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- EMDB-12549: Paired helical filament from primary age-related tauopathy brain -

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Basic information

Entry
Database: EMDB / ID: EMD-12549
TitlePaired helical filament from primary age-related tauopathy brain
Map dataThe calibrated pixel size was used during post-processing procedures in RELION.
Sample
  • Tissue: Sarkosyl-insoluble fractions from primary age-related tauopathy brain
    • Protein or peptide: Microtubule-associated protein tau
KeywordsTau filament / PROTEIN FIBRIL
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 mitochondrial fission / regulation of microtubule-based movement / 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 / protein polymerization / 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 / regulation of cellular response to heat / positive regulation of microtubule polymerization / positive regulation of protein localization / Activation of AMPK downstream of NMDARs / positive regulation of superoxide anion generation / regulation of calcium-mediated signaling / cytoplasmic microtubule organization / cellular response to brain-derived neurotrophic factor stimulus / regulation of long-term synaptic depression / axon cytoplasm / supramolecular fiber organization / somatodendritic compartment / synapse assembly / astrocyte activation / nuclear periphery / phosphatidylinositol binding / protein phosphatase 2A binding / enzyme inhibitor activity / stress granule assembly / regulation of autophagy / regulation of microtubule cytoskeleton organization / cellular response to reactive oxygen species / microglial cell activation / cellular response to nerve growth factor stimulus / Hsp90 protein binding / memory / regulation of synaptic plasticity / SH3 domain binding / synapse organization / protein homooligomerization / PKR-mediated signaling / microtubule cytoskeleton organization / 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
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 2.76 Å
AuthorsShi Y / Murzin AG
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-
UpdateJul 9, 2025-
Current statusJul 9, 2025Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.0212
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.0212
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7nrq
  • Surface level: 0.0212
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-7nrq
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_12549.png

Downloads & links

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Map

FileDownload / File: emd_12549.map.gz / Format: CCP4 / Size: 137.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationThe calibrated pixel size was used during post-processing procedures in RELION.
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.82 Å/pix.
x 330 pix.
= 270.6 Å		0.82 Å/pix.
x 330 pix.
= 270.6 Å		0.82 Å/pix.
x 330 pix.
= 270.6 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.82 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0212 / Movie #1: 0.0212
Minimum - Maximum-0.05333272 - 0.10641742
Average (Standard dev.)0.00043307256 (±0.005208062)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions330330330
Spacing330330330
CellA=B=C: 270.6 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.820.820.82
M x/y/z330330330
origin x/y/z0.0000.0000.000
length x/y/z270.600270.600270.600
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS330330330
D min/max/mean-0.0530.1060.000

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Supplemental data

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Mask #1

Fileemd_12549_msk_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_12549_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_12549_half_map_2.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Sarkosyl-insoluble fractions from primary age-related tauopathy brain

EntireName: Sarkosyl-insoluble fractions from primary age-related tauopathy brain
Components
  • Tissue: Sarkosyl-insoluble fractions from primary age-related tauopathy brain
    • Protein or peptide: Microtubule-associated protein tau

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Supramolecule #1: Sarkosyl-insoluble fractions from primary age-related tauopathy brain

SupramoleculeName: Sarkosyl-insoluble fractions from primary age-related tauopathy 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 / Number of copies: 10 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 45.919871 KDa
SequenceString: MAEPRQEFEV MEDHAGTYGL GDRKDQGGYT MHQDQEGDTD AGLKESPLQT PTEDGSEEPG SETSDAKSTP TAEDVTAPLV DEGAPGKQA AAQPHTEIPE GTTAEEAGIG DTPSLEDEAA GHVTQARMVS KSKDGTGSDD KKAKGADGKT KIATPRGAAP P GQKGQANA ...String:
MAEPRQEFEV MEDHAGTYGL GDRKDQGGYT MHQDQEGDTD AGLKESPLQT PTEDGSEEPG SETSDAKSTP TAEDVTAPLV DEGAPGKQA AAQPHTEIPE GTTAEEAGIG DTPSLEDEAA GHVTQARMVS KSKDGTGSDD KKAKGADGKT KIATPRGAAP P GQKGQANA TRIPAKTPPA PKTPPSSGEP PKSGDRSGYS SPGSPGTPGS RSRTPSLPTP PTREPKKVAV VRTPPKSPSS AK SRLQTAP VPMPDLKNVK SKIGSTENLK HQPGGGKVQI INKKLDLSNV QSKCGSKDNI KHVPGGGSVQ IVYKPVDLSK VTS KCGSLG NIHHKPGGGQ VEVKSEKLDF KDRVQSKIGS LDNITHVPGG GNKKIETHKL TFRENAKAKT DHGAEIVYKS PVVS GDTSP RHLSNVSSTG SIDMVDSPQL ATLADEVSAS LAKQGL

UniProtKB: Microtubule-associated protein tau

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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: 58.0 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: 2.76 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 425943
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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