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- PDB-8cg3: Structure of TDP-43 amyloid filament from type A FTLD-TDP (variant 1) -

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Basic information

Entry
Database: PDB / ID: 8cg3
TitleStructure of TDP-43 amyloid filament from type A FTLD-TDP (variant 1)
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 membraneless 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 membraneless organelle / negative regulation by host of viral transcription / pre-mRNA intronic binding / response to endoplasmic reticulum stress / RNA splicing / negative regulation of protein phosphorylation / mRNA 3'-UTR binding / molecular condensate scaffold activity / regulation of circadian rhythm / regulation of protein stability / positive regulation of insulin secretion / positive regulation of protein import into nucleus / mRNA processing / cytoplasmic stress granule / 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 / chromatin / mitochondrion / DNA binding / RNA binding / nucleoplasm / identical protein binding / nucleus
Similarity search - Function
TAR DNA-binding protein 43, N-terminal / : / TAR DNA-binding protein 43, N-terminal domain / TAR DNA-binding protein 43, C-terminal / 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: 2.39 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 3, 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
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551
Noncrystallographic symmetry (NCS)NCS oper:
IDCodeMatrixVector
1given(1), (1), (1)
2given(0.999789, 0.020517), (-0.020517, 0.999789), (1)-2.23534, 2.28168, -4.99609
3given(0.999789, -0.020517), (0.020517, 0.999789), (1)2.28168, -2.23534, 4.99609
4given(0.999158, -0.041025), (0.041025, 0.999158), (1)4.60875, -4.4234, 9.99218
5given(0.998106, -0.061516), (0.061516, 0.998106), (1)6.98022, -6.56325, 14.98827

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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) / Tissue: Brain / Gene: TARDBP, TDP43 / Production host: Homo sapiens (human) / Tissue (production host): Brain / 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 FIELD / 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
12RELION43D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: 1.175 ° / Axial rise/subunit: 4.996 Å / Axial symmetry: C1
3D reconstructionResolution: 2.39 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 71963 / Symmetry type: HELICAL
RefinementResolution: 2.39→86 Å / Cor.coef. Fo:Fc: 0.822 / SU B: 5.44 / SU ML: 0.118 / ESU R: 0.099
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflection
Rwork0.39133 --
obs0.39133 56669 100 %
Solvent computationSolvent model: PARAMETERS FOR MASK CACLULATION
Displacement parametersBiso mean: 51.961 Å2
Refinement stepCycle: 1 / Total: 608
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0080.011617
ELECTRON MICROSCOPYr_bond_other_d00.016492
ELECTRON MICROSCOPYr_angle_refined_deg1.7131.609820
ELECTRON MICROSCOPYr_angle_other_deg0.4831.5411160
ELECTRON MICROSCOPYr_dihedral_angle_1_deg6.851588
ELECTRON MICROSCOPYr_dihedral_angle_2_deg4.121103
ELECTRON MICROSCOPYr_dihedral_angle_3_deg14.1361089
ELECTRON MICROSCOPYr_dihedral_angle_4_deg
ELECTRON MICROSCOPYr_chiral_restr0.0620.269
ELECTRON MICROSCOPYr_gen_planes_refined0.0050.02783
ELECTRON MICROSCOPYr_gen_planes_other00.02125
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_it4.134.695355
ELECTRON MICROSCOPYr_mcbond_other4.0624.692355
ELECTRON MICROSCOPYr_mcangle_it7.0567.003442
ELECTRON MICROSCOPYr_mcangle_other7.0527.014443
ELECTRON MICROSCOPYr_scbond_it5.5885.997262
ELECTRON MICROSCOPYr_scbond_other5.5585.967261
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other9.2188.471379
ELECTRON MICROSCOPYr_long_range_B_refined12.65855.711534
ELECTRON MICROSCOPYr_long_range_B_other12.755.909535
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
LS refinement shellResolution: 2.39→2.452 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork1.188 4203 -
obs--100 %

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