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- EMDB-23059: TDP-43 LCD amyloid fibrils -

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Basic information

Entry
Database: EMDB / ID: EMD-23059
TitleTDP-43 LCD amyloid fibrils
Map data
Sample
  • Complex: Amyloid fibrils formed by TDP-43 low complexity domain
    • Protein or peptide: Isoform 2 of TAR DNA-binding protein 43
KeywordsTDP-43 / amyloid / neurodegenerative diseases / amyotropic lateral sclerosis / 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: 3.2 Å
AuthorsLi Q / Babinchak WM
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Aging (NIH/NIA)AG061797 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM094357 United States
CitationJournal: Nat Commun / Year: 2021
Title: Cryo-EM structure of amyloid fibrils formed by the entire low complexity domain of TDP-43.
Authors: Qiuye Li / W Michael Babinchak / Witold K Surewicz /
Abstract: Amyotrophic lateral sclerosis and several other neurodegenerative diseases are associated with brain deposits of amyloid-like aggregates formed by the C-terminal fragments of TDP-43 that contain the ...Amyotrophic lateral sclerosis and several other neurodegenerative diseases are associated with brain deposits of amyloid-like aggregates formed by the C-terminal fragments of TDP-43 that contain the low complexity domain of the protein. Here, we report the cryo-EM structure of amyloid formed from the entire TDP-43 low complexity domain in vitro at pH 4. This structure reveals single protofilament fibrils containing a large (139-residue), tightly packed core. While the C-terminal part of this core region is largely planar and characterized by a small proportion of hydrophobic amino acids, the N-terminal region contains numerous hydrophobic residues and has a non-planar backbone conformation, resulting in rugged surfaces of fibril ends. The structural features found in these fibrils differ from those previously found for fibrils generated from short protein fragments. The present atomic model for TDP-43 LCD fibrils provides insight into potential structural perturbations caused by phosphorylation and disease-related mutations.
History
DepositionDec 2, 2020-
Header (metadata) releaseFeb 24, 2021-
Map releaseFeb 24, 2021-
UpdateMar 6, 2024-
Current statusMar 6, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.0067
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.0067
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7kwz
  • Surface level: 0.0067
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-7kwz
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_23059.png

Downloads & links

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Map

FileDownload / File: emd_23059.map.gz / Format: CCP4 / Size: 30.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.828 Å
Density
Contour LevelBy AUTHOR: 0.0067 / Movie #1: 0.0067
Minimum - Maximum-0.017726323 - 0.038905915
Average (Standard dev.)0.0001682079 (±0.0016654085)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions200200200
Spacing200200200
CellA=B=C: 165.6 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.8280.8280.828
M x/y/z200200200
origin x/y/z0.0000.0000.000
length x/y/z165.600165.600165.600
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS200200200
D min/max/mean-0.0180.0390.000

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Supplemental data

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Sample components

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Entire : Amyloid fibrils formed by TDP-43 low complexity domain

EntireName: Amyloid fibrils formed by TDP-43 low complexity domain
Components
  • Complex: Amyloid fibrils formed by TDP-43 low complexity domain
    • Protein or peptide: Isoform 2 of TAR DNA-binding protein 43

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Supramolecule #1: Amyloid fibrils formed by TDP-43 low complexity domain

SupramoleculeName: Amyloid fibrils formed by TDP-43 low complexity domain
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Isoform 2 of TAR DNA-binding protein 43

MacromoleculeName: Isoform 2 of TAR DNA-binding protein 43 / type: protein_or_peptide / ID: 1 / Number of copies: 5 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 14.570482 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
NRQLERSGRF GGNPGGFGNQ GGFGNSRGGG AGLGNNQGSN MGGGMNFGAF SINPAMMAAA QAALQSSWGM MGMLASQQNQ SGPSGNNQN QGNMQREPNQ AFGSGNNSYS GSNSGAAIGW GSASNAGSGS GFNGGFGSSM DSKSSGWGM

UniProtKB: TAR DNA-binding protein 43

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statefilament

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Sample preparation

BufferpH: 4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: OTHER
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 42.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final angle assignmentType: NOT APPLICABLE
Final reconstructionApplied symmetry - Helical parameters - Δz: 4.73 Å
Applied symmetry - Helical parameters - Δ&Phi: -1.66 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 11026

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