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Yorodumi- EMDB-13710: Structure of pathological TDP-43 filaments from ALS with FTLD (In... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-13710 | |||||||||
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Title | Structure of pathological TDP-43 filaments from ALS with FTLD (Individual 1, motor cortex) | |||||||||
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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 / mRNA 3'-UTR binding / molecular condensate scaffold activity / regulation of circadian rhythm / regulation of protein stability / positive regulation of insulin secretion / positive regulation of protein import into nucleus / cytoplasmic stress granule / mRNA processing / 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 / chromatin / mitochondrion / DNA binding / RNA binding / nucleoplasm / identical protein binding / nucleus Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | helical reconstruction / cryo EM / Resolution: 2.94 Å | |||||||||
Authors | Arseni D / Hasegawa H | |||||||||
Funding support | United Kingdom, 1 items
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Citation | Journal: 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 |
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-Structure visualization
Movie |
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Structure viewer | EM map: SurfViewMolmilJmol/JSmol |
Supplemental images |
-Downloads & links
-EMDB archive
Map data | emd_13710.map.gz | 17.3 MB | EMDB map data format | |
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Header (meta data) | emd-13710-v30.xml emd-13710.xml | 12.4 KB 12.4 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_13710_fsc.xml | 9.1 KB | Display | FSC data file |
Images | emd_13710.png | 100 KB | ||
Masks | emd_13710_msk_1.map | 64 MB | Mask map | |
Others | emd_13710_half_map_1.map.gz emd_13710_half_map_2.map.gz | 49.6 MB 49.5 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-13710 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-13710 | HTTPS FTP |
-Validation report
Summary document | emd_13710_validation.pdf.gz | 546 KB | Display | EMDB validaton report |
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Full document | emd_13710_full_validation.pdf.gz | 545.6 KB | Display | |
Data in XML | emd_13710_validation.xml.gz | 16.3 KB | Display | |
Data in CIF | emd_13710_validation.cif.gz | 21.2 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-13710 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-13710 | HTTPS FTP |
-Related structure data
Related structure data | 7py2C C: citing same article (ref.) |
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Similar structure data | |
EM raw data | EMPIAR-10831 (Title: Structure of pathological TDP-43 filaments from ALS with FTLD (Individual 1, motor cortex) Data size: 2.0 TB Data #1: Unaligned multiframe movies [micrographs - multiframe]) EMPIAR-10832 (Title: Structure of pathological TDP-43 filaments from ALS with FTLD (Individual 2, frontal cortex) Data size: 2.9 TB Data #1: Unaligned multiframe movies [micrographs - multiframe]) |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_13710.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 0.93 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Mask #1
File | emd_13710_msk_1.map | ||||||||||||
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Density Histograms |
-Half map: #1
File | emd_13710_half_map_1.map | ||||||||||||
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Density Histograms |
-Half map: #2
File | emd_13710_half_map_2.map | ||||||||||||
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Density Histograms |
-Sample components
-Entire : Pathological TDP-43 filaments extracted from the motor cortex of ...
Entire | Name: Pathological TDP-43 filaments extracted from the motor cortex of an individual that succumbed to ALS with FTLD. |
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Components |
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-Supramolecule #1: Pathological TDP-43 filaments extracted from the motor cortex of ...
Supramolecule | Name: Pathological TDP-43 filaments extracted from the motor cortex of an individual that succumbed to ALS with FTLD. type: tissue / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: Homo sapiens (human) / Tissue: Brain |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | helical reconstruction |
Aggregation state | filament |
-Sample preparation
Buffer | pH: 7.4 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 39.7 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |