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- EMDB-3744: Pronase-treated straight filament in Alzheimer's disease brain -

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Basic information

Entry
Database: EMDB / ID: EMD-3744
TitlePronase-treated straight filament in Alzheimer's disease brain
Map data
Sample
  • Tissue: Tau
    • Protein or peptide: Tau
Biological speciesHomo sapiens (human) / Human (human)
Methodhelical reconstruction / cryo EM / Resolution: 4.9 Å
AuthorsFitzpatrick AWP / Falcon B / He S / Murzin AG / Murshudov G / Garringer HG / Crowther RA / Ghetti B / Goedert M / Scheres SHW
CitationJournal: Nature / Year: 2017
Title: Cryo-EM structures of tau filaments from Alzheimer's disease.
Authors: Anthony W P Fitzpatrick / Benjamin Falcon / Shaoda He / Alexey G Murzin / Garib Murshudov / Holly J Garringer / R Anthony Crowther / Bernardino Ghetti / Michel Goedert / Sjors H W Scheres /
Abstract: Alzheimer's disease is the most common neurodegenerative disease, and there are no mechanism-based therapies. The disease is defined by the presence of abundant neurofibrillary lesions and neuritic ...Alzheimer's disease is the most common neurodegenerative disease, and there are no mechanism-based therapies. The disease is defined by the presence of abundant neurofibrillary lesions and neuritic plaques in the cerebral cortex. Neurofibrillary lesions comprise paired helical and straight tau filaments, whereas tau filaments with different morphologies characterize other neurodegenerative diseases. No high-resolution structures of tau filaments are available. Here we present cryo-electron microscopy (cryo-EM) maps at 3.4-3.5 Å resolution and corresponding atomic models of paired helical and straight filaments from the brain of an individual with Alzheimer's disease. Filament cores are made of two identical protofilaments comprising residues 306-378 of tau protein, which adopt a combined cross-β/β-helix structure and define the seed for tau aggregation. Paired helical and straight filaments differ in their inter-protofilament packing, showing that they are ultrastructural polymorphs. These findings demonstrate that cryo-EM allows atomic characterization of amyloid filaments from patient-derived material, and pave the way for investigation of a range of neurodegenerative diseases.
History
DepositionMay 25, 2017-
Header (metadata) releaseJul 26, 2017-
Map releaseJul 26, 2017-
UpdateAug 2, 2017-
Current statusAug 2, 2017Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.012
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.012
  • Imaged by UCSF Chimera
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Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_3744.png

Downloads & links

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Map

FileDownload / File: emd_3744.map.gz / Format: CCP4 / Size: 75.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.15 Å
Density
Contour LevelBy AUTHOR: 0.012 / Movie #1: 0.012
Minimum - Maximum-0.011788864 - 0.046356678
Average (Standard dev.)0.00036828752 (±0.0024246783)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions270270270
Spacing270270270
CellA=B=C: 310.5 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.151.151.15
M x/y/z270270270
origin x/y/z0.0000.0000.000
length x/y/z310.500310.500310.500
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS270270270
D min/max/mean-0.0120.0460.000

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Supplemental data

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Half map: #1

Fileemd_3744_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_3744_half_map_2.map
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

EntireName: Tau
Components
  • Tissue: Tau
    • Protein or peptide: Tau

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Supramolecule #1: Tau

SupramoleculeName: Tau / type: tissue / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Tau

MacromoleculeName: Tau / type: protein_or_peptide / ID: 1 / Enantiomer: LEVO
Source (natural)Organism: Human (human)
SequenceString:
VQIVYKPVDL SKVTSKCGSL GNIHHKPGGG QVEVKSEKLD FKDRVQSKIG SLDNITHVPG GGNKKIETHK LTF

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statetissue

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Sample preparation

Concentration1.0 mg/mL
BufferpH: 7.4 / Details: 20 mM Tris-HCl pH 7.4 containing 100 MM NaCl
GridModel: Quanitifoil Au R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV
DetailsSarkosyl-insoluble material was extracted from grey matter of frontal and temporal cortex from the patients brain and treated with pronase, as described in the Methods section of the paper.

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Calibrated defocus max: 3.0 µm / Calibrated defocus min: 0.9 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 3.0 µm / Nominal defocus min: 0.9 µm
Specialist opticsEnergy filter - Name: GIF Quantum / Energy filter - Lower energy threshold: -10 eV / Energy filter - Upper energy threshold: 10 eV
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Image recordingFilm or detector model: GATAN K2 QUANTUM (4k x 4k) / Detector mode: SUPER-RESOLUTION / Digitization - Dimensions - Width: 3710 pixel / Digitization - Dimensions - Height: 3710 pixel / Digitization - Frames/image: 2-20 / Number grids imaged: 1 / Number real images: 523 / Average exposure time: 0.8 sec. / Average electron dose: 2.5 e/Å2
Details: images were collected in movie-mode at 1.2 frames per second
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Segment selectionNumber selected: 9273 / Software - Name: RELION (ver. 2.0)
CTF correctionSoftware - Name: Gctf
Startup modelType of model: INSILICO MODEL
In silico model: Initial models were reconstructed from 2D class averages of segments that were extracted in a box that was large enough to almost comprise an entire pitch length.
Final angle assignmentType: NOT APPLICABLE / Software - Name: RELION (ver. 2.0)
Final reconstructionNumber classes used: 1
Applied symmetry - Helical parameters - Δz: 4.78 Å
Applied symmetry - Helical parameters - Δ&Phi: -1.01 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 4.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 8627
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

2rnm


Chain - Chain ID: A / Chain - Residue range: 226-242
DetailsFourier-space refinement of the complete atomic model against the paired helical filament and straight filament maps was performed in REFMAC. A stack of three consecutive monomers from each of the protofilaments was refined to preserve nearest-neighbour interactions for the middle chain.
RefinementSpace: RECIPROCAL / Protocol: AB INITIO MODEL / Overall B value: 79 / Target criteria: Fourier shell correlation

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