+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-13795 | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
Title | Cryo-EM structure of TDP43 core peptide amyloid fiber | |||||||||
Map data | ||||||||||
Sample |
| |||||||||
Keywords | TDP-43 / Amyloid / Neurodegeneration / Helical / Cryo-EM / RNA BINDING PROTEIN | |||||||||
Function / homology | Function and homology information nuclear inner membrane organization / interchromatin granule / perichromatin fibrils / negative regulation by host of viral transcription / 3'-UTR-mediated mRNA destabilization / 3'-UTR-mediated mRNA stabilization / intracellular non-membrane-bounded organelle / pre-mRNA intronic binding / response to endoplasmic reticulum stress / RNA splicing ...nuclear inner membrane organization / interchromatin granule / perichromatin fibrils / negative regulation by host of viral transcription / 3'-UTR-mediated mRNA destabilization / 3'-UTR-mediated mRNA stabilization / intracellular non-membrane-bounded organelle / pre-mRNA intronic binding / response to endoplasmic reticulum stress / RNA splicing / molecular condensate scaffold activity / negative regulation of protein phosphorylation / mRNA 3'-UTR binding / regulation of circadian rhythm / regulation of protein stability / positive regulation of insulin secretion / cytoplasmic stress granule / positive regulation of protein import into nucleus / 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: 3.7 Å | |||||||||
Authors | Nazarov S / Lashuel H | |||||||||
Funding support | Switzerland, 1 items
| |||||||||
Citation | Journal: Nat Neurosci / Year: 2023 Title: Seeding the aggregation of TDP-43 requires post-fibrillization proteolytic cleavage. Authors: Senthil T Kumar / Sergey Nazarov / Sílvia Porta / Niran Maharjan / Urszula Cendrowska / Malek Kabani / Francesco Finamore / Yan Xu / Virginia M-Y Lee / Hilal A Lashuel / Abstract: Despite the strong evidence linking the transactive response DNA-binding protein 43 (TDP-43) aggregation to the pathogenesis of frontotemporal lobar degeneration with TDP-43, amyotrophic lateral ...Despite the strong evidence linking the transactive response DNA-binding protein 43 (TDP-43) aggregation to the pathogenesis of frontotemporal lobar degeneration with TDP-43, amyotrophic lateral sclerosis and several neurodegenerative diseases, our knowledge of the sequence and structural determinants of its aggregation and neurotoxicity remains incomplete. Herein, we present a new method for producing recombinant full-length TDP-43 filaments that exhibit sequence and morphological features similar to those of brain-derived TDP-43 filaments. We show that TDP-43 filaments contain a β-sheet-rich helical amyloid core that is fully buried by the flanking structured domains of the protein. We demonstrate that the proteolytic cleavage of TDP-43 filaments and exposure of this amyloid core are necessary for propagating TDP-43 pathology and enhancing the seeding of brain-derived TDP-43 aggregates. Only TDP-43 filaments with exposed amyloid core efficiently seeded the aggregation of endogenous TDP-43 in cells. These findings suggest that inhibiting the enzymes mediating cleavage of TDP-43 aggregates represents a viable disease-modifying strategy to slow the progression of amyotrophic lateral sclerosis and other TDP-43 proteinopathies. | |||||||||
History |
|
-Structure visualization
Supplemental images |
---|
-Downloads & links
-EMDB archive
Map data | emd_13795.map.gz | 4.4 MB | EMDB map data format | |
---|---|---|---|---|
Header (meta data) | emd-13795-v30.xml emd-13795.xml | 17.5 KB 17.5 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_13795_fsc.xml | 9.2 KB | Display | FSC data file |
Images | emd_13795.png | 1 MB | ||
Masks | emd_13795_msk_1.map | 64 MB | Mask map | |
Filedesc metadata | emd-13795.cif.gz | 5.5 KB | ||
Others | emd_13795_additional_1.map.gz emd_13795_half_map_1.map.gz emd_13795_half_map_2.map.gz | 6.1 MB 49.7 MB 49.7 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-13795 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-13795 | HTTPS FTP |
-Validation report
Summary document | emd_13795_validation.pdf.gz | 781.5 KB | Display | EMDB validaton report |
---|---|---|---|---|
Full document | emd_13795_full_validation.pdf.gz | 781.1 KB | Display | |
Data in XML | emd_13795_validation.xml.gz | 16.1 KB | Display | |
Data in CIF | emd_13795_validation.cif.gz | 20.9 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-13795 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-13795 | HTTPS FTP |
-Related structure data
Related structure data | 7q3uMC M: atomic model generated by this map C: citing same article (ref.) |
---|---|
Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
---|
-Map
File | Download / File: emd_13795.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Voxel size | X=Y=Z: 1.06 Å | ||||||||||||||||||||
Density |
| ||||||||||||||||||||
Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
|
-Supplemental data
-Mask #1
File | emd_13795_msk_1.map | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Projections & Slices |
| ||||||||||||
Density Histograms |
-Additional map: Post-processed and symmetrized map of the first (one...
File | emd_13795_additional_1.map | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Annotation | Post-processed and symmetrized map of the first (one protofilament) conformation of TDP-43 CP fibrils | ||||||||||||
Projections & Slices |
| ||||||||||||
Density Histograms |
-Half map: #2
File | emd_13795_half_map_1.map | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Projections & Slices |
| ||||||||||||
Density Histograms |
-Half map: #1
File | emd_13795_half_map_2.map | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Projections & Slices |
| ||||||||||||
Density Histograms |
-Sample components
-Entire : Helical filament from TDP43 core peptide
Entire | Name: Helical filament from TDP43 core peptide |
---|---|
Components |
|
-Supramolecule #1: Helical filament from TDP43 core peptide
Supramolecule | Name: Helical filament from TDP43 core peptide / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all |
---|---|
Source (natural) | Organism: Homo sapiens (human) |
-Macromolecule #1: TAR DNA-binding protein 43
Macromolecule | Name: TAR DNA-binding protein 43 / type: protein_or_peptide / ID: 1 / Number of copies: 5 / Enantiomer: LEVO |
---|---|
Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 8.042687 KDa |
Recombinant expression | Organism: Escherichia coli (E. coli) |
Sequence | String: NPGGFGNQGG FGNSRGGGAG LGNNQGSNMG GGMNFGAFSI NPAMMAAAQA ALQSSWGMMG MLASQQNQSG PSGNNQNQGN MQ UniProtKB: TAR DNA-binding protein 43 |
-Experimental details
-Structure determination
Method | cryo EM |
---|---|
Processing | helical reconstruction |
Aggregation state | helical array |
-Sample preparation
Buffer | pH: 7 |
---|---|
Grid | Model: Quantifoil R1.2/1.3 / Material: GOLD / Support film - Material: CARBON / Support film - topology: HOLEY ARRAY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec. |
Vitrification | Cryogen name: ETHANE / Chamber humidity: 90 % / Instrument: FEI VITROBOT MARK IV |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
---|---|
Image recording | Film or detector model: GATAN K3 (6k x 4k) / Number real images: 3171 / Average exposure time: 3.99 sec. / Average electron dose: 40.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | C2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.9 µm / Nominal magnification: 81000 |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
-Atomic model buiding 1
Refinement | Space: REAL / Protocol: AB INITIO MODEL / Overall B value: 103 |
---|---|
Output model | PDB-7q3u: |