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- EMDB-18716: TDP-43 amyloid fibrils: Morphology-1b -

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Basic information

Entry
Database: EMDB / ID: EMD-18716
TitleTDP-43 amyloid fibrils: Morphology-1b
Map data
Sample
  • Complex: TDP-43 amyloid fibrils: Morphology-1b
    • Protein or peptide: TAR DNA-binding protein 43
KeywordsAmyloidosis / Protein misfolding disease / Amyloid fibrils / Cryo electron microscopy / Amyloid key / PROTEIN FIBRIL
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)
Methodhelical reconstruction / cryo EM / Resolution: 4.05 Å
AuthorsSharma K / Shenoy J / Loquet A / Schmidt M / Faendrich M
Funding support1 items
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, 2023-
Header (metadata) releaseJan 24, 2024-
Map releaseJan 24, 2024-
UpdateJan 24, 2024-
Current statusJan 24, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_18716.png

Downloads & links

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Map

FileDownload / File: emd_18716.map.gz / Format: CCP4 / Size: 46.4 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.04 Å
Density
Contour LevelBy AUTHOR: 0.014
Minimum - Maximum-0.044180445 - 0.06534384
Average (Standard dev.)0.00017026447 (±0.002012369)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions230230230
Spacing230230230
CellA=B=C: 239.2 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_18716_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_18716_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : TDP-43 amyloid fibrils: Morphology-1b

EntireName: TDP-43 amyloid fibrils: Morphology-1b
Components
  • Complex: TDP-43 amyloid fibrils: Morphology-1b
    • Protein or peptide: TAR DNA-binding protein 43

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Supramolecule #1: TDP-43 amyloid fibrils: Morphology-1b

SupramoleculeName: TDP-43 amyloid fibrils: Morphology-1b / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all / Details: In vitro formed TDP-43 amyloid fibrils
Source (natural)Organism: Homo sapiens (human)

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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: 12 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 44.784742 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
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

UniProtKB: TAR DNA-binding protein 43

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statehelical array

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Sample preparation

BufferpH: 7.4
GridModel: C-flat-1.2/1.3 / Material: COPPER / Mesh: 400 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 85 % / Instrument: GATAN CRYOPLUNGE 3

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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 / Cs: 2.7 mm / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.0 µm
Sample stageCooling holder cryogen: NITROGEN
Image recordingFilm or detector model: GATAN K2 QUANTUM (4k x 4k) / Detector mode: COUNTING / Number real images: 1641 / Average exposure time: 10.0 sec. / Average electron dose: 52.08 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Segment selectionNumber selected: 26881 / Software - Name: RELION (ver. 3.1.1)
Startup modelType of model: NONE
Final angle assignmentType: NOT APPLICABLE
Final reconstructionApplied symmetry - Helical parameters - Δz: 4.792 Å
Applied symmetry - Helical parameters - Δ&Phi: -1.802 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 4.05 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.1.1) / Number images used: 26881
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: BACKBONE TRACE / Target criteria: correlation coefficient
Output model

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

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