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- EMDB-13708: Structure of pathological TDP-43 filaments from ALS with FTLD -

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Basic information

Entry
Database: EMDB / ID: EMD-13708
TitleStructure of pathological TDP-43 filaments from ALS with FTLD
Map data
Sample
  • Tissue: Pathological TDP-43 filaments extracted from the frontal cortex of an individual that succumbed to ALS with FTLD.
    • Protein or peptide: TAR DNA-binding protein 43
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 / molecular condensate scaffold activity / response to endoplasmic reticulum stress ...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 / molecular condensate scaffold activity / response to endoplasmic reticulum stress / RNA splicing / negative regulation of protein phosphorylation / 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 / double-stranded DNA binding / regulation of gene expression / 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) / Human (human)
Methodhelical reconstruction / cryo EM / Resolution: 2.59 Å
AuthorsArseni D / Hasegawa H / Murzin AG / Kametani F / Arai M / Yoshida M / Falcon B
Funding support United Kingdom, 1 items
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, 2021-
Header (metadata) releaseDec 15, 2021-
Map releaseDec 15, 2021-
UpdateJan 19, 2022-
Current statusJan 19, 2022Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.015
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.015
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  • Surface view with fitted model
  • Atomic models: PDB-7py2
  • Surface level: 0.015
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-7py2
  • Imaged by Jmol
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Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_13708.png

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Map

FileDownload / File: emd_13708.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
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AxesZ (Sec.)Y (Row.)X (Col.)
0.93 Å/pix.
x 256 pix.
= 238.08 Å		0.93 Å/pix.
x 256 pix.
= 238.08 Å		0.93 Å/pix.
x 256 pix.
= 238.08 Å

Surface

Projections

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Slices (1/2)

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.93 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.015 / Movie #1: 0.015
Minimum - Maximum-0.032455537 - 0.077482395
Average (Standard dev.)0.00033411334 (±0.00354062)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 238.08 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.930.930.93
M x/y/z256256256
origin x/y/z0.0000.0000.000
length x/y/z238.080238.080238.080
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ448448448
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS256256256
D min/max/mean-0.0320.0770.000

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Supplemental data

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Mask #1

Fileemd_13708_msk_1.map
Projections & Slices
AxesZYX

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Half map: #1

Fileemd_13708_half_map_1.map
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Histogram

Histogram (log scale)

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Half map: #2

Fileemd_13708_half_map_2.map
Projections & Slices
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Sample components

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Entire : Pathological TDP-43 filaments extracted from the frontal cortex o...

EntireName: Pathological TDP-43 filaments extracted from the frontal cortex of an individual that succumbed to ALS with FTLD.
Components
  • Tissue: Pathological TDP-43 filaments extracted from the frontal cortex of an individual that succumbed to ALS with FTLD.
    • Protein or peptide: TAR DNA-binding protein 43

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Supramolecule #1: Pathological TDP-43 filaments extracted from the frontal cortex o...

SupramoleculeName: Pathological TDP-43 filaments extracted from the frontal cortex of an individual that succumbed to ALS with FTLD.
type: tissue / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human) / Tissue: Brain

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Macromolecule #1: TAR DNA-binding protein 43

MacromoleculeName: TAR DNA-binding protein 43 / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Human (human) / Tissue: Brain
Molecular weightTheoretical: 44.784742 KDa
SequenceString: MSEYIRVTED ENDEPIEIPS EDDGTVLLST VTAQFPGACG LRYRNPVSQC MRGVRLVEGI LHAPDAGWGN LVYVVNYPKD NKRKMDETD ASSAVKVKRA VQKTSDLIVL GLPWKTTEQD LKEYFSTFGE VLMVQVKKDL KTGHSKGFGF VRFTEYETQV K VMSQRHMI ...String:
MSEYIRVTED ENDEPIEIPS EDDGTVLLST VTAQFPGACG LRYRNPVSQC MRGVRLVEGI LHAPDAGWGN LVYVVNYPKD NKRKMDETD ASSAVKVKRA VQKTSDLIVL GLPWKTTEQD LKEYFSTFGE VLMVQVKKDL KTGHSKGFGF VRFTEYETQV K VMSQRHMI DGRWCDCKLP NSKQSQDEPL RSRKVFVGRC TEDMTEDELR EFFSQYGDVM DVFIPKPFRA FAFVTFADDQ IA QSLCGED LIIKGISVHI SNAEPKHNSN RQLERSGRFG GNPGGFGNQG GFGNSRGGGA GLGNNQGSNM GGGMNFGAFS INP AMMAAA QAALQSSWGM MGMLASQQNQ SGPSGNNQNQ GNMQREPNQA FGSGNNSYSG SNSGAAIGWG SASNAGSGSG FNGG FGSSM DSKSSGWGM

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statefilament

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 39.7 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Details: Initial 3D reference models were generated de novo by producing sinograms from 2D class averages.
Final angle assignmentType: NOT APPLICABLE
Final reconstructionApplied symmetry - Helical parameters - Δz: 4.842 Å
Applied symmetry - Helical parameters - Δ&Phi: 1.422 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 2.59 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 308822
FSC plot (resolution estimation)

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