5-type ATPase cation transporter / P-type ATPase, subfamily V / P-type ATPase actuator domain / HAD superfamily/HAD-like / 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 / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER / Polyamine-transporting ATPase 13A2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsTomita, A. / Yamashita, K. / Nishizawa, T. / Nureki, O.
Funding support Japan, 3items
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, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 29, 2021Provider: repository / Type: Initial release
Revision 1.1Jun 19, 2024Group: Data collection / Refinement description / Category: chem_comp_atom / chem_comp_bond / refine / Item: _refine.ls_d_res_high / _refine.ls_d_res_low

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Assembly

Deposited unit
A: Polyamine-transporting ATPase 13A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)129,8433
Polymers129,3131
Non-polymers5302
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Polyamine-transporting ATPase 13A2


Mass: 129313.391 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ATP13A2, PARK9 / Cell line (production host): HEK293SGNTI- / Production host: Homo sapiens (human)
References: UniProt: Q9NQ11, Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate
#2: Chemical ChemComp-ACP / PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER / ADENOSINE-5'-[BETA, GAMMA-METHYLENE]TRIPHOSPHATE


Mass: 505.208 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H18N5O12P3 / Feature type: SUBJECT OF INVESTIGATION / Comment: AMP-PCP, energy-carrying molecule analogue*YM
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: ATP13A2 / Type: COMPLEX / Details: Human ATP13A2 in complex with AMPPCP / Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Cell: HEK293SGNTI-
Buffer solutionpH: 8
SpecimenConc.: 10 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER/RHODIUM / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationCryogen name: ETHANE / Humidity: 100 %

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

SoftwareName: REFMAC / Version: 5.8.0267 / Classification: refinement
EM software
IDNameVersionCategory
2SerialEMimage acquisition
4CTFFINDCTF correction
7REFMACmodel fitting
9REFMACmodel refinement
10RELION3.1initial Euler assignment
11RELION3.1final Euler assignment
13RELION3.13D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 3114 / Algorithm: FOURIER SPACE / Symmetry type: POINT
Atomic model buildingProtocol: AB INITIO MODEL / Space: RECIPROCAL
RefinementResolution: 3.6→3.6 Å / Cor.coef. Fo:Fc: 0.855 / SU B: 36.291 / SU ML: 0.557 / ESU R: 0.891
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflection
Rwork0.44749 --
obs0.44749 52286 100 %
Solvent computationSolvent model: PARAMETERS FOR MASK CACLULATION
Displacement parametersBiso mean: 179.388 Å2
Refinement stepCycle: 1 / Total: 7375
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0080.0137540
ELECTRON MICROSCOPYr_bond_other_d0.0230.0177451
ELECTRON MICROSCOPYr_angle_refined_deg1.9391.6410287
ELECTRON MICROSCOPYr_angle_other_deg1.2661.56417142
ELECTRON MICROSCOPYr_dihedral_angle_1_deg6.4115955
ELECTRON MICROSCOPYr_dihedral_angle_2_deg37.51520.774323
ELECTRON MICROSCOPYr_dihedral_angle_3_deg26.874151247
ELECTRON MICROSCOPYr_dihedral_angle_4_deg17.9851553
ELECTRON MICROSCOPYr_chiral_restr0.1050.2989
ELECTRON MICROSCOPYr_gen_planes_refined0.0090.028325
ELECTRON MICROSCOPYr_gen_planes_other0.0050.021636
ELECTRON MICROSCOPYr_nbd_refined
ELECTRON MICROSCOPYr_nbd_other
ELECTRON MICROSCOPYr_nbtor_refined
ELECTRON MICROSCOPYr_nbtor_other
ELECTRON MICROSCOPYr_xyhbond_nbd_refined
ELECTRON MICROSCOPYr_xyhbond_nbd_other
ELECTRON MICROSCOPYr_metal_ion_refined
ELECTRON MICROSCOPYr_metal_ion_other
ELECTRON MICROSCOPYr_symmetry_vdw_refined
ELECTRON MICROSCOPYr_symmetry_vdw_other
ELECTRON MICROSCOPYr_symmetry_hbond_refined
ELECTRON MICROSCOPYr_symmetry_hbond_other
ELECTRON MICROSCOPYr_symmetry_metal_ion_refined
ELECTRON MICROSCOPYr_symmetry_metal_ion_other
ELECTRON MICROSCOPYr_mcbond_it1.9619.2223832
ELECTRON MICROSCOPYr_mcbond_other1.9619.2233831
ELECTRON MICROSCOPYr_mcangle_it3.75528.8244783
ELECTRON MICROSCOPYr_mcangle_other3.75528.8234784
ELECTRON MICROSCOPYr_scbond_it0.6719.5173708
ELECTRON MICROSCOPYr_scbond_other0.66919.5173708
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other1.74729.2155505
ELECTRON MICROSCOPYr_long_range_B_refined20.48831108
ELECTRON MICROSCOPYr_long_range_B_other20.48831109
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
LS refinement shellResolution: 3.5→3.591 Å / Total num. of bins used: 20 /
Num. reflection% reflection
Rfree0 -
Rwork3868 -
obs-100 %

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