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- PDB-8qxa: TDP-43 amyloid fibrils: Morphology-1b -

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Basic information

Entry
Database: PDB / ID: 8qxa
TitleTDP-43 amyloid fibrils: Morphology-1b
ComponentsTAR DNA-binding protein 43
KeywordsPROTEIN FIBRIL / Amyloidosis / Protein misfolding disease / Amyloid fibrils / Cryo electron microscopy / Amyloid key
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 / molecular condensate scaffold activity ...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 / molecular condensate scaffold activity / 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)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 4.05 Å
AuthorsSharma, K. / Shenoy, J. / Loquet, A. / Schmidt, M. / Faendrich, M.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Commun / Year: 2024
Title: Cryo-EM observation of the amyloid key structure of polymorphic TDP-43 amyloid fibrils.
Authors: Kartikay Sharma / Fabian Stockert / Jayakrishna Shenoy / Mélanie Berbon / Muhammed Bilal Abdul-Shukkoor / Birgit Habenstein / Antoine Loquet / Matthias Schmidt / Marcus Fändrich /
Abstract: The transactive response DNA-binding protein-43 (TDP-43) is a multi-facet protein involved in phase separation, RNA-binding, and alternative splicing. In the context of neurodegenerative diseases, ...The transactive response DNA-binding protein-43 (TDP-43) is a multi-facet protein involved in phase separation, RNA-binding, and alternative splicing. In the context of neurodegenerative diseases, abnormal aggregation of TDP-43 has been linked to amyotrophic lateral sclerosis and frontotemporal lobar degeneration through the aggregation of its C-terminal domain. Here, we report a cryo-electron microscopy (cryo-EM)-based structural characterization of TDP-43 fibrils obtained from the full-length protein. We find that the fibrils are polymorphic and contain three different amyloid structures. The structures differ in the number and relative orientation of the protofilaments, although they share a similar fold containing an amyloid key motif. The observed fibril structures differ from previously described conformations of TDP-43 fibrils and help to better understand the structural landscape of the amyloid fibril structures derived from this protein.
History
DepositionOct 24, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 24, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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
E: TAR DNA-binding protein 43
F: TAR DNA-binding protein 43
G: TAR DNA-binding protein 43
H: TAR DNA-binding protein 43
I: TAR DNA-binding protein 43
J: TAR DNA-binding protein 43
K: TAR DNA-binding protein 43
L: TAR DNA-binding protein 43


Theoretical massNumber of molelcules
Total (without water)537,41712
Polymers537,41712
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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


Mass: 44784.742 Da / Num. of mol.: 12
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

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Experimental details

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Experiment

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

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Sample preparation

ComponentName: TDP-43 amyloid fibrils: Morphology-1b / Type: COMPLEX / Details: In vitro formed TDP-43 amyloid fibrils / Entity ID: all / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 400 divisions/in. / Grid type: C-flat-1.2/1.3
VitrificationInstrument: GATAN CRYOPLUNGE 3 / Cryogen name: ETHANE / Humidity: 85 %

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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 / Nominal defocus max: 2500 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm
Specimen holderCryogen: NITROGEN
Image recordingAverage exposure time: 10 sec. / Electron dose: 52.08 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 QUANTUM (4k x 4k) / Num. of real images: 1641
Image scansMovie frames/image: 40

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Processing

EM software
IDNameVersionCategory
1RELION3.1.1particle selection
2SerialEMimage acquisition
4CTFFIND4.1CTF correction
7Coot0.9.1model fitting
11RELION3.1.1classification
12RELION3.1.13D reconstruction
13PHENIX1.20-4459model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: -1.802 ° / Axial rise/subunit: 4.792 Å / Axial symmetry: C1
Particle selectionNum. of particles selected: 26881
3D reconstructionResolution: 4.05 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 26881 / Symmetry type: HELICAL
Atomic model buildingProtocol: BACKBONE TRACE / Space: REAL / Target criteria: correlation coefficient

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