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- EMDB-16643: Structure of TDP-43 amyloid filament from type A FTLD-TDP (variant 3) -
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Open data
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Basic information
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Title | Structure of TDP-43 amyloid filament from type A FTLD-TDP (variant 3) | |||||||||
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![]() | TDP-43 / FTD / FTLD / amyloid / filaments / fibril / neurodegeneration / neurodegenerative disease / RBP / RNA-binding protein / LCD / low-complexity domain / frontotemporal dementia / frontotemporal lobar degeneration / pathological / RNA BINDING PROTEIN / PROTEIN FIBRIL | |||||||||
Function / homology | ![]() 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 / RNA splicing ...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 / RNA splicing / molecular condensate scaffold activity / negative regulation of protein phosphorylation / mRNA 3'-UTR binding / regulation of protein stability / positive regulation of insulin secretion / regulation of circadian rhythm / cytoplasmic stress granule / positive regulation of protein import into nucleus / mRNA processing / rhythmic process / regulation of gene expression / double-stranded DNA binding / 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 | ![]() | |||||||||
Method | helical reconstruction / cryo EM / Resolution: 2.68 Å | |||||||||
![]() | Arseni D / Ryskeldi-Falcon B | |||||||||
Funding support | ![]()
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![]() | ![]() Title: TDP-43 forms amyloid filaments with a distinct fold in type A FTLD-TDP. Authors: Diana Arseni / Renren Chen / Alexey G Murzin / Sew Y Peak-Chew / Holly J Garringer / Kathy L Newell / Fuyuki Kametani / Andrew C Robinson / Ruben Vidal / Bernardino Ghetti / Masato Hasegawa ...Authors: Diana Arseni / Renren Chen / Alexey G Murzin / Sew Y Peak-Chew / Holly J Garringer / Kathy L Newell / Fuyuki Kametani / Andrew C Robinson / Ruben Vidal / Bernardino Ghetti / Masato Hasegawa / Benjamin Ryskeldi-Falcon / ![]() ![]() ![]() Abstract: The abnormal assembly of TAR DNA-binding protein 43 (TDP-43) in neuronal and glial cells characterizes nearly all cases of amyotrophic lateral sclerosis (ALS) and around half of cases of ...The abnormal assembly of TAR DNA-binding protein 43 (TDP-43) in neuronal and glial cells characterizes nearly all cases of amyotrophic lateral sclerosis (ALS) and around half of cases of frontotemporal lobar degeneration (FTLD). A causal role for TDP-43 assembly in neurodegeneration is evidenced by dominantly inherited missense mutations in TARDBP, the gene encoding TDP-43, that promote assembly and give rise to ALS and FTLD. At least four types (A-D) of FTLD with TDP-43 pathology (FTLD-TDP) are defined by distinct brain distributions of assembled TDP-43 and are associated with different clinical presentations of frontotemporal dementia. We previously showed, using cryo-electron microscopy, that TDP-43 assembles into amyloid filaments in ALS and type B FTLD-TDP. However, the structures of assembled TDP-43 in FTLD without ALS remained unknown. Here we report the cryo-electron microscopy structures of assembled TDP-43 from the brains of three individuals with the most common type of FTLD-TDP, type A. TDP-43 formed amyloid filaments with a new fold that was the same across individuals, indicating that this fold may characterize type A FTLD-TDP. The fold resembles a chevron badge and is unlike the double-spiral-shaped fold of ALS and type B FTLD-TDP, establishing that distinct filament folds of TDP-43 characterize different neurodegenerative conditions. The structures, in combination with mass spectrometry, led to the identification of two new post-translational modifications of assembled TDP-43, citrullination and monomethylation of R293, and indicate that they may facilitate filament formation and observed structural variation in individual filaments. The structures of TDP-43 filaments from type A FTLD-TDP will guide mechanistic studies of TDP-43 assembly, as well as the development of diagnostic and therapeutic compounds for TDP-43 proteinopathies. | |||||||||
History |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 19.4 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 14.7 KB 14.7 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 9.1 KB | Display | ![]() |
Images | ![]() | 36.8 KB | ||
Masks | ![]() | 64 MB | ![]() | |
Others | ![]() ![]() | 49.6 MB 49.6 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8cghMC ![]() 8cg3C ![]() 8cggC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Map
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Voxel size | X=Y=Z: 0.86 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Mask #1
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Density Histograms |
-Half map: #2
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Density Histograms |
-Half map: #1
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Density Histograms |
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Sample components
-Entire : TDP-43 amyloid filaments extracted from the frontal cortex of an ...
Entire | Name: TDP-43 amyloid filaments extracted from the frontal cortex of an individual with type A FTLD-TDP |
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Components |
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-Supramolecule #1: TDP-43 amyloid filaments extracted from the frontal cortex of an ...
Supramolecule | Name: TDP-43 amyloid filaments extracted from the frontal cortex of an individual with type A FTLD-TDP type: tissue / ID: 1 / Parent: 0 / Macromolecule list: all |
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Source (natural) | Organism: ![]() |
-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 |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 44.784742 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: 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 |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | helical reconstruction |
Aggregation state | filament |
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Sample preparation
Buffer | pH: 7.4 |
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Vitrification | Cryogen name: ETHANE |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 35.896 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.0 µm |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |