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- EMDB-0077: Narrow Pick Filament from Pick's disease brain -

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Basic information

Entry
Database: EMDB / ID: EMD-0077
TitleNarrow Pick Filament from Pick's disease brain
Map data
Sample
  • Tissue: Tau filaments extracted from the frontotemporal cortex of a patient with Pick's disease
    • Protein or peptide: Microtubule-associated protein tau
Keywordstau protein / tau / Pick's disease / tauopathy / neurodegenerative disease / proteinopathy / amyloid / filament / helical / Pick body / fibril / neurodegeneration / MAPT / microtubule-associated protein tau / PROTEIN FIBRIL
Function / homology
Function and homology information


plus-end-directed organelle transport along microtubule / histone-dependent DNA binding / : / neurofibrillary tangle assembly / negative regulation of establishment of protein localization to mitochondrion / positive regulation of protein localization to synapse / neurofibrillary tangle / microtubule lateral binding / axonal transport / main axon ...plus-end-directed organelle transport along microtubule / histone-dependent DNA binding / : / neurofibrillary tangle assembly / negative regulation of establishment of protein localization to mitochondrion / positive regulation of protein localization to synapse / neurofibrillary tangle / microtubule lateral binding / axonal transport / main axon / phosphatidylinositol bisphosphate binding / tubulin complex / regulation of long-term synaptic depression / negative regulation of tubulin deacetylation / negative regulation of kinase activity / generation of neurons / internal protein amino acid acetylation / regulation of chromosome organization / rRNA metabolic process / axonal transport of mitochondrion / regulation of mitochondrial fission / axon development / intracellular distribution of mitochondria / central nervous system neuron development / regulation of microtubule polymerization / microtubule polymerization / minor groove of adenine-thymine-rich DNA binding / lipoprotein particle binding / dynactin binding / negative regulation of mitochondrial membrane potential / glial cell projection / apolipoprotein binding / protein polymerization / negative regulation of mitochondrial fission / axolemma / regulation of microtubule polymerization or depolymerization / Caspase-mediated cleavage of cytoskeletal proteins / positive regulation of axon extension / regulation of microtubule cytoskeleton organization / synapse assembly / cytoplasmic microtubule organization / Activation of AMPK downstream of NMDARs / regulation of cellular response to heat / positive regulation of protein localization / supramolecular fiber organization / regulation of calcium-mediated signaling / axon cytoplasm / somatodendritic compartment / stress granule assembly / cellular response to brain-derived neurotrophic factor stimulus / positive regulation of microtubule polymerization / phosphatidylinositol binding / nuclear periphery / positive regulation of superoxide anion generation / protein phosphatase 2A binding / regulation of autophagy / astrocyte activation / cellular response to reactive oxygen species / response to lead ion / Hsp90 protein binding / microglial cell activation / synapse organization / cellular response to nerve growth factor stimulus / : / PKR-mediated signaling / protein homooligomerization / regulation of synaptic plasticity / memory / SH3 domain binding / microtubule cytoskeleton organization / cytoplasmic ribonucleoprotein granule / neuron projection development / microtubule cytoskeleton / cell-cell signaling / single-stranded DNA binding / protein-folding chaperone binding / actin binding / cellular response to heat / growth cone / protein-macromolecule adaptor activity / cell body / double-stranded DNA binding / microtubule binding / microtubule / sequence-specific DNA binding / amyloid fibril formation / dendritic spine / learning or memory / nuclear speck / neuron projection / membrane raft / axon / negative regulation of gene expression / neuronal cell body / dendrite / DNA damage response / protein kinase binding / enzyme binding / mitochondrion / DNA binding
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: 3.2 Å
AuthorsFalcon B / Zhang W
Funding support United Kingdom, United States, 6 items
OrganizationGrant numberCountry
Medical Research Council (United Kingdom)MC_U105184291 United Kingdom
Medical Research Council (United Kingdom)MC_UP_A025_1013 United Kingdom
Medical Research Council (United Kingdom)MC_UP_A025_1012 United Kingdom
National Institutes of Health/National Institute on Aging (NIH/NIA)P30-AG010133 United States
European UnionJoint Programme-Neurodegeneration Research United Kingdom
European UnionHorizon 2020 IMPRiND United Kingdom
CitationJournal: Nature / Year: 2018
Title: Structures of filaments from Pick's disease reveal a novel tau protein fold.
Authors: Benjamin Falcon / Wenjuan Zhang / Alexey G Murzin / Garib Murshudov / Holly J Garringer / Ruben Vidal / R Anthony Crowther / Bernardino Ghetti / Sjors H W Scheres / Michel Goedert /
Abstract: The ordered assembly of tau protein into abnormal filamentous inclusions underlies many human neurodegenerative diseases. Tau assemblies seem to spread through specific neural networks in each ...The ordered assembly of tau protein into abnormal filamentous inclusions underlies many human neurodegenerative diseases. Tau assemblies seem to spread through specific neural networks in each disease, with short filaments having the greatest seeding activity. The abundance of tau inclusions strongly correlates with disease symptoms. Six tau isoforms are expressed in the normal adult human brain-three isoforms with four microtubule-binding repeats each (4R tau) and three isoforms that lack the second repeat (3R tau). In various diseases, tau filaments can be composed of either 3R or 4R tau, or of both. Tau filaments have distinct cellular and neuroanatomical distributions, with morphological and biochemical differences suggesting that they may be able to adopt disease-specific molecular conformations. Such conformers may give rise to different neuropathological phenotypes, reminiscent of prion strains. However, the underlying structures are not known. Using electron cryo-microscopy, we recently reported the structures of tau filaments from patients with Alzheimer's disease, which contain both 3R and 4R tau. Here we determine the structures of tau filaments from patients with Pick's disease, a neurodegenerative disorder characterized by frontotemporal dementia. The filaments consist of residues Lys254-Phe378 of 3R tau, which are folded differently from the tau filaments in Alzheimer's disease, establishing the existence of conformers of assembled tau. The observed tau fold in the filaments of patients with Pick's disease explains the selective incorporation of 3R tau in Pick bodies, and the differences in phosphorylation relative to the tau filaments of Alzheimer's disease. Our findings show how tau can adopt distinct folds in the human brain in different diseases, an essential step for understanding the formation and propagation of molecular conformers.
History
DepositionJun 26, 2018-
Header (metadata) releaseAug 22, 2018-
Map releaseSep 12, 2018-
UpdateJul 10, 2024-
Current statusJul 10, 2024Processing site: PDBe / Status: Released

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Structure visualization

Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_0077.png

Downloads & links

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Map

FileDownload / File: emd_0077.map.gz / Format: CCP4 / Size: 75.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1.15 Å/pix.
x 270 pix.
= 310.5 Å		1.15 Å/pix.
x 270 pix.
= 310.5 Å		1.15 Å/pix.
x 270 pix.
= 310.5 Å

Surface

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Slices (1/2)

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.15 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.04
Minimum - Maximum-0.066882834 - 0.17804243
Average (Standard dev.)0.000031686854 (±0.0016635783)
SymmetrySpace group: 1
Details

EMDB XML:

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

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Supplemental data

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Mask #1

Fileemd_0077_msk_1.map
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Half map: #2

Fileemd_0077_half_map_1.map
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Half map: #1

Fileemd_0077_half_map_2.map
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Sample components

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Entire : Tau filaments extracted from the frontotemporal cortex of a patie...

EntireName: Tau filaments extracted from the frontotemporal cortex of a patient with Pick's disease
Components
  • Tissue: Tau filaments extracted from the frontotemporal cortex of a patient with Pick's disease
    • Protein or peptide: Microtubule-associated protein tau

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Supramolecule #1: Tau filaments extracted from the frontotemporal cortex of a patie...

SupramoleculeName: Tau filaments extracted from the frontotemporal cortex of a patient with Pick's disease
type: tissue / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human) / Organ: Brain / Tissue: Frontotemporal cortex

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Macromolecule #1: Microtubule-associated protein tau

MacromoleculeName: Microtubule-associated protein tau / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human) / Organ: Brain / Tissue: Frontotemporal cortex
Molecular weightTheoretical: 10.135665 KDa
SequenceString:
KNVKSKIGST ENLKHQPGGG KVQIVYKPVD LSKVTSKCGS LGNIHHKPGG GQVEVKSEKL DFKDRVQSKI GSLDNITHVP GGGNKKIET HKLTF

UniProtKB: Microtubule-associated protein tau

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statetissue

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Sample preparation

Concentration0.5 mg/mL
BufferpH: 7.4
Component:
ConcentrationFormulaName
50.0 mMTris-HCl
150.0 mMNaCl
0.02 %A8-35Amphipol
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV
DetailsDispersed filaments

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Specialist opticsEnergy filter - Name: GIF Quantum LS
Image recordingFilm or detector model: GATAN K2 QUANTUM (4k x 4k) / Detector mode: COUNTING / Average electron dose: 1.06 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 / Nominal defocus max: 2.8000000000000003 µm / Nominal defocus min: 1.7 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 4.78 Å
Applied symmetry - Helical parameters - Δ&Phi: -0.75 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 2.1) / Number images used: 16097
Startup modelType of model: INSILICO MODEL
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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Atomic model buiding 1

DetailsFourier-space refinement of the complete atomic model against the narrow Pick filament map was performed in REFMAC. A stack of three consecutive monomers was refined to preserve nearest-neighbour interactions for the middle chain.
RefinementSpace: RECIPROCAL / Protocol: AB INITIO MODEL / Overall B value: 57 / Target criteria: Fourier shell correlation
Output model

PDB-6gx5:
Narrow Pick Filament from Pick's disease brain

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