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- EMDB-18990: CryoEM map of tau PHF sarkosyl-extracted from a human AD patient ... -

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Basic information

Entry
Database: EMDB / ID: EMD-18990
TitleCryoEM map of tau PHF sarkosyl-extracted from a human AD patient (associated with in situ tomography)
Map dataPostprocessed sharpened map of tau PHF fibrils extracted from AD patient brain
Sample
  • Complex: tau PHF amyloid fibril
    • Protein or peptide: Microtubule-associated protein tau
KeywordsAmyloid / Alzheimer's / tauopathy / fibril / filament / helical / PROTEIN FIBRIL
Function / homology
Function and homology information


plus-end-directed organelle transport along microtubule / axonal transport / histone-dependent DNA binding / neurofibrillary tangle assembly / positive regulation of diacylglycerol kinase activity / 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 / axonal transport / histone-dependent DNA binding / neurofibrillary tangle assembly / positive regulation of diacylglycerol kinase activity / 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 / regulation of long-term synaptic depression / negative regulation of kinase activity / negative regulation of tubulin deacetylation / generation of neurons / positive regulation of protein localization / regulation of chromosome organization / rRNA metabolic process / internal protein amino acid acetylation / regulation of mitochondrial fission / intracellular distribution of mitochondria / axonal transport of mitochondrion / axon development / central nervous system neuron development / regulation of microtubule polymerization / microtubule polymerization / minor groove of adenine-thymine-rich DNA binding / lipoprotein particle binding / dynactin binding / apolipoprotein binding / glial cell projection / negative regulation of mitochondrial membrane potential / protein polymerization / negative regulation of mitochondrial fission / axolemma / Caspase-mediated cleavage of cytoskeletal proteins / regulation of microtubule polymerization or depolymerization / positive regulation of axon extension / regulation of microtubule cytoskeleton organization / Activation of AMPK downstream of NMDARs / supramolecular fiber organization / regulation of cellular response to heat / stress granule assembly / cytoplasmic microtubule organization / regulation of calcium-mediated signaling / axon cytoplasm / positive regulation of microtubule polymerization / somatodendritic compartment / cellular response to brain-derived neurotrophic factor stimulus / synapse assembly / phosphatidylinositol binding / nuclear periphery / 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 / synapse organization / microglial cell activation / Hsp90 protein binding / regulation of synaptic plasticity / PKR-mediated signaling / protein homooligomerization / memory / cytoplasmic ribonucleoprotein granule / SH3 domain binding / microtubule cytoskeleton organization / cellular response to reactive oxygen species / activation of cysteine-type endopeptidase activity involved in apoptotic process / neuron projection development / microtubule cytoskeleton / cell-cell signaling / protein-macromolecule adaptor activity / actin binding / cellular response to heat / single-stranded DNA binding / protein-folding chaperone binding / cell body / growth cone / microtubule binding / double-stranded DNA binding / microtubule / amyloid fibril formation / sequence-specific DNA binding / 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, tubulin-binding repeat / Microtubule-associated protein Tau / 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: 3.0 Å
AuthorsWilkinson MW / Gilbert MAG / Fatima N / Jenkins J / O'Sullivan TJ / Schertel A / Halfon Y / Morrema THJ / Geibel M / Ranson NA ...Wilkinson MW / Gilbert MAG / Fatima N / Jenkins J / O'Sullivan TJ / Schertel A / Halfon Y / Morrema THJ / Geibel M / Ranson NA / Radford SE / Hoozemans JJM / Frank RAW
Funding support United Kingdom, 4 items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MR/T011149/1 United Kingdom
Wellcome Trust204963 United Kingdom
UK Research and Innovation (UKRI)MR/V022644/1 United Kingdom
Wellcome Trust221524/Z/20/Z United Kingdom
CitationJournal: Nature / Year: 2024
Title: CryoET of β-amyloid and tau within postmortem Alzheimer's disease brain.
Authors: Madeleine A G Gilbert / Nayab Fatima / Joshua Jenkins / Thomas J O'Sullivan / Andreas Schertel / Yehuda Halfon / Martin Wilkinson / Tjado H J Morrema / Mirjam Geibel / Randy J Read / Neil A ...Authors: Madeleine A G Gilbert / Nayab Fatima / Joshua Jenkins / Thomas J O'Sullivan / Andreas Schertel / Yehuda Halfon / Martin Wilkinson / Tjado H J Morrema / Mirjam Geibel / Randy J Read / Neil A Ranson / Sheena E Radford / Jeroen J M Hoozemans / René A W Frank /
Abstract: A defining pathological feature of most neurodegenerative diseases is the assembly of proteins into amyloid that form disease-specific structures. In Alzheimer's disease, this is characterized by the ...A defining pathological feature of most neurodegenerative diseases is the assembly of proteins into amyloid that form disease-specific structures. In Alzheimer's disease, this is characterized by the deposition of β-amyloid and tau with disease-specific conformations. The in situ structure of amyloid in the human brain is unknown. Here, using cryo-fluorescence microscopy-targeted cryo-sectioning, cryo-focused ion beam-scanning electron microscopy lift-out and cryo-electron tomography, we determined in-tissue architectures of β-amyloid and tau pathology in a postmortem Alzheimer's disease donor brain. β-amyloid plaques contained a mixture of fibrils, some of which were branched, and protofilaments, arranged in parallel arrays and lattice-like structures. Extracellular vesicles and cuboidal particles defined the non-amyloid constituents of β-amyloid plaques. By contrast, tau inclusions formed parallel clusters of unbranched filaments. Subtomogram averaging a cluster of 136 tau filaments in a single tomogram revealed the polypeptide backbone conformation and filament polarity orientation of paired helical filaments within tissue. Filaments within most clusters were similar to each other, but were different between clusters, showing amyloid heterogeneity that is spatially organized by subcellular location. The in situ structural approaches outlined here for human donor tissues have applications to a broad range of neurodegenerative diseases.
History
DepositionNov 27, 2023-
Header (metadata) releaseJul 24, 2024-
Map releaseJul 24, 2024-
UpdateJul 24, 2024-
Current statusJul 24, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_18990.png

Downloads & links

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Map

FileDownload / File: emd_18990.map.gz / Format: CCP4 / Size: 144.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationPostprocessed sharpened map of tau PHF fibrils extracted from AD patient brain
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 336 pix.
= 278.88 Å		0.83 Å/pix.
x 336 pix.
= 278.88 Å		0.83 Å/pix.
x 336 pix.
= 278.88 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.83 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.006
Minimum - Maximum-0.015044396 - 0.027869225
Average (Standard dev.)0.0001333058 (±0.0015110647)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions336336336
Spacing336336336
CellA=B=C: 278.88 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: halfmap1

Fileemd_18990_half_map_1.map
Annotationhalfmap1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: halfmap2

Fileemd_18990_half_map_2.map
Annotationhalfmap2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : tau PHF amyloid fibril

EntireName: tau PHF amyloid fibril
Components
  • Complex: tau PHF amyloid fibril
    • Protein or peptide: Microtubule-associated protein tau

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Supramolecule #1: tau PHF amyloid fibril

SupramoleculeName: tau PHF amyloid fibril / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human) / Organ: Brain

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Macromolecule #1: Microtubule-associated protein tau

MacromoleculeName: Microtubule-associated protein tau / type: protein_or_peptide / ID: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human) / Organ: Brain
SequenceString: MAEPRQEFEV MEDHAGTYGL GDRKDQGGYT MHQDQEGDTD AGLKESPLQT PTEDGSEEPG SETSDAKST PTAEDVTAPL VDEGAPGKQA AAQPHTEIPE GTTAEEAGIG DTPSLEDEAA G HVTQEPES GKVVQEGFLR EPGPPGLSHQ LMSGMPGAPL LPEGPREATR ...String:
MAEPRQEFEV MEDHAGTYGL GDRKDQGGYT MHQDQEGDTD AGLKESPLQT PTEDGSEEPG SETSDAKST PTAEDVTAPL VDEGAPGKQA AAQPHTEIPE GTTAEEAGIG DTPSLEDEAA G HVTQEPES GKVVQEGFLR EPGPPGLSHQ LMSGMPGAPL LPEGPREATR QPSGTGPEDT EG GRHAPEL LKHQLLGDLH QEGPPLKGAG GKERPGSKEE VDEDRDVDES SPQDSPPSKA SPA QDGRPP QTAAREATSI PGFPAEGAIP LPVDFLSKVS TEIPASEPDG PSVGRAKGQD APLE FTFHV EITPNVQKEQ AHSEEHLGRA AFPGAPGEGP EARGPSLGED TKEADLPEPS EKQPA AAPR GKPVSRVPQL KARMVSKSKD GTGSDDKKAK TSTRSSAKTL KNRPCLSPKH PTPGSS DPL IQPSSPAVCP EPPSSPKYVS SVTSRTGSSG AKEMKLKGAD GKTKIATPRG AAPPGQK GQ ANATRIPAKT PPAPKTPPSS GEPPKSGDRS GYSSPGSPGT PGSRSRTPSL PTPPTREP K KVAVVRTPPK SPSSAKSRLQ TAPVPMPDLK NVKSKIGSTE NLKHQPGGGK VQIINKKLD LSNVQSKCGS KDNIKHVPGG GSVQIVYKPV DLSKVTSKCG SLGNIHHKPG GGQVEVKSEK LDFKDRVQS KIGSLDNITH VPGGGNKKIE THKLTFRENA KAKTDHGAEI VYKSPVVSGD T SPRHLSNV SSTGSIDMVD SPQLATLADE VSASLAKQGL

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 / Component:
ConcentrationNameFormula
20.0 mMTris
50.0 mMNaCl
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Pretreatment - Type: PLASMA CLEANING / Pretreatment - Time: 60 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 90 % / Chamber temperature: 279 K / Instrument: FEI VITROBOT MARK IV
DetailsFrozen brain section was homogenised and purified using sarkosyl detergent.

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Digitization - Dimensions - Width: 4096 pixel / Digitization - Dimensions - Height: 4096 pixel / Number grids imaged: 1 / Number real images: 10860 / Average exposure time: 4.0 sec. / Average electron dose: 44.0 e/Å2
Details: Each EER movie was fractionated and tif compressed into 38 frames with a dose of 1.16 e-/A2/frame prior to processing
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.7 µm / Nominal defocus min: 1.5 µm / Nominal magnification: 96000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 2.405 Å
Applied symmetry - Helical parameters - Δ&Phi: 179.44 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 4) / Number images used: 40180
Segment selectionNumber selected: 667095 / Software - Name: crYOLO (ver. 1.8)
Details: 100 micrographs manually picked and used to train crYOLO model to pick all micrographs, focusing on wider tau filaments rather than thinner abeta
Startup modelType of model: EMDB MAP
EMDB ID:

12551

Final angle assignmentType: NOT APPLICABLE / Software - Name: RELION (ver. 4)
FSC plot (resolution estimation)

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