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- PDB-8cgh: Structure of TDP-43 amyloid filament from type A FTLD-TDP (variant 3) -

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Basic information

Entry
Database: PDB / ID: 8cgh
TitleStructure of TDP-43 amyloid filament from type A FTLD-TDP (variant 3)
ComponentsTAR DNA-binding protein 43
KeywordsPROTEIN FIBRIL / 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
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 / negative regulation of protein phosphorylation / RNA splicing / 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: 2.68 Å
AuthorsArseni, D. / Ryskeldi-Falcon, B.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MC_UP_1201/25 United Kingdom
CitationJournal: Nature / Year: 2023
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
DepositionFeb 4, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 2, 2023Provider: repository / Type: Initial release
Revision 1.1Aug 16, 2023Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Aug 30, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
U: TAR DNA-binding protein 43
A: TAR DNA-binding protein 43
B: TAR DNA-binding protein 43
C: TAR DNA-binding protein 43
D: TAR DNA-binding protein 43


Theoretical massNumber of molelcules
Total (without water)223,9245
Polymers223,9245
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551
Noncrystallographic symmetry (NCS)NCS oper:
IDCodeMatrixVector
1given(1), (1), (1)
2given(0.99905, 0.043584), (-0.043584, 0.99905), (1)-4.69314, 4.90235, -9.96018
3given(0.999762, 0.021797), (-0.021797, 0.999762), (1)-2.37329, 2.4256, -4.98009
4given(0.999762, -0.021797), (0.021797, 0.999762), (1)2.4256, -2.37329, 4.98009
5given(0.99905, -0.043584), (0.043584, 0.99905), (1)4.90235, -4.69314, 9.96018

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Components

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


Mass: 44784.742 Da / Num. of mol.: 5
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TARDBP, TDP43 / Production host: Homo sapiens (human) / References: UniProt: Q13148

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Experimental details

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Experiment

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

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Sample preparation

ComponentName: TDP-43 amyloid filaments extracted from the frontal cortex of an individual with type A FTLD-TDP
Type: TISSUE / Entity ID: all / Source: NATURAL
Source (natural)Organism: Homo sapiens (human) / Tissue: Brain
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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: 2200 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 35.896 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: REFMAC / Version: 5.8.0350 / Classification: refinement
EM software
IDNameVersionCategory
2EPUimage acquisition
13RELION43D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: 1.248 ° / Axial rise/subunit: 4.98 Å / Axial symmetry: C1
3D reconstructionResolution: 2.68 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 16260 / Symmetry type: HELICAL
RefinementResolution: 2.68→2.68 Å / Cor.coef. Fo:Fc: 0.824 / SU B: 9.956 / SU ML: 0.197 / ESU R: 0.126
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflection
Rwork0.40576 --
obs0.40576 40158 100 %
Solvent computationSolvent model: PARAMETERS FOR MASK CACLULATION
Displacement parametersBiso mean: 44.648 Å2
Refinement stepCycle: 1 / Total: 542
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0070.011549
ELECTRON MICROSCOPYr_bond_other_d00.016437
ELECTRON MICROSCOPYr_angle_refined_deg1.471.601730
ELECTRON MICROSCOPYr_angle_other_deg0.4821.541031
ELECTRON MICROSCOPYr_dihedral_angle_1_deg8.183579
ELECTRON MICROSCOPYr_dihedral_angle_2_deg4.144101
ELECTRON MICROSCOPYr_dihedral_angle_3_deg14.6031080
ELECTRON MICROSCOPYr_dihedral_angle_4_deg
ELECTRON MICROSCOPYr_chiral_restr0.0660.263
ELECTRON MICROSCOPYr_gen_planes_refined0.0050.02690
ELECTRON MICROSCOPYr_gen_planes_other0.0010.02106
ELECTRON MICROSCOPYr_nbd_refined
ELECTRON MICROSCOPYr_nbd_other
ELECTRON MICROSCOPYr_nbtor_refined
ELECTRON MICROSCOPYr_nbtor_other
ELECTRON MICROSCOPYr_xyhbond_nbd_refined
ELECTRON MICROSCOPYr_xyhbond_nbd_other
ELECTRON MICROSCOPYr_metal_ion_refined
ELECTRON MICROSCOPYr_metal_ion_other
ELECTRON MICROSCOPYr_symmetry_vdw_refined
ELECTRON MICROSCOPYr_symmetry_vdw_other
ELECTRON MICROSCOPYr_symmetry_hbond_refined
ELECTRON MICROSCOPYr_symmetry_hbond_other
ELECTRON MICROSCOPYr_symmetry_metal_ion_refined
ELECTRON MICROSCOPYr_symmetry_metal_ion_other
ELECTRON MICROSCOPYr_mcbond_it3.7094.323319
ELECTRON MICROSCOPYr_mcbond_other3.6554.317319
ELECTRON MICROSCOPYr_mcangle_it6.0716.474397
ELECTRON MICROSCOPYr_mcangle_other6.1036.489398
ELECTRON MICROSCOPYr_scbond_it5.1964.887230
ELECTRON MICROSCOPYr_scbond_other5.1614.851229
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other8.3616.99334
ELECTRON MICROSCOPYr_long_range_B_refined11.22352.105509
ELECTRON MICROSCOPYr_long_range_B_other11.32752.293510
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
LS refinement shellResolution: 2.6→2.668 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork0.857 2956 -
obs--100 %

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