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- PDB-8ons: TAF15 amyloid fold in atypical FTLD - Individual 1 -

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Basic information

Entry
Database: PDB / ID: 8ons
TitleTAF15 amyloid fold in atypical FTLD - Individual 1
ComponentsTATA-binding protein-associated factor 2N
KeywordsRNA BINDING PROTEIN / amyloid / amyloid-forming protein / neurodegeneration
Function / homology
Function and homology information


mRNA stabilization / HIV Transcription Initiation / RNA Polymerase II HIV Promoter Escape / Transcription of the HIV genome / RNA Polymerase II Promoter Escape / RNA Polymerase II Transcription Pre-Initiation And Promoter Opening / RNA Polymerase II Transcription Initiation / RNA Polymerase II Transcription Initiation And Promoter Clearance / RNA Polymerase II Pre-transcription Events / RNA splicing ...mRNA stabilization / HIV Transcription Initiation / RNA Polymerase II HIV Promoter Escape / Transcription of the HIV genome / RNA Polymerase II Promoter Escape / RNA Polymerase II Transcription Pre-Initiation And Promoter Opening / RNA Polymerase II Transcription Initiation / RNA Polymerase II Transcription Initiation And Promoter Clearance / RNA Polymerase II Pre-transcription Events / RNA splicing / mRNA 3'-UTR binding / transcription coregulator activity / Regulation of TP53 Activity through Phosphorylation / positive regulation of DNA-templated transcription / DNA binding / RNA binding / nucleoplasm / nucleus / metal ion binding / cytoplasm
Similarity search - Function
TAF15/EWS/TLS family / Zinc finger domain / Zinc finger RanBP2 type profile. / Zinc finger RanBP2-type signature. / Zinc finger, RanBP2-type superfamily / Zinc finger, RanBP2-type / RNA recognition motif / RNA recognition motif / Eukaryotic RNA Recognition Motif (RRM) profile. / RNA recognition motif domain ...TAF15/EWS/TLS family / Zinc finger domain / Zinc finger RanBP2 type profile. / Zinc finger RanBP2-type signature. / Zinc finger, RanBP2-type superfamily / Zinc finger, RanBP2-type / 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
TATA-binding protein-associated factor 2N
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 1.97 Å
AuthorsTetter, S. / Ryskeldi-Falcon, B.
Funding support United Kingdom, Switzerland, 4items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MC_UP_1201/25 United Kingdom
Alzheimers Research UK (ARUK)ARUK-RS2019-001 United Kingdom
Swiss National Science FoundationP500PB_206890 Switzerland
Leverhulme TrustECF-2022-610 United Kingdom
CitationJournal: Nature / Year: 2024
Title: TAF15 amyloid filaments in frontotemporal lobar degeneration.
Authors: Stephan Tetter / Diana Arseni / Alexey G Murzin / Yazead Buhidma / Sew Y Peak-Chew / Holly J Garringer / Kathy L Newell / Ruben Vidal / Liana G Apostolova / Tammaryn Lashley / Bernardino ...Authors: Stephan Tetter / Diana Arseni / Alexey G Murzin / Yazead Buhidma / Sew Y Peak-Chew / Holly J Garringer / Kathy L Newell / Ruben Vidal / Liana G Apostolova / Tammaryn Lashley / Bernardino Ghetti / Benjamin Ryskeldi-Falcon /
Abstract: Frontotemporal lobar degeneration (FTLD) causes frontotemporal dementia (FTD), the most common form of dementia after Alzheimer's disease, and is often also associated with motor disorders. The ...Frontotemporal lobar degeneration (FTLD) causes frontotemporal dementia (FTD), the most common form of dementia after Alzheimer's disease, and is often also associated with motor disorders. The pathological hallmarks of FTLD are neuronal inclusions of specific, abnormally assembled proteins. In the majority of cases the inclusions contain amyloid filament assemblies of TAR DNA-binding protein 43 (TDP-43) or tau, with distinct filament structures characterizing different FTLD subtypes. The presence of amyloid filaments and their identities and structures in the remaining approximately 10% of FTLD cases are unknown but are widely believed to be composed of the protein fused in sarcoma (FUS, also known as translocated in liposarcoma). As such, these cases are commonly referred to as FTLD-FUS. Here we used cryogenic electron microscopy (cryo-EM) to determine the structures of amyloid filaments extracted from the prefrontal and temporal cortices of four individuals with FTLD-FUS. Surprisingly, we found abundant amyloid filaments of the FUS homologue TATA-binding protein-associated factor 15 (TAF15, also known as TATA-binding protein-associated factor 2N) rather than of FUS itself. The filament fold is formed from residues 7-99 in the low-complexity domain (LCD) of TAF15 and was identical between individuals. Furthermore, we found TAF15 filaments with the same fold in the motor cortex and brainstem of two of the individuals, both showing upper and lower motor neuron pathology. The formation of TAF15 amyloid filaments with a characteristic fold in FTLD establishes TAF15 proteinopathy in neurodegenerative disease. The structure of TAF15 amyloid filaments provides a basis for the development of model systems of neurodegenerative disease, as well as for the design of diagnostic and therapeutic tools targeting TAF15 proteinopathy.
History
DepositionApr 3, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 6, 2023Provider: repository / Type: Initial release
Revision 1.1Dec 20, 2023Group: Database references / Category: citation / citation_author / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Jan 24, 2024Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year
Revision 1.3Feb 7, 2024Group: Database references / Category: citation_author / Item: _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: TATA-binding protein-associated factor 2N
C: TATA-binding protein-associated factor 2N
E: TATA-binding protein-associated factor 2N
G: TATA-binding protein-associated factor 2N
I: TATA-binding protein-associated factor 2N


Theoretical massNumber of molelcules
Total (without water)309,5455
Polymers309,5455
Non-polymers00
Water2,072115
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Noncrystallographic symmetry (NCS)NCS oper:
IDCodeMatrixVector
1given(1), (), ()
2given(0.997253, -0.074076), (), ()8.10277
3given(0.999313, -0.037064), (), ()3.98165
4given(0.999313, 0.037064), (), ()-3.83671
5given(0.997253, 0.074076), (-0.074076, 0.997253), (1)-7.52322, 8.10277, 9.55048

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Components

#1: Protein
TATA-binding protein-associated factor 2N / 68 kDa TATA-binding protein-associated factor / TAF(II)68 / TAFII68 / RNA-binding protein 56


Mass: 61909.000 Da / Num. of mol.: 5
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TAF15, RBP56, TAF2N / Organ (production host): Brain / Production host: Homo sapiens (human) / Tissue (production host): Frontal/temporal lobe / References: UniProt: Q92804
#2: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 115 / Source method: isolated from a natural source / Formula: H2O

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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: TAF15 atypical FTLD amyloid fold / Type: TISSUE / Entity ID: #1 / Source: NATURAL
Source (natural)Organism: Homo sapiens (human) / Organ: brain / Tissue: frontal and temporal lobe
Buffer solutionpH: 7.4 / Details: 100 mM NaCl, 10 mM Tris-HCl, pH 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 200 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

SoftwareName: REFMAC / Version: 5.8.0352 / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: -2.12 ° / Axial rise/subunit: 4.78 Å / Axial symmetry: C1
3D reconstructionResolution: 1.97 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 95582 / Symmetry type: HELICAL
RefinementResolution: 1.97→1.97 Å / Cor.coef. Fo:Fc: 0.822 / SU B: 2.434 / SU ML: 0.061 / ESU R: 0.051
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflection
Rwork0.33771 --
obs0.33771 132602 100 %
Solvent computationSolvent model: PARAMETERS FOR MASK CACLULATION
Displacement parametersBiso mean: 35.299 Å2
Refinement stepCycle: 1 / Total: 720
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0030.011712
ELECTRON MICROSCOPYr_bond_other_d00.017484
ELECTRON MICROSCOPYr_angle_refined_deg0.8271.656957
ELECTRON MICROSCOPYr_angle_other_deg0.3331.5411164
ELECTRON MICROSCOPYr_dihedral_angle_1_deg6.712592
ELECTRON MICROSCOPYr_dihedral_angle_2_deg
ELECTRON MICROSCOPYr_dihedral_angle_3_deg9.1521099
ELECTRON MICROSCOPYr_dihedral_angle_4_deg
ELECTRON MICROSCOPYr_chiral_restr0.0430.278
ELECTRON MICROSCOPYr_gen_planes_refined0.0030.02878
ELECTRON MICROSCOPYr_gen_planes_other0.0010.02146
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_it2.253.758371
ELECTRON MICROSCOPYr_mcbond_other2.2253.742370
ELECTRON MICROSCOPYr_mcangle_it3.8925.612462
ELECTRON MICROSCOPYr_mcangle_other3.8915.625463
ELECTRON MICROSCOPYr_scbond_it3.1594.058341
ELECTRON MICROSCOPYr_scbond_other3.1554.07342
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other5.2515.981496
ELECTRON MICROSCOPYr_long_range_B_refined7.10142.13740
ELECTRON MICROSCOPYr_long_range_B_other7.08941.964737
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
LS refinement shellResolution: 2.03→2.083 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork0.778 9858 -
obs--100 %

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