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- PDB-7m5v: human ATP13A2 in the AMPPNP-bound occluded state -

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Basic information

Entry
Database: PDB / ID: 7m5v
Titlehuman ATP13A2 in the AMPPNP-bound occluded state
ComponentsPolyamine-transporting ATPase 13A2
KeywordsTRANSPORT PROTEIN / ion transport occluded state / MEMBRANE PROTEIN
Function / homology
Function and homology information


polyamine transmembrane transporter activity / ABC-type polyamine transporter activity / polyamine transmembrane transport / spermine transmembrane transport / peptidyl-aspartic acid autophosphorylation / regulation of ubiquitin-specific protease activity / regulation of autophagosome size / extracellular exosome biogenesis / regulation of chaperone-mediated autophagy / P-type ion transporter activity ...polyamine transmembrane transporter activity / ABC-type polyamine transporter activity / polyamine transmembrane transport / spermine transmembrane transport / peptidyl-aspartic acid autophosphorylation / regulation of ubiquitin-specific protease activity / regulation of autophagosome size / extracellular exosome biogenesis / regulation of chaperone-mediated autophagy / P-type ion transporter activity / negative regulation of lysosomal protein catabolic process / regulation of lysosomal protein catabolic process / autophagosome-lysosome fusion / intracellular monoatomic cation homeostasis / regulation of autophagy of mitochondrion / autophagosome organization / protein localization to lysosome / phosphatidic acid binding / multivesicular body membrane / positive regulation of exosomal secretion / ATPase-coupled monoatomic cation transmembrane transporter activity / intracellular zinc ion homeostasis / Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate / regulation of protein localization to nucleus / cupric ion binding / phosphatidylinositol-3,5-bisphosphate binding / regulation of mitochondrion organization / regulation of endopeptidase activity / lysosomal transport / cellular response to zinc ion / regulation of intracellular protein transport / lipid homeostasis / autophagosome membrane / Ion transport by P-type ATPases / autophagosome / regulation of macroautophagy / cellular response to manganese ion / regulation of neuron apoptotic process / transport vesicle / monoatomic ion transmembrane transport / multivesicular body / lysosomal lumen / positive regulation of protein secretion / transmembrane transport / intracellular calcium ion homeostasis / autophagy / late endosome / late endosome membrane / cellular response to oxidative stress / manganese ion binding / 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
1-DODECANOL / PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / DECANE / DODECANE / Chem-EUJ / CHOLESTEROL HEMISUCCINATE / Polyamine-transporting ATPase 13A2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsLee, K.P.K.
Funding support1items
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 24, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 30, 2022Provider: repository / Type: Initial release
Revision 2.0Apr 27, 2022Group: Advisory / Atomic model ...Advisory / Atomic model / Author supporting evidence / Data collection / Database references / Derived calculations / Polymer sequence / Source and taxonomy / Structure summary
Category: atom_site / database_PDB_caveat ...atom_site / database_PDB_caveat / em_imaging / em_software / entity / entity_poly / entity_poly_seq / entity_src_gen / pdbx_audit_support / pdbx_nonpoly_scheme / pdbx_poly_seq_scheme / pdbx_unobs_or_zero_occ_atoms / pdbx_unobs_or_zero_occ_residues / pdbx_validate_chiral / pdbx_validate_close_contact / struct / struct_conn / struct_conn_type / struct_ref_seq_dif
Item: _atom_site.Cartn_x / _atom_site.Cartn_y ..._atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _em_imaging.nominal_defocus_max / _em_imaging.nominal_defocus_min / _entity.formula_weight / _entity_poly.pdbx_seq_one_letter_code / _entity_poly.pdbx_seq_one_letter_code_can / _entity_src_gen.gene_src_common_name / _entity_src_gen.pdbx_end_seq_num / _pdbx_nonpoly_scheme.auth_seq_num / _struct.title
Description: Chirality error / Provider: author / Type: Coordinate replacement

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)136,14225
Polymers129,8201
Non-polymers6,32224
Water1086
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Polyamine-transporting ATPase 13A2


Mass: 129819.945 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ATP13A2, PARK9 / Production host: Homo sapiens (human)
References: UniProt: Q9NQ11, Translocases; Catalysing the translocation of other compounds; Linked to the hydrolysis of a nucleoside triphosphate

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Sugars , 2 types, 2 molecules

#4: Sugar ChemComp-LMT / DODECYL-BETA-D-MALTOSIDE


Type: D-saccharide / Mass: 510.615 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H46O11 / Comment: detergent*YM
#8: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 8 types, 28 molecules

#2: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-1DO / 1-DODECANOL / Dodecanol


Mass: 186.334 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C12H26O
#5: Chemical
ChemComp-Y01 / CHOLESTEROL HEMISUCCINATE


Mass: 486.726 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C31H50O4
#6: Chemical
ChemComp-D10 / DECANE / Decane


Mass: 142.282 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: C10H22
#7: Chemical ChemComp-D12 / DODECANE / Dodecane


Mass: 170.335 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C12H26
#9: Chemical ChemComp-ANP / PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER


Mass: 506.196 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H17N6O12P3 / Feature type: SUBJECT OF INVESTIGATION / Comment: AMP-PNP, energy-carrying molecule analogue*YM
#10: Chemical 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


Mass: 746.566 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H49O19P3 / Feature type: SUBJECT OF INVESTIGATION
#11: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 6 / Source method: isolated from a natural source / Formula: H2O

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Details

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: Transport protein in an occluded state / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.13 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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 FIELDBright-field microscopy / Nominal defocus max: 2500 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 76 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

Software
NameVersionClassificationNB
phenix.real_space_refine1.19.2_4158refinement
PHENIX1.19.2_4158refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 515611 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 69.06 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00448468
ELECTRON MICROSCOPYf_angle_d0.770911510
ELECTRON MICROSCOPYf_chiral_restr0.16061384
ELECTRON MICROSCOPYf_plane_restr0.00491407
ELECTRON MICROSCOPYf_dihedral_angle_d14.3293104

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