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- EMDB-12553: Paired helical filament from posterior cortical atrophy brain -

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Basic information

Entry
Database: EMDB / ID: EMD-12553
TitlePaired helical filament from posterior cortical atrophy brain
Map data
Sample
  • Tissue: Sarkosyl-insoluble fractions from posterior cortical atrophy brain
    • Protein or peptide: Microtubule-associated protein tau
Biological speciesHomo sapiens (human) / Human (human)
Methodhelical reconstruction / cryo EM / Resolution: 3.55 Å
AuthorsShi Y / Murzin AG / Falcon B / Epstein A / Machin J / Tempest P / Newell KL / Vidal R / Garringer HJ / Sahara N ...Shi Y / Murzin AG / Falcon B / Epstein A / Machin J / Tempest P / Newell KL / Vidal R / Garringer HJ / Sahara N / Higuchi M / Ghetti B / Jang M / Scheres SHW / Goedert M
Funding support United Kingdom, European Union, United States, Japan, 6 items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MC_UP_A025_1013 United Kingdom
Medical Research Council (MRC, United Kingdom)MC_U105184291 United Kingdom
Innovative Medicines Initiative116060European Union
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)U01-NS110437 United States
Japan Agency for Medical Research and Development (AMED)JP20dm0207072 Japan
CitationJournal: Acta Neuropathol / Year: 2021
Title: Cryo-EM structures of tau filaments from Alzheimer's disease with PET ligand APN-1607.
Authors: Yang Shi / Alexey G Murzin / Benjamin Falcon / Alexander Epstein / Jonathan Machin / Paul Tempest / Kathy L Newell / Ruben Vidal / Holly J Garringer / Naruhiko Sahara / Makoto Higuchi / ...Authors: Yang Shi / Alexey G Murzin / Benjamin Falcon / Alexander Epstein / Jonathan Machin / Paul Tempest / Kathy L Newell / Ruben Vidal / Holly J Garringer / Naruhiko Sahara / Makoto Higuchi / Bernardino Ghetti / Ming-Kuei Jang / Sjors H W Scheres / Michel Goedert /
Abstract: Tau and Aβ assemblies of Alzheimer's disease (AD) can be visualized in living subjects using positron emission tomography (PET). Tau assemblies comprise paired helical and straight filaments (PHFs ...Tau and Aβ assemblies of Alzheimer's disease (AD) can be visualized in living subjects using positron emission tomography (PET). Tau assemblies comprise paired helical and straight filaments (PHFs and SFs). APN-1607 (PM-PBB3) is a recently described PET ligand for AD and other tau proteinopathies. Since it is not known where in the tau folds PET ligands bind, we used electron cryo-microscopy (cryo-EM) to determine the binding sites of APN-1607 in the Alzheimer fold. We identified two major sites in the β-helix of PHFs and SFs and a third major site in the C-shaped cavity of SFs. In addition, we report that tau filaments from posterior cortical atrophy (PCA) and primary age-related tauopathy (PART) are identical to those from AD. In support, fluorescence labelling showed binding of APN-1607 to intraneuronal inclusions in AD, PART and PCA. Knowledge of the binding modes of APN-1607 to tau filaments may lead to the development of new ligands with increased specificity and binding activity. We show that cryo-EM can be used to identify the binding sites of small molecules in amyloid filaments.
History
DepositionMar 4, 2021-
Header (metadata) releaseMar 24, 2021-
Map releaseMar 24, 2021-
UpdateApr 28, 2021-
Current statusApr 28, 2021Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.0262
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by cylindrical radius
  • Surface level: 0.0262
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_12553.png

Downloads & links

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Map

FileDownload / File: emd_12553.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.15 Å/pix.
x 256 pix.
= 294.4 Å		1.15 Å/pix.
x 256 pix.
= 294.4 Å		1.15 Å/pix.
x 256 pix.
= 294.4 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.15 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0262 / Movie #1: 0.0262
Minimum - Maximum-0.055081982 - 0.09967155
Average (Standard dev.)0.0007817207 (±0.005629222)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 294.4 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.151.151.15
M x/y/z256256256
origin x/y/z0.0000.0000.000
length x/y/z294.400294.400294.400
α/β/γ90.00090.00090.000
start NX/NY/NZ278280246
NX/NY/NZ474891
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS256256256
D min/max/mean-0.0550.1000.001

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Supplemental data

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Mask #1

Fileemd_12553_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_12553_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_12553_half_map_2.map
Projections & Slices
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Sample components

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Entire : Sarkosyl-insoluble fractions from posterior cortical atrophy brain

EntireName: Sarkosyl-insoluble fractions from posterior cortical atrophy brain
Components
  • Tissue: Sarkosyl-insoluble fractions from posterior cortical atrophy brain
    • Protein or peptide: Microtubule-associated protein tau

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Supramolecule #1: Sarkosyl-insoluble fractions from posterior cortical atrophy brain

SupramoleculeName: Sarkosyl-insoluble fractions from posterior cortical atrophy brain
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: Human (human)
SequenceString: MAEPRQEFEV MEDHAGTYGL GDRKDQGGYT MHQDQEGDTD AGLKESPLQT PTEDGSEEPG SETSDAKST PTAEDVTAPL VDEGAPGKQA AAQPHTEIPE GTTAEEAGIG DTPSLEDEAA G HVTQARMV SKSKDGTGSD DKKAKGADGK TKIATPRGAA PPGQKGQANA ...String:
MAEPRQEFEV MEDHAGTYGL GDRKDQGGYT MHQDQEGDTD AGLKESPLQT PTEDGSEEPG SETSDAKST PTAEDVTAPL VDEGAPGKQA AAQPHTEIPE GTTAEEAGIG DTPSLEDEAA G HVTQARMV SKSKDGTGSD DKKAKGADGK TKIATPRGAA PPGQKGQANA TRIPAKTPPA PK TPPSSGE PPKSGDRSGY SSPGSPGTPG SRSRTPSLPT PPTREPKKVA VVRTPPKSPS SAK SRLQTA PVPMPDLKNV KSKIGSTENL KHQPGGGKVQ IINKKLDLSN VQSKCGSKDN IKHV PGGGS VQIVYKPVDL SKVTSKCGSL GNIHHKPGGG QVEVKSEKLD FKDRVQSKIG SLDNI THVP GGGNKKIETH KLTFRENAKA KTDHGAEIVY KSPVVSGDTS PRHLSNVSST GSIDMV DSP QLATLADEVS ASLAKQGL

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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: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average electron dose: 52.96 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 2.37 Å
Applied symmetry - Helical parameters - Δ&Phi: 179.44 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 3.55 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 95375
Startup modelType of model: EMDB MAP
EMDB ID:

0259

Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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