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- EMDB-51319: P301L tau filaments from human brain -

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Basic information

Entry
Database: EMDB / ID: EMD-51319
TitleP301L tau filaments from human brain
Map dataP301L tau fold
Sample
  • Tissue: P301L Tau Protein Filament
    • Protein or peptide: Isoform Tau-D of Microtubule-associated protein tau
KeywordsP301L tau / Frontotemporal dementia and parkinsonism linked to chromosome 17 / Electron cryo-microscopy / PROTEIN FIBRIL
Function / homology
Function and homology information


plus-end-directed organelle transport along microtubule / histone-dependent DNA binding / neurofibrillary tangle assembly / positive regulation of diacylglycerol kinase activity / axonal transport / negative regulation of establishment of protein localization to mitochondrion / neurofibrillary tangle / positive regulation of protein localization to synapse / microtubule lateral binding / tubulin complex ...plus-end-directed organelle transport along microtubule / histone-dependent DNA binding / neurofibrillary tangle assembly / positive regulation of diacylglycerol kinase activity / axonal transport / negative regulation of establishment of protein localization to mitochondrion / neurofibrillary tangle / positive regulation of protein localization to synapse / microtubule lateral binding / tubulin complex / phosphatidylinositol bisphosphate binding / main axon / negative regulation of kinase activity / regulation of long-term synaptic depression / negative regulation of tubulin deacetylation / generation of neurons / rRNA metabolic process / internal protein amino acid acetylation / regulation of chromosome organization / regulation of mitochondrial fission / axonal transport of mitochondrion / intracellular distribution of mitochondria / axon development / central nervous system neuron development / regulation of microtubule polymerization / apolipoprotein binding / microtubule polymerization / lipoprotein particle binding / minor groove of adenine-thymine-rich DNA binding / dynactin binding / negative regulation of mitochondrial membrane potential / glial cell projection / protein polymerization / axolemma / negative regulation of mitochondrial fission / regulation of microtubule polymerization or depolymerization / Caspase-mediated cleavage of cytoskeletal proteins / positive regulation of axon extension / regulation of microtubule cytoskeleton organization / Activation of AMPK downstream of NMDARs / regulation of cellular response to heat / positive regulation of protein localization / cytoplasmic microtubule organization / stress granule assembly / supramolecular fiber organization / regulation of calcium-mediated signaling / axon cytoplasm / somatodendritic compartment / positive regulation of microtubule polymerization / synapse assembly / cellular response to brain-derived neurotrophic factor stimulus / nuclear periphery / phosphatidylinositol binding / cellular response to nerve growth factor stimulus / positive regulation of superoxide anion generation / protein phosphatase 2A binding / regulation of autophagy / astrocyte activation / response to lead ion / microglial cell activation / synapse organization / Hsp90 protein binding / protein homooligomerization / PKR-mediated signaling / regulation of synaptic plasticity / : / memory / SH3 domain binding / microtubule cytoskeleton organization / cytoplasmic ribonucleoprotein granule / cellular response to reactive oxygen species / microtubule cytoskeleton / neuron projection development / cell-cell signaling / protein-folding chaperone binding / single-stranded DNA binding / actin binding / cellular response to heat / protein-macromolecule adaptor activity / double-stranded DNA binding / growth cone / cell body / microtubule binding / sequence-specific DNA binding / microtubule / amyloid fibril formation / dendritic spine / learning or memory / nuclear speck / neuron projection / membrane raft / axon / negative regulation of gene expression / neuronal cell body / DNA damage response / dendrite / protein kinase binding / enzyme binding / mitochondrion / DNA binding
Similarity search - Function
Microtubule-associated protein Tau / Microtubule associated protein, tubulin-binding repeat / : / Tau and MAP protein, tubulin-binding repeat / Tau and MAP proteins tubulin-binding repeat signature. / Tau and MAP proteins tubulin-binding repeat profile.
Similarity search - Domain/homology
Microtubule-associated protein tau
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 2.81 Å
AuthorsSchweighauser M / Shi Y / Murzin AG / Garringer HJ / Vidal R / Murrell JR / Erro ME / Seelaar H / Ferrer I / van Swieten JC ...Schweighauser M / Shi Y / Murzin AG / Garringer HJ / Vidal R / Murrell JR / Erro ME / Seelaar H / Ferrer I / van Swieten JC / Ghetti B / Scheres SHW / Goedert M
Funding support United Kingdom, China, United States, 6 items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MC_UP_A025_1013 United Kingdom
Medical Research Council (MRC, United Kingdom)MC_1051284291 United Kingdom
National Natural Science Foundation of China (NSFC)82371415 China
National Institutes of Health/National Institute on Aging (NIH/NIA)P30-AG010133 United States
National Institutes of Health/National Institute on Aging (NIH/NIA)R01-AG080001 United States
National Institutes of Health/National Institute on Aging (NIH/NIA)RF1-AG071177 United States
CitationJournal: bioRxiv / Year: 2024
Title: Novel tau filament folds in individuals with mutations P301L and P301T.
Authors: Manuel Schweighauser / Yang Shi / Alexey G Murzin / Holly J Garringer / Ruben Vidal / Jill R Murrell / M Elena Erro / Harro Seelaar / Isidro Ferrer / John C van Swieten / Bernardino Ghetti / ...Authors: Manuel Schweighauser / Yang Shi / Alexey G Murzin / Holly J Garringer / Ruben Vidal / Jill R Murrell / M Elena Erro / Harro Seelaar / Isidro Ferrer / John C van Swieten / Bernardino Ghetti / Sjors H W Scheres / Michel Goedert /
Abstract: Mutations in , the microtubule-associated protein tau gene, give rise to cases of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) with abundant filamentous tau inclusions ...Mutations in , the microtubule-associated protein tau gene, give rise to cases of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) with abundant filamentous tau inclusions in brain cells. Individuals with pathological variants exhibit behavioural changes, cognitive impairment and signs of parkinsonism. Missense mutations of residue P301, which are the most common mutations associated with FTDP-17, give rise to the assembly of mutant four-repeat tau into filamentous inclusions, in the absence of extracellular deposits. Here we report the cryo-EM structures of tau filaments from five individuals belonging to three unrelated families with mutation P301L and from one individual belonging to a family with mutation P301T. A novel three-lobed tau fold resembling the two-layered tau fold of Pick's disease was present in all cases with the P301L tau mutation. Two different tau folds were found in the case with mutation P301T, the less abundant of which was a variant of the three-lobed fold. The major P301T tau fold was V-shaped, with partial similarity to the four-layered tau folds of corticobasal degeneration and argyrophilic grain disease. These findings suggest that FTDP-17 with mutations in P301 should be considered distinct inherited tauopathies and that model systems with these mutations should be used with caution in the study of sporadic tauopathies.
History
DepositionAug 12, 2024-
Header (metadata) releaseSep 11, 2024-
Map releaseSep 11, 2024-
UpdateSep 11, 2024-
Current statusSep 11, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_51319.png

Downloads & links

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Map

FileDownload / File: emd_51319.map.gz / Format: CCP4 / Size: 325 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationP301L tau fold
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.82 Å/pix.
x 440 pix.
= 362.56 Å		0.82 Å/pix.
x 440 pix.
= 362.56 Å		0.82 Å/pix.
x 440 pix.
= 362.56 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.824 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.007
Minimum - Maximum-0.022167394 - 0.04580325
Average (Standard dev.)0.00012456246 (±0.0014967343)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions440440440
Spacing440440440
CellA=B=C: 362.56 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_51319_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: P301L tau fold

Fileemd_51319_half_map_1.map
AnnotationP301L tau fold
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: P301L tau fold

Fileemd_51319_half_map_2.map
AnnotationP301L tau fold
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : P301L Tau Protein Filament

EntireName: P301L Tau Protein Filament
Components
  • Tissue: P301L Tau Protein Filament
    • Protein or peptide: Isoform Tau-D of Microtubule-associated protein tau

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Supramolecule #1: P301L Tau Protein Filament

SupramoleculeName: P301L Tau Protein Filament / type: tissue / ID: 1 / Parent: 0 / Macromolecule list: all
Details: P301L tau filaments extracted from the brain of an individual with frontotemporal dementia.
Source (natural)Organism: Homo sapiens (human) / Organ: Brain / Tissue: Parietal Cortex

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Macromolecule #1: Isoform Tau-D of Microtubule-associated protein tau

MacromoleculeName: Isoform Tau-D of Microtubule-associated protein tau / type: protein_or_peptide / ID: 1 / Details: P301L / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human) / Organ: Brain
Molecular weightTheoretical: 11.362093 KDa
SequenceString:
GGGKVQIINK KLDLSNVQSK CGSKDNIKHV LGGGSVQIVY KPVDLSKVTS KCGSLGNIHH KPGGGQVEVK SEKLDFKDRV QSKIGSLDN ITHVPGGGNK KIETHKLT

UniProtKB: Microtubule-associated protein tau

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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
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 30.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.4 µm / Nominal defocus min: 1.7 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 4.8 Å
Applied symmetry - Helical parameters - Δ&Phi: -0.63 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 2.81 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 4.0) / Number images used: 68559
Segment selectionNumber selected: 183040 / Software - Name: RELION (ver. 4.0)
Startup modelType of model: NONE
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementProtocol: AB INITIO MODEL
Output model

PDB-9gg0:
P301L tau filaments from human brain

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