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- PDB-7py2: Structure of pathological TDP-43 filaments from ALS with FTLD -

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Basic information

Entry
Database: PDB / ID: 7py2
TitleStructure of pathological TDP-43 filaments from ALS with FTLD
ComponentsTAR DNA-binding protein 43
KeywordsPROTEIN FIBRIL / TDP-43 / ALS / amyotrophic lateral sclerosis / FTD / frontotemporal dementia / FTLD / frontotemporal lobar degeneration / amyloid / filament / fibril / neurodegenerative / neurodegeneration
Function / homology
Function and homology information


nuclear inner membrane organization / interchromatin granule / perichromatin fibrils / 3'-UTR-mediated mRNA destabilization / 3'-UTR-mediated mRNA stabilization / intracellular non-membrane-bounded organelle / negative regulation by host of viral transcription / pre-mRNA intronic binding / response to endoplasmic reticulum stress / RNA splicing ...nuclear inner membrane organization / interchromatin granule / perichromatin fibrils / 3'-UTR-mediated mRNA destabilization / 3'-UTR-mediated mRNA stabilization / intracellular non-membrane-bounded organelle / negative regulation by host of viral transcription / pre-mRNA intronic binding / response to endoplasmic reticulum stress / RNA splicing / negative regulation of protein phosphorylation / molecular condensate scaffold activity / mRNA 3'-UTR binding / regulation of protein stability / regulation of circadian rhythm / positive regulation of insulin secretion / mRNA processing / cytoplasmic stress granule / positive regulation of protein import into nucleus / rhythmic process / regulation of gene expression / double-stranded DNA binding / regulation of apoptotic process / amyloid fibril formation / regulation of cell cycle / nuclear speck / RNA polymerase II cis-regulatory region sequence-specific DNA binding / negative regulation of gene expression / lipid binding / mitochondrion / DNA binding / RNA binding / nucleoplasm / identical protein binding / nucleus
Similarity search - Function
: / TAR DNA-binding protein 43, C-terminal / TAR DNA-binding protein 43, N-terminal / TAR DNA-binding protein 43, N-terminal domain / RNA recognition motif / RNA recognition motif / Eukaryotic RNA Recognition Motif (RRM) profile. / RNA recognition motif domain / RNA-binding domain superfamily / Nucleotide-binding alpha-beta plait domain superfamily
Similarity search - Domain/homology
TAR DNA-binding protein 43
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 2.59 Å
AuthorsArseni, D. / Hasegawa, H. / Murzin, A.G. / Kametani, F. / Arai, M. / Yoshida, M. / Falcon, B.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MC_UP_1201/25 United Kingdom
CitationJournal: Nature / Year: 2022
Title: Structure of pathological TDP-43 filaments from ALS with FTLD.
Authors: Diana Arseni / Masato Hasegawa / Alexey G Murzin / Fuyuki Kametani / Makoto Arai / Mari Yoshida / Benjamin Ryskeldi-Falcon /
Abstract: The abnormal aggregation of TAR DNA-binding protein 43 kDa (TDP-43) in neurons and glia is the defining pathological hallmark of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) ...The abnormal aggregation of TAR DNA-binding protein 43 kDa (TDP-43) in neurons and glia is the defining pathological hallmark of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) and multiple forms of frontotemporal lobar degeneration (FTLD). It is also common in other diseases, including Alzheimer's and Parkinson's. No disease-modifying therapies exist for these conditions and early diagnosis is not possible. The structures of pathological TDP-43 aggregates are unknown. Here we used cryo-electron microscopy to determine the structures of aggregated TDP-43 in the frontal and motor cortices of an individual who had ALS with FTLD and from the frontal cortex of a second individual with the same diagnosis. An identical amyloid-like filament structure comprising a single protofilament was found in both brain regions and individuals. The ordered filament core spans residues 282-360 in the TDP-43 low-complexity domain and adopts a previously undescribed double-spiral-shaped fold, which shows no similarity to those of TDP-43 filaments formed in vitro. An abundance of glycine and neutral polar residues facilitates numerous turns and restricts β-strand length, which results in an absence of β-sheet stacking that is associated with cross-β amyloid structure. An uneven distribution of residues gives rise to structurally and chemically distinct surfaces that face external densities and suggest possible ligand-binding sites. This work enhances our understanding of the molecular pathogenesis of ALS and FTLD and informs the development of diagnostic and therapeutic agents that target aggregated TDP-43.
History
DepositionOct 8, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 15, 2021Provider: repository / Type: Initial release
Revision 1.1Dec 22, 2021Group: Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Jan 19, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year

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Assembly

Deposited unit
A: TAR DNA-binding protein 43
B: TAR DNA-binding protein 43
C: TAR DNA-binding protein 43
D: TAR DNA-binding protein 43


Theoretical massNumber of molelcules
Total (without water)179,1394
Polymers179,1394
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Noncrystallographic symmetry (NCS)NCS oper:
IDCodeMatrixVector
1given(1), (1), (1)
2given(0.999692, -0.024824), (0.024824, 0.999692), (1)2.9917, -2.91835, 4.84171
3given(0.998768, 0.049632), (-0.049632, 0.998768), (1)-5.76151, 6.05485, -9.68342
4given(0.999692, 0.024824), (-0.024824, 0.999692), (1)-2.91837, 2.9917, -4.84171

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Components

#1: Protein
TAR DNA-binding protein 43 / / TDP-43


Mass: 44784.742 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Tissue: Brain / References: UniProt: Q13148

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: FILAMENT / 3D reconstruction method: helical reconstruction

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Sample preparation

ComponentName: Pathological TDP-43 filaments extracted from the frontal cortex of an individual that succumbed to ALS with FTLD.
Type: TISSUE / Entity ID: all / Source: NATURAL
Source (natural)Organism: Homo sapiens (human) / Cellular location: Cytoplasm / Tissue: Brain
Buffer solutionpH: 7.4
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
Image recordingElectron dose: 39.7 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: REFMAC / Version: 5.8.0272 / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: 1.422 ° / Axial rise/subunit: 4.842 Å / Axial symmetry: C1
3D reconstructionResolution: 2.59 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 308822 / Symmetry type: HELICAL
RefinementResolution: 2.6→85.56 Å / Cor.coef. Fo:Fc: 0.721 / SU B: 7.738 / SU ML: 0.161 / ESU R: 0.151
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
Solvent computationSolvent model: PARAMETERS FOR MASK CACLULATION
Displacement parametersBiso mean: 64.971 Å2
Refinement stepCycle: 1 / Total: 538
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0070.013545
ELECTRON MICROSCOPYr_bond_other_d0.0360.018480
ELECTRON MICROSCOPYr_angle_refined_deg1.6011.609725
ELECTRON MICROSCOPYr_angle_other_deg1.2041.591093
ELECTRON MICROSCOPYr_dihedral_angle_1_deg8.241578
ELECTRON MICROSCOPYr_dihedral_angle_2_deg47.75426.89729
ELECTRON MICROSCOPYr_dihedral_angle_3_deg17.1221580
ELECTRON MICROSCOPYr_dihedral_angle_4_deg6.736151
ELECTRON MICROSCOPYr_chiral_restr0.0550.260
ELECTRON MICROSCOPYr_gen_planes_refined0.0060.02723
ELECTRON MICROSCOPYr_gen_planes_other0.0020.02151
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_it6.1196.497315
ELECTRON MICROSCOPYr_mcbond_other6.1036.491314
ELECTRON MICROSCOPYr_mcangle_it8.5579.735392
ELECTRON MICROSCOPYr_mcangle_other8.5589.746393
ELECTRON MICROSCOPYr_scbond_it7.9557.321230
ELECTRON MICROSCOPYr_scbond_other7.9487.332231
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other12.10610.6334
ELECTRON MICROSCOPYr_long_range_B_refined13.97579.116539
ELECTRON MICROSCOPYr_long_range_B_other13.9779.271540
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
LS refinement shellResolution: 2.6→2.668 Å / Num. reflection Rfree: 0 / Total num. of bins used: 20

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