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- PDB-9tkk: TAF15 amyloid filament fold C variant 1 -

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Basic information

Entry
Database: PDB / ID: 9tkk
TitleTAF15 amyloid filament fold C variant 1
ComponentsTATA-binding protein-associated factor 2N
KeywordsPROTEIN FIBRIL / Amyloid Neurodegeneration Frontotemporal lobar degeneration
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 / transcription coregulator activity / mRNA 3'-UTR binding / Regulation of TP53 Activity through Phosphorylation / positive regulation of DNA-templated transcription / DNA binding / RNA binding / zinc ion binding / nucleoplasm / nucleus / cytoplasm
Similarity search - Function
TAF15/EWS/TLS family / Zinc finger domain / Zinc finger RanBP2 type profile. / Zinc finger, RanBP2-type superfamily / Zinc finger RanBP2-type signature. / 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 superfamily / Zinc finger RanBP2-type signature. / 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: 2.38 Å
AuthorsTetter, S. / Varghese, N.R. / Ryskeldi-Falcon, B.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MC_UP_1201/25 United Kingdom
CitationJournal: bioRxiv / Year: 2026
Title: Distinct TAF15 amyloid filament folds define multiple subtypes of FTLD-TAF15.
Authors: Stephan Tetter / Nikhil R Varghese / Alexey G Murzin / Wouter De Coster / Marleen Van den Broeck / Sigrun Roeber / Jeffrey T Joseph / Kathy Newell / Rudolf Castellani / Sumit Das / Lee-Cyn ...Authors: Stephan Tetter / Nikhil R Varghese / Alexey G Murzin / Wouter De Coster / Marleen Van den Broeck / Sigrun Roeber / Jeffrey T Joseph / Kathy Newell / Rudolf Castellani / Sumit Das / Lee-Cyn Ang / Matthis Synofzik / Jochen Herms / Rosa Rademakers / Bernardino Ghetti / Tammaryn Lashley / Ian R A Mackenzie / Manuela Neumann / Benjamin Ryskeldi-Falcon /
Abstract: Neurodegenerative diseases are characterised by the assembly of a limited number of disease-specific proteins into amyloid filaments, which form intracellular inclusions or extracellular deposits in ...Neurodegenerative diseases are characterised by the assembly of a limited number of disease-specific proteins into amyloid filaments, which form intracellular inclusions or extracellular deposits in the central nervous system (CNS). We previously found that amyloid filaments of TATA-binding protein-associated factor 15 (TAF15) characterise a subtype of frontotemporal lobar degeneration with FET protein-immunoreactive inclusions (FTLD-FET), termed atypical FTLD with ubiquitin-positive inclusions (aFTLD-U), which causes early-onset, rapidly progressive behavioural variant frontotemporal dementia (FTD). However, it was not clear if TAF15 proteinopathy was more widespread in neurodegenerative diseases. Two additional FTLD-FET subtypes have been proposed, neuronal intermediate filament inclusion body disease (NIFID) and basophilic inclusion body disease (BIBD), which have more heterogenous clinical presentations including FTD, motor neuron diseases (MND) and movement disorders. Here, we used electron cryo-microscopy (cryo-EM) to determine a total of 32 amyloid filament structures from the brains of 17 individuals encompassing all three proposed subtypes of FTLD-FET and their diverse clinical presentations. All cases were characterised by TAF15 filaments, in the absence of filaments of the other FET proteins, fused in sarcoma (FUS) and Ewing's sarcoma (EWS). All three aFTLD-U cases had the previously-reported TAF15 fold. Unexpectedly, we found four distinct TAF15 folds among 11 NIFID cases. Eight of these cases shared a common fold, while the remaining three were each distinct. Furthermore, we found distinct TAF15 folds for each of the three BIBD cases. Neuropathological reassessment of the neocortical TAF15 inclusion pathology of these cases distinguished the NIFID cases with the common fold from the others. Thus, TAF15 filament structures form the basis of a new, expanded classification of FTLD-FET subtypes. Moreover, we discovered a TAF15 Y38C variant in the filament fold of one of the individuals with BIBD. The structure is unable to incorporate wild-type TAF15, despite the individual being heterozygous, suggesting that this variant drives TAF15 filament assembly. This study provides structural and genetic evidence that TAF15 amyloid filaments underlie the diverse group of neurodegenerative diseases currently termed FTLD-FET, which we therefore rename FTLD-TAF15.
History
DepositionDec 10, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 18, 2026Provider: repository / Type: Initial release
Revision 1.0Feb 18, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Feb 18, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Feb 18, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Feb 18, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Feb 18, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Feb 18, 2026Data content type: Mask / Part number: 1 / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0Feb 18, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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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
B: TATA-binding protein-associated factor 2N
C: TATA-binding protein-associated factor 2N
D: TATA-binding protein-associated factor 2N


Theoretical massNumber of molelcules
Total (without water)247,6364
Polymers247,6364
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Noncrystallographic symmetry (NCS)NCS oper:
IDCodeMatrixVector
1given(1), (1), (1)
2given(0.999648, -0.026526), (0.026526, 0.999648), (1)2.2362, -2.1777, -4.83
3given(0.999648, 0.026526), (-0.026526, 0.999648), (1)-2.1777, 2.2362, 4.83
4given(0.998593, 0.053033), (-0.053033, 0.998593), (1)-4.2953, 4.5294, 9.66

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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.: 4 / Source method: isolated from a natural source
Details: Amyloid filament formed by TAF15. Each chain is comprised of TAF15 residues 20-98.
Source: (natural) Homo sapiens (human) / References: UniProt: Q92804
Has protein modificationN

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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: TATA-binding protein-associated factor 2N / Type: TISSUE / Details: TAF15 amyloid filament fold C variant 1 / Entity ID: all / Source: NATURAL
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human) / Organ: Brain / Tissue: Prefrontal cortex
Buffer solutionpH: 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

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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: 1500 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: TFS FALCON 4i (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 36121

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Processing

EM software
IDNameVersionCategory
1RELION5.0.1particle selection
13RELION5.0.13D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: -1.52 ° / Axial rise/subunit: 4.83 Å / Axial symmetry: C1
Particle selectionNum. of particles selected: 136044
3D reconstructionResolution: 2.38 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 71272 / Symmetry type: HELICAL
RefinementResolution: 2.38→81.9 Å / Cor.coef. Fo:Fc: 0.838 / WRfactor Rwork: 0.361 / SU B: 5.574 / SU ML: 0.121 / Average fsc free: 0 / Average fsc overall: 0.8496 / Average fsc work: 0.8496 / ESU R: 0.106
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rwork0.3611 41693 -
all0.361 --
Rfree--0 %
obs--100 %
Solvent computationSolvent model: NONE
Displacement parametersBiso mean: 42.713 Å2
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0070.011617
ELECTRON MICROSCOPYr_bond_other_d00.016465
ELECTRON MICROSCOPYr_angle_refined_deg1.5131.755830
ELECTRON MICROSCOPYr_angle_other_deg0.5271.7221077
ELECTRON MICROSCOPYr_dihedral_angle_1_deg6.413578
ELECTRON MICROSCOPYr_dihedral_angle_3_deg10.8981086
ELECTRON MICROSCOPYr_dihedral_angle_6_deg13.0631039
ELECTRON MICROSCOPYr_chiral_restr0.0780.267
ELECTRON MICROSCOPYr_gen_planes_refined0.0070.02802
ELECTRON MICROSCOPYr_gen_planes_other0.0010.02174
ELECTRON MICROSCOPYr_nbd_refined0.2250.273
ELECTRON MICROSCOPYr_symmetry_nbd_other0.2090.2311
ELECTRON MICROSCOPYr_nbtor_refined0.1960.2321
ELECTRON MICROSCOPYr_symmetry_nbtor_other0.0810.2371
ELECTRON MICROSCOPYr_xyhbond_nbd_refined0.1840.29
ELECTRON MICROSCOPYr_symmetry_nbd_refined0.1390.215
ELECTRON MICROSCOPYr_nbd_other0.1910.290
ELECTRON MICROSCOPYr_symmetry_xyhbond_nbd_refined0.0550.212
ELECTRON MICROSCOPYr_mcbond_it3.9993.86315
ELECTRON MICROSCOPYr_mcbond_other3.9693.86315
ELECTRON MICROSCOPYr_mcangle_it5.1926.977392
ELECTRON MICROSCOPYr_mcangle_other5.1876.978393
ELECTRON MICROSCOPYr_scbond_it7.2574.812302
ELECTRON MICROSCOPYr_scbond_other7.2454.817303
ELECTRON MICROSCOPYr_scangle_it11.1038.461438
ELECTRON MICROSCOPYr_scangle_other11.098.463439
ELECTRON MICROSCOPYr_lrange_it13.13241.466672
ELECTRON MICROSCOPYr_lrange_other13.12341.475673
LS refinement shell

Refine-ID: ELECTRON MICROSCOPY / Num. reflection Rfree: _ / Total num. of bins used: 20 / % reflection obs: 100 %

Resolution (Å)Rfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc workWRfactor Rwork
2.38-2.4421.46231001.46231000.5671.462
2.442-2.5090.82329990.82329990.6760.823
2.509-2.5810.71629400.71629400.7410.716
2.581-2.6610.60628230.60628230.7840.606
2.661-2.7480.53627580.53627580.8140.536
2.748-2.8440.43226080.43226080.8630.432
2.844-2.9510.35726210.35726210.8890.357
2.951-3.0720.3124480.3124480.9080.31
3.072-3.2080.30223830.30223830.9150.302
3.208-3.3640.26122620.26122620.9370.261
3.364-3.5460.2721560.2721560.950.27
3.546-3.7610.27220560.27220560.9540.272
3.761-4.020.25818950.25818950.9560.258
4.02-4.3410.28817730.28817730.9490.288
4.341-4.7540.29616560.29616560.9460.296
4.754-5.3130.2814550.2814550.9410.28
5.313-6.1310.27413300.27413300.9330.274
6.131-7.4980.30211000.30211000.9170.302
7.498-10.5590.3748520.3748520.8880.374
10.559-81.90.6994770.6994770.9490.699

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