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- EMDB-35406: Straight filament from primary age-related tauopathy brain with P... -

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Basic information

Entry
Database: EMDB / ID: EMD-35406
TitleStraight filament from primary age-related tauopathy brain with PET ligand flortaucipir (+flortaucipir)
Map data
Sample
  • Tissue: Sarkosyl-insoluble fraction from the hippocampus of an individual with primary age-related tauopathy
    • Protein or peptide: Microtubule-associated protein tau
KeywordsPrimary age-related tauopathy / Tau filaments / Straight filament / PET ligand / Flortaucipir / PROTEIN FIBRIL
Biological speciesHomo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 2.62 Å
AuthorsShi Y / Ghetti B / Goedert M / Scheres SHW
Funding support United Kingdom, Switzerland, United States, 6 items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MC_U105184291 United Kingdom
Medical Research Council (MRC, United Kingdom)MC_UP_A025_1013 United Kingdom
Innovative Medicines Initiative116060 Switzerland
National Institutes of Health/National Institute on Aging (NIH/NIA)P30-AG010133 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)UO1-NS110437 United States
National Institutes of Health/National Institute on Aging (NIH/NIA)RF1-AG071177 United States
CitationJournal: J Mol Biol / Year: 2023
Title: Cryo-EM Structures of Chronic Traumatic Encephalopathy Tau Filaments with PET Ligand Flortaucipir.
Authors: Yang Shi / Bernardino Ghetti / Michel Goedert / Sjors H W Scheres /
Abstract: Positron emission tomography (PET) imaging allows monitoring the progression of amyloid aggregation in the living brain. [F]-Flortaucipir is the only approved PET tracer compound for the ...Positron emission tomography (PET) imaging allows monitoring the progression of amyloid aggregation in the living brain. [F]-Flortaucipir is the only approved PET tracer compound for the visualisation of tau aggregation. Here, we describe cryo-EM experiments on tau filaments in the presence and absence of flortaucipir. We used tau filaments isolated from the brain of an individual with Alzheimer's disease (AD), and from the brain of an individual with primary age-related tauopathy (PART) with a co-pathology of chronic traumatic encephalopathy (CTE). Unexpectedly, we were unable to visualise additional cryo-EM density for flortaucipir for AD paired helical or straight filaments (PHFs or SFs), but we did observe density for flortaucipir binding to CTE Type I filaments from the case with PART. In the latter, flortaucipir binds in a 1:1 molecular stoichiometry with tau, adjacent to lysine 353 and aspartate 358. By adopting a tilted geometry with respect to the helical axis, the 4.7 Å distance between neighbouring tau monomers is reconciled with the 3.5 Å distance consistent with π-π-stacking between neighbouring molecules of flortaucipir.
History
DepositionFeb 17, 2023-
Header (metadata) releaseJul 12, 2023-
Map releaseJul 12, 2023-
UpdateNov 1, 2023-
Current statusNov 1, 2023Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_35406.png

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Map

FileDownload / File: emd_35406.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.82 Å/pix.
x 400 pix.
= 329.6 Å		0.82 Å/pix.
x 400 pix.
= 329.6 Å		0.82 Å/pix.
x 400 pix.
= 329.6 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.824 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.012
Minimum - Maximum-0.028245784 - 0.07174898
Average (Standard dev.)0.0002821958 (±0.0033834814)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 329.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_35406_msk_1.map
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AxesZYX

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Half map: #1

Fileemd_35406_half_map_1.map
Projections & Slices
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Histogram

Histogram (log scale)

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Half map: #2

Fileemd_35406_half_map_2.map
Projections & Slices
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Sample components

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Entire : Sarkosyl-insoluble fraction from the hippocampus of an individual...

EntireName: Sarkosyl-insoluble fraction from the hippocampus of an individual with primary age-related tauopathy
Components
  • Tissue: Sarkosyl-insoluble fraction from the hippocampus of an individual with primary age-related tauopathy
    • Protein or peptide: Microtubule-associated protein tau

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Supramolecule #1: Sarkosyl-insoluble fraction from the hippocampus of an individual...

SupramoleculeName: Sarkosyl-insoluble fraction from the hippocampus of an individual with primary age-related tauopathy
type: tissue / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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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)
SequenceString: MAEPRQEFEV MEDHAGTYGL GDRKDQGGYT MHQDQEGDTD AGLKESPLQT PTEDGSEEPG SETSDAKSTP TAEDVTAPLV DEGAPGKQAA AQPHTEIPEG TTAEEAGIGD TPSLEDEAAG HVTQARMVSK SKDGTGSDDK KAKGADGKTK IATPRGAAPP GQKGQANATR ...String:
MAEPRQEFEV MEDHAGTYGL GDRKDQGGYT MHQDQEGDTD AGLKESPLQT PTEDGSEEPG SETSDAKSTP TAEDVTAPLV DEGAPGKQAA AQPHTEIPEG TTAEEAGIGD TPSLEDEAAG HVTQARMVSK SKDGTGSDDK KAKGADGKTK IATPRGAAPP GQKGQANATR IPAKTPPAPK TPPSSGEPPK SGDRSGYSSP GSPGTPGSRS RTPSLPTPPT REPKKVAVVR TPPKSPSSAK SRLQTAPVPM PDLKNVKSKI GSTENLKHQP GGGKVQIINK KLDLSNVQSK CGSKDNIKHV PGGGSVQIVY KPVDLSKVTS KCGSLGNIHH KPGGGQVEVK SEKLDFKDRV QSKIGSLDNI THVPGGGNKK IETHKLTFRE NAKAKTDHGA EIVYKSPVVS GDTSPRHLSN VSSTGSIDMV DSPQLATLAD EVSASLAKQG L

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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
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 4.77 Å
Applied symmetry - Helical parameters - Δ&Phi: -1.08 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 2.62 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 42917
Startup modelType of model: INSILICO MODEL
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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