+Open data
-Basic information
Entry | Database: PDB / ID: 7q3u | ||||||
---|---|---|---|---|---|---|---|
Title | Cryo-EM structure of TDP43 core peptide amyloid fiber | ||||||
Components | TAR DNA-binding protein 43 | ||||||
Keywords | RNA BINDING PROTEIN / TDP-43 / Amyloid / Neurodegeneration / Helical / Cryo-EM | ||||||
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 | ELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3.7 Å | ||||||
Authors | Nazarov, S. | ||||||
Funding support | Switzerland, 1items
| ||||||
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
Structure viewer | Molecule: MolmilJmol/JSmol |
---|
-Downloads & links
-Download
PDBx/mmCIF format | 7q3u.cif.gz | 59.8 KB | Display | PDBx/mmCIF format |
---|---|---|---|---|
PDB format | pdb7q3u.ent.gz | 45.5 KB | Display | PDB format |
PDBx/mmJSON format | 7q3u.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 7q3u_validation.pdf.gz | 1.1 MB | Display | wwPDB validaton report |
---|---|---|---|---|
Full document | 7q3u_full_validation.pdf.gz | 1.1 MB | Display | |
Data in XML | 7q3u_validation.xml.gz | 27.2 KB | Display | |
Data in CIF | 7q3u_validation.cif.gz | 37.5 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/q3/7q3u ftp://data.pdbj.org/pub/pdb/validation_reports/q3/7q3u | HTTPS FTP |
-Related structure data
Related structure data | 13795MC M: map data used to model this data C: citing same article (ref.) |
---|---|
Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
|
---|---|
1 |
|
-Components
#1: Protein | Mass: 8042.687 Da / Num. of mol.: 5 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: TARDBP, TDP43 / Production host: Escherichia coli (E. coli) / References: UniProt: Q13148 |
---|
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
---|---|
EM experiment | Aggregation state: HELICAL ARRAY / 3D reconstruction method: helical reconstruction |
-Sample preparation
Component | Name: Helical filament from TDP43 core peptide / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT |
---|---|
Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Escherichia coli (E. coli) |
Buffer solution | pH: 7 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Specimen support | Grid material: GOLD / Grid type: Quantifoil R1.2/1.3 |
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 90 % |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
---|---|
Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD / Nominal magnification: 81000 X / Nominal defocus max: 2000 nm / Nominal defocus min: 900 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm |
Specimen holder | Cryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Image recording | Average exposure time: 3.99 sec. / Electron dose: 40 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of real images: 3171 |
-Processing
EM software |
| ||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||||||||||
Helical symmerty | Angular rotation/subunit: -3.09 ° / Axial rise/subunit: 4.83 Å / Axial symmetry: C1 | ||||||||||||||||||||||||||||||||
3D reconstruction | Resolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 5795 / Symmetry type: HELICAL | ||||||||||||||||||||||||||||||||
Atomic model building | B value: 103 / Protocol: AB INITIO MODEL / Space: REAL |