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- EMDB-0528: Chronic traumatic encephalopathy Type II Tau filament -

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Basic information

Entry
Database: EMDB / ID: EMD-0528
TitleChronic traumatic encephalopathy Type II Tau filament
Map data
Sample
  • Tissue: Tau filaments extracted from the temporal cortex of a patient with chronic traumatic encephalopathy
    • Protein or peptide: Microtubule-associated protein tauTau protein
Function / homology
Function and homology information


plus-end-directed organelle transport along microtubule / axonal transport / histone-dependent DNA binding / neurofibrillary tangle assembly / positive regulation of diacylglycerol kinase activity / negative regulation of establishment of protein localization to mitochondrion / neurofibrillary tangle / positive regulation of protein localization to synapse / microtubule lateral binding / tubulin complex ...plus-end-directed organelle transport along microtubule / axonal transport / histone-dependent DNA binding / neurofibrillary tangle assembly / positive regulation of diacylglycerol kinase activity / negative regulation of establishment of protein localization to mitochondrion / neurofibrillary tangle / positive regulation of protein localization to synapse / microtubule lateral binding / tubulin complex / phosphatidylinositol bisphosphate binding / main axon / regulation of long-term synaptic depression / negative regulation of kinase activity / negative regulation of tubulin deacetylation / generation of neurons / regulation of chromosome organization / positive regulation of protein localization / rRNA metabolic process / internal protein amino acid acetylation / regulation of mitochondrial fission / lipoprotein particle binding / intracellular distribution of mitochondria / axonal transport of mitochondrion / axon development / central nervous system neuron development / regulation of microtubule polymerization / microtubule polymerization / minor groove of adenine-thymine-rich DNA binding / negative regulation of mitochondrial membrane potential / dynactin binding / glial cell projection / apolipoprotein binding / protein polymerization / negative regulation of mitochondrial fission / axolemma / Caspase-mediated cleavage of cytoskeletal proteins / regulation of microtubule polymerization or depolymerization / positive regulation of axon extension / supramolecular fiber organization / Activation of AMPK downstream of NMDARs / regulation of microtubule cytoskeleton organization / stress granule assembly / cytoplasmic microtubule organization / regulation of cellular response to heat / regulation of calcium-mediated signaling / axon cytoplasm / positive regulation of microtubule polymerization / cellular response to brain-derived neurotrophic factor stimulus / somatodendritic compartment / synapse assembly / phosphatidylinositol binding / nuclear periphery / cellular response to nerve growth factor stimulus / positive regulation of superoxide anion generation / protein phosphatase 2A binding / regulation of autophagy / astrocyte activation / synapse organization / microglial cell activation / response to lead ion / Hsp90 protein binding / regulation of synaptic plasticity / PKR-mediated signaling / protein homooligomerization / cytoplasmic ribonucleoprotein granule / memory / microtubule cytoskeleton organization / SH3 domain binding / cellular response to reactive oxygen species / neuron projection development / activation of cysteine-type endopeptidase activity involved in apoptotic process / microtubule cytoskeleton / protein-macromolecule adaptor activity / single-stranded DNA binding / cell-cell signaling / cellular response to heat / cell body / actin binding / growth cone / protein-folding chaperone binding / double-stranded DNA binding / microtubule binding / microtubule / amyloid fibril formation / sequence-specific DNA binding / dendritic spine / learning or memory / neuron projection / nuclear speck / membrane raft / axon / negative regulation of gene expression / dendrite / neuronal cell body / DNA damage response / protein kinase binding / enzyme binding / mitochondrion / DNA binding
Similarity search - Function
: / Microtubule associated protein, tubulin-binding repeat / Microtubule-associated protein Tau / 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) / Human (human)
Methodhelical reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsFalcon B / Zivanov J / Zhang W / Murzin AG / Garringer HJ / Vidal R / Crowther RA / Newell KL / Ghetti B / Goedert M / Scheres HW
Funding support United Kingdom, United States, 6 items
OrganizationGrant numberCountry
Medical Research Council (United Kingdom)MC_UP_A025_1013 United Kingdom
Medical Research Council (United Kingdom)MC_U105184291 United Kingdom
European UnionJoint Programme- Neurodegeneration Research REfrAME United Kingdom
Innovative Medicines Initiative116060 United Kingdom
National Institutes of Health/National Institute on Aging (NIH/NIA)P30AG010133 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)U01NS110437 United States
CitationJournal: Nature / Year: 2019
Title: Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules.
Authors: Benjamin Falcon / Jasenko Zivanov / Wenjuan Zhang / Alexey G Murzin / Holly J Garringer / Ruben Vidal / R Anthony Crowther / Kathy L Newell / Bernardino Ghetti / Michel Goedert / Sjors H W Scheres /
Abstract: Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy that is associated with repetitive head impacts or exposure to blast waves. First described as punch-drunk syndrome and ...Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy that is associated with repetitive head impacts or exposure to blast waves. First described as punch-drunk syndrome and dementia pugilistica in retired boxers, CTE has since been identified in former participants of other contact sports, ex-military personnel and after physical abuse. No disease-modifying therapies currently exist, and diagnosis requires an autopsy. CTE is defined by an abundance of hyperphosphorylated tau protein in neurons, astrocytes and cell processes around blood vessels. This, together with the accumulation of tau inclusions in cortical layers II and III, distinguishes CTE from Alzheimer's disease and other tauopathies. However, the morphologies of tau filaments in CTE and the mechanisms by which brain trauma can lead to their formation are unknown. Here we determine the structures of tau filaments from the brains of three individuals with CTE at resolutions down to 2.3 Å, using cryo-electron microscopy. We show that filament structures are identical in the three cases but are distinct from those of Alzheimer's and Pick's diseases, and from those formed in vitro. Similar to Alzheimer's disease, all six brain tau isoforms assemble into filaments in CTE, and residues K274-R379 of three-repeat tau and S305-R379 of four-repeat tau form the ordered core of two identical C-shaped protofilaments. However, a different conformation of the β-helix region creates a hydrophobic cavity that is absent in tau filaments from the brains of patients with Alzheimer's disease. This cavity encloses an additional density that is not connected to tau, which suggests that the incorporation of cofactors may have a role in tau aggregation in CTE. Moreover, filaments in CTE have distinct protofilament interfaces to those of Alzheimer's disease. Our structures provide a unifying neuropathological criterion for CTE, and support the hypothesis that the formation and propagation of distinct conformers of assembled tau underlie different neurodegenerative diseases.
History
DepositionFeb 7, 2019-
Header (metadata) releaseMar 27, 2019-
Map releaseMar 27, 2019-
UpdateMar 30, 2022-
Current statusMar 30, 2022Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.02
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  • Surface view with fitted model
  • Atomic models: PDB-6nwq
  • Surface level: 0.02
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-6nwq
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Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_0528.png

Downloads & links

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Map

FileDownload / File: emd_0528.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.15 Å
Density
Contour LevelBy AUTHOR: 0.02 / Movie #1: 0.02
Minimum - Maximum-0.0412029 - 0.090029605
Average (Standard dev.)0.0015025522 (±0.0049414746)
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
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS256256256
D min/max/mean-0.0410.0900.002

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Supplemental data

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Mask #1

Fileemd_0528_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map 1

Fileemd_0528_half_map_1.map
AnnotationHalf map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map 2

Fileemd_0528_half_map_2.map
AnnotationHalf map 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : Tau filaments extracted from the temporal cortex of a patient wit...

EntireName: Tau filaments extracted from the temporal cortex of a patient with chronic traumatic encephalopathy
Components
  • Tissue: Tau filaments extracted from the temporal cortex of a patient with chronic traumatic encephalopathy
    • Protein or peptide: Microtubule-associated protein tauTau protein

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Supramolecule #1: Tau filaments extracted from the temporal cortex of a patient wit...

SupramoleculeName: Tau filaments extracted from the temporal cortex of a patient with chronic traumatic encephalopathy
type: tissue / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human) / Organ: Brain / Tissue: Temporal 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: 6 / Enantiomer: LEVO
Source (natural)Organism: Human (human) / Organ: Brain / Tissue: Temporal cortex
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

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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:
ConcentrationFormula
20.0 mMTris-HClTris
100.0 mMNaClSodium chloride
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 2.8000000000000003 µm / Nominal defocus min: 1.7 µm / Nominal magnification: 130000
Specialist opticsEnergy filter - Name: GIF Quantum LS / Energy filter - Slit width: 25 eV
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average exposure time: 9.0 sec. / Average electron dose: 55.48 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER / Details: De novo
Final angle assignmentType: NOT APPLICABLE
Final reconstructionApplied symmetry - Helical parameters - Δz: 2.37 Å
Applied symmetry - Helical parameters - Δ&Phi: 179.4 °
Applied symmetry - Helical parameters - Axial symmetry: C2 (2 fold cyclic)
Resolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.0) / Number images used: 7621
FSC plot (resolution estimation)

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Atomic model buiding 1

DetailsFourier-space refinement of the complete atomic model against the chronic traumatic encephalopathy Type II Tau 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 / Overall B value: 51.7 / Target criteria: Fourier shell correlation
Output model

PDB-6nwq:
Chronic traumatic encephalopathy Type II Tau filament

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