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- EMDB-23890: Straight tau filament extracted from PrP-CAA Patient brain tissue... -

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Basic information

Entry
Database: EMDB / ID: EMD-23890
TitleStraight tau filament extracted from PrP-CAA Patient brain tissue | tau filament | SF Tau
Map data
Sample
  • Organelle or cellular component: Paired helical filament (PHF) from PrP-CAA
Function / homologyActivation of AMPK downstream of NMDARs / PKR-mediated signaling / Isoform Tau-F of Microtubule-associated protein tau
Function and homology information
Biological speciesHomo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 3.07 Å
AuthorsHoq MR
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R01-AG071177 United States
CitationJournal: Acta Neuropathol / Year: 2021
Title: Structure of Tau filaments in Prion protein amyloidoses.
Authors: Grace I Hallinan / Md Rejaul Hoq / Manali Ghosh / Frank S Vago / Anllely Fernandez / Holly J Garringer / Ruben Vidal / Wen Jiang / Bernardino Ghetti /
Abstract: In human neurodegenerative diseases associated with the intracellular aggregation of Tau protein, the ordered cores of Tau filaments adopt distinct folds. Here, we analyze Tau filaments isolated from ...In human neurodegenerative diseases associated with the intracellular aggregation of Tau protein, the ordered cores of Tau filaments adopt distinct folds. Here, we analyze Tau filaments isolated from the brain of individuals affected by Prion-Protein cerebral amyloid angiopathy (PrP-CAA) with a nonsense mutation in the PRNP gene that leads to early termination of translation of PrP (Q160Ter or Q160X), and Gerstmann-Sträussler-Scheinker (GSS) disease, with a missense mutation in the PRNP gene that leads to an amino acid substitution at residue 198 (F198S) of PrP. The clinical and neuropathologic phenotypes associated with these two mutations in PRNP are different; however, the neuropathologic analyses of these two genetic variants have consistently shown the presence of numerous neurofibrillary tangles (NFTs) made of filamentous Tau aggregates in neurons. We report that Tau filaments in PrP-CAA (Q160X) and GSS (F198S) are composed of 3-repeat and 4-repeat Tau isoforms, having a striking similarity to NFTs in Alzheimer disease (AD). In PrP-CAA (Q160X), Tau filaments are made of both paired helical filaments (PHFs) and straight filaments (SFs), while in GSS (F198S), only PHFs were found. Mass spectrometry analyses of Tau filaments extracted from PrP-CAA (Q160X) and GSS (F198S) brains show the presence of post-translational modifications that are comparable to those seen in Tau aggregates from AD. Cryo-EM analysis reveals that the atomic models of the Tau filaments obtained from PrP-CAA (Q160X) and GSS (F198S) are identical to those of the Tau filaments from AD, and are therefore distinct from those of Pick disease, chronic traumatic encephalopathy, and corticobasal degeneration. Our data support the hypothesis that in the presence of extracellular amyloid deposits and regardless of the primary amino acid sequence of the amyloid protein, similar molecular mechanisms are at play in the formation of identical Tau filaments.
History
DepositionApr 23, 2021-
Header (metadata) releaseJul 28, 2021-
Map releaseJul 28, 2021-
UpdateFeb 16, 2022-
Current statusFeb 16, 2022Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.019
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.019
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7mkg
  • Surface level: 0.019
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-7mkg
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_23890.png

Downloads & links

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Map

FileDownload / File: emd_23890.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.078 Å
Density
Contour LevelBy AUTHOR: 0.019 / Movie #1: 0.019
Minimum - Maximum-0.01874203 - 0.055257116
Average (Standard dev.)0.0010094055 (±0.0037687)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 323.4 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0781.0781.078
M x/y/z300300300
origin x/y/z0.0000.0000.000
length x/y/z323.400323.400323.400
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS300300300
D min/max/mean-0.0190.0550.001

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Supplemental data

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Sample components

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Entire : Paired helical filament (PHF) from PrP-CAA

EntireName: Paired helical filament (PHF) from PrP-CAA
Components
  • Organelle or cellular component: Paired helical filament (PHF) from PrP-CAA

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Supramolecule #1: Paired helical filament (PHF) from PrP-CAA

SupramoleculeName: Paired helical filament (PHF) from PrP-CAA / type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: #1
Details: PHF tau in PrP-CAA, caused by the Q160X truncating mutation in PRNP
Source (natural)Organism: Homo sapiens (human)
Molecular weightExperimental: 55 kDa/nm

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statefilament

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Sample preparation

Concentration1 mg/mL
BufferpH: 7.4
Sugar embeddingMaterial: affinity tag
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Instrument: GATAN CRYOPLUNGE 3
DetailsFilament extracted from frontal cortex of PrP-CAA patient brain

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number real images: 2004 / Average electron dose: 1.067 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 4.79 Å
Applied symmetry - Helical parameters - Δ&Phi: -1.07 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 3.07 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 60
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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Atomic model buiding 1

DetailsEach model was refined using Rosetta
RefinementSpace: RECIPROCAL / Overall B value: 24 / Target criteria: Fourier shell correlation
Output model

PDB-7mkg:
Straight tau filament extracted from PrP-CAA Patient brain tissue | tau filament | SF Tau

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