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- EMDB-23871: Paired helical tau filament extracted from PrP-CAA Patient brain ... -

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Basic information

Entry
Database: EMDB / ID: EMD-23871
TitlePaired helical tau filament extracted from PrP-CAA Patient brain tissue | tau filament | PHF Tau
Map data3 Angstrom resolution of PHF Tau from PrP-CAA
Sample
  • Organelle or cellular component: Paired helical filament (PHF) from PrP-CAA
    • Other: PHF Tau from PrP-CAA Patient
Function / homology
Function and homology information


plus-end-directed organelle transport along microtubule / histone-dependent DNA binding / negative regulation of protein localization to mitochondrion / neurofibrillary tangle / microtubule lateral binding / axonal transport / tubulin complex / positive regulation of protein localization to synapse / phosphatidylinositol bisphosphate binding / generation of neurons ...plus-end-directed organelle transport along microtubule / histone-dependent DNA binding / negative regulation of protein localization to mitochondrion / neurofibrillary tangle / microtubule lateral binding / axonal transport / tubulin complex / positive regulation of protein localization to synapse / phosphatidylinositol bisphosphate binding / generation of neurons / axon development / axonal transport of mitochondrion / rRNA metabolic process / central nervous system neuron development / regulation of microtubule-based movement / regulation of mitochondrial fission / intracellular distribution of mitochondria / regulation of chromosome organization / minor groove of adenine-thymine-rich DNA binding / lipoprotein particle binding / microtubule polymerization / negative regulation of mitochondrial membrane potential / regulation of microtubule polymerization / dynactin binding / apolipoprotein binding / regulation of calcium-mediated signaling / main axon / Caspase-mediated cleavage of cytoskeletal proteins / glial cell projection / regulation of microtubule polymerization or depolymerization / negative regulation of mitochondrial fission / axolemma / positive regulation of axon extension / neurofibrillary tangle assembly / protein polymerization / positive regulation of microtubule polymerization / regulation of cellular response to heat / positive regulation of protein localization / Activation of AMPK downstream of NMDARs / positive regulation of superoxide anion generation / cytoplasmic microtubule organization / cellular response to brain-derived neurotrophic factor stimulus / regulation of long-term synaptic depression / axon cytoplasm / supramolecular fiber organization / synapse assembly / somatodendritic compartment / astrocyte activation / nuclear periphery / phosphatidylinositol binding / protein phosphatase 2A binding / stress granule assembly / enzyme inhibitor activity / cellular response to reactive oxygen species / regulation of microtubule cytoskeleton organization / memory / microglial cell activation / cellular response to nerve growth factor stimulus / regulation of synaptic plasticity / Hsp90 protein binding / SH3 domain binding / regulation of autophagy / synapse organization / protein homooligomerization / microtubule cytoskeleton organization / PKR-mediated signaling / response to lead ion / neuron projection development / cytoplasmic ribonucleoprotein granule / microtubule cytoskeleton / cell-cell signaling / cellular response to heat / single-stranded DNA binding / growth cone / protein-folding chaperone binding / actin binding / cell body / double-stranded DNA binding / sequence-specific DNA binding / microtubule binding / amyloid fibril formation / dendritic spine / microtubule / learning or memory / protein-macromolecule adaptor activity / neuron projection / membrane raft / negative regulation of gene expression / axon / neuronal cell body / DNA damage response / dendrite / protein kinase binding / enzyme binding / mitochondrion / DNA binding / RNA binding / extracellular region / identical protein binding / nucleus
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 / Isoform Tau-F of Microtubule-associated protein tau
Similarity search - Component
Biological speciesHomo sapiens (human) / Human (human)
Methodhelical reconstruction / cryo EM / Resolution: 3.0 Å
AuthorsHoq M
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 20, 2021-
Header (metadata) releaseJul 21, 2021-
Map releaseJul 21, 2021-
UpdateJan 26, 2022-
Current statusJan 26, 2022Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.0219
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.0219
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7mkf
  • Surface level: 0.0219
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-7mkf
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_23871.png

Downloads & links

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Map

FileDownload / File: emd_23871.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotation3 Angstrom resolution of PHF Tau from PrP-CAA
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.08 Å/pix.
x 300 pix.
= 323.4 Å		1.08 Å/pix.
x 300 pix.
= 323.4 Å		1.08 Å/pix.
x 300 pix.
= 323.4 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.078 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0219 / Movie #1: 0.0219
Minimum - Maximum-0.025854126 - 0.055417214
Average (Standard dev.)0.0010129404 (±0.0040244916)
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-0.0260.0550.001

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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
    • Other: PHF Tau from PrP-CAA Patient

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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: all
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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Macromolecule #1: PHF Tau from PrP-CAA Patient

MacromoleculeName: PHF Tau from PrP-CAA Patient / type: other / ID: 1 / Classification: other
Source (natural)Organism: Human (human)
SequenceString:
QX

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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
GridModel: PELCO Ultrathin Carbon with Lacey Carbon / Material: COPPER / Mesh: 400
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: 4.77 Å
Applied symmetry - Helical parameters - Δ&Phi: -1.20 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 3.0 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-7mkf:
Paired helical tau filament extracted from PrP-CAA Patient brain tissue | tau filament | PHF Tau

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