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- EMDB-16999: TAF15 amyloid fold in atypical FTLD - Individual 1 -

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Basic information

Entry
Database: EMDB / ID: EMD-16999
TitleTAF15 amyloid fold in atypical FTLD - Individual 1
Map data
Sample
  • Tissue: TAF15 atypical FTLD amyloid fold
    • Protein or peptide: TATA-binding protein-associated factor 2N
  • Ligand: water
Keywordsamyloid / amyloid-forming protein / neurodegeneration / RNA BINDING PROTEIN
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 / metal ion binding / nucleus / 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)
Methodhelical reconstruction / cryo EM / Resolution: 1.97 Å
AuthorsTetter S / Ryskeldi-Falcon B
Funding support United Kingdom, Switzerland, 4 items
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, 2023-
Header (metadata) releaseDec 6, 2023-
Map releaseDec 6, 2023-
UpdateFeb 7, 2024-
Current statusFeb 7, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_16999.png

Downloads & links

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Map

FileDownload / File: emd_16999.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.824 Å
Density
Contour LevelBy AUTHOR: 0.0172
Minimum - Maximum-0.031621322 - 0.079031184
Average (Standard dev.)0.00018621002 (±0.0041928496)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 210.944 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_16999_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_16999_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_16999_half_map_2.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : TAF15 atypical FTLD amyloid fold

EntireName: TAF15 atypical FTLD amyloid fold
Components
  • Tissue: TAF15 atypical FTLD amyloid fold
    • Protein or peptide: TATA-binding protein-associated factor 2N
  • Ligand: water

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Supramolecule #1: TAF15 atypical FTLD amyloid fold

SupramoleculeName: TAF15 atypical FTLD amyloid fold / type: tissue / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human) / Organ: brain / Tissue: frontal and temporal lobe

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Macromolecule #1: TATA-binding protein-associated factor 2N

MacromoleculeName: TATA-binding protein-associated factor 2N / type: protein_or_peptide / ID: 1 / Number of copies: 5 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 61.909 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MSDSGSYGQS GGEQQSYSTY GNPGSQGYGQ ASQSYSGYGQ TTDSSYGQNY SGYSSYGQSQ SGYSQSYGGY ENQKQSSYSQ QPYNNQGQQ QNMESSGSQG GRAPSYDQPD YGQQDSYDQQ SGYDQHQGSY DEQSNYDQQH DSYSQNQQSY HSQRENYSHH T QDDRRDVS ...String:
MSDSGSYGQS GGEQQSYSTY GNPGSQGYGQ ASQSYSGYGQ TTDSSYGQNY SGYSSYGQSQ SGYSQSYGGY ENQKQSSYSQ QPYNNQGQQ QNMESSGSQG GRAPSYDQPD YGQQDSYDQQ SGYDQHQGSY DEQSNYDQQH DSYSQNQQSY HSQRENYSHH T QDDRRDVS RYGEDNRGYG GSQGGGRGRG GYDKDGRGPM TGSSGGDRGG FKNFGGHRDY GPRTDADSES DNSDNNTIFV QG LGEGVST DQVGEFFKQI GIIKTNKKTG KPMINLYTDK DTGKPKGEAT VSFDDPPSAK AAIDWFDGKE FHGNIIKVSF ATR RPEFMR GGGSGGGRRG RGGYRGRGGF QGRGGDPKSG DWVCPNPSCG NMNFARRNSC NQCNEPRPED SRPSGGDFRG RGYG GERGY RGRGGRGGDR GGYGGDRSGG GYGGDRSSGG GYSGDRSGGG YGGDRSGGGY GGDRGGGYGG DRGGGYGGDR GGGYG GDRG GYGGDRGGGY GGDRGGYGGD RGGYGGDRGG YGGDRGGYGG DRSRGGYGGD RGGGSGYGGD RSGGYGGDRS GGGYGG DRG GGYGGDRGGY GGKMGGRNDY RNDQRNRPY

UniProtKB: TATA-binding protein-associated factor 2N

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Macromolecule #2: water

MacromoleculeName: water / type: ligand / ID: 2 / Number of copies: 115 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER / Water

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statefilament

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Sample preparation

BufferpH: 7.4 / Details: 100 mM NaCl, 10 mM Tris-HCl, pH 7.4
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 200 / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 µm
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 40.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
In silico model: generated from 2D classes using the sinogram approach
Final angle assignmentType: NOT APPLICABLE
Final reconstructionApplied symmetry - Helical parameters - Δz: 4.78 Å
Applied symmetry - Helical parameters - Δ&Phi: -2.12 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 1.97 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 95582
FSC plot (resolution estimation)

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