EMDB-0528: Chronic traumatic encephalopathy Type II Tau filament

Basic information

• Entry: Database: EMDB / ID: EMD-0528
• Title: Chronic traumatic encephalopathy Type II Tau filament

Sample

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

• Keywords: Tau / chronic traumatic encephalopathy / filament / amyloid / PROTEIN FIBRIL

Function / homology

Function:

plus-end-directed organelle transport along microtubule / histone-dependent DNA binding / neurofibrillary tangle assembly / positive regulation of diacylglycerol kinase activity / axonal transport / 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 / negative regulation of kinase activity / regulation of long-term synaptic depression / negative regulation of tubulin deacetylation / generation of neurons / rRNA metabolic process / internal protein amino acid acetylation / regulation of chromosome organization / regulation of mitochondrial fission / axonal transport of mitochondrion / intracellular distribution of mitochondria / axon development / central nervous system neuron development / regulation of microtubule polymerization / apolipoprotein binding / microtubule polymerization / lipoprotein particle binding / minor groove of adenine-thymine-rich DNA binding / dynactin binding / negative regulation of mitochondrial membrane potential / glial cell projection / protein polymerization / axolemma / negative regulation of mitochondrial fission / regulation of microtubule polymerization or depolymerization / Caspase-mediated cleavage of cytoskeletal proteins / positive regulation of axon extension / regulation of microtubule cytoskeleton organization / Activation of AMPK downstream of NMDARs / regulation of cellular response to heat / cytoplasmic microtubule organization / positive regulation of protein localization / supramolecular fiber organization / stress granule assembly / regulation of calcium-mediated signaling / axon cytoplasm / somatodendritic compartment / positive regulation of microtubule polymerization / synapse assembly / cellular response to brain-derived neurotrophic factor stimulus / nuclear periphery / phosphatidylinositol binding / cellular response to nerve growth factor stimulus / positive regulation of superoxide anion generation / protein phosphatase 2A binding / regulation of autophagy / astrocyte activation / response to lead ion / microglial cell activation / synapse organization / Hsp90 protein binding / protein homooligomerization / PKR-mediated signaling / regulation of synaptic plasticity / : / memory / SH3 domain binding / microtubule cytoskeleton organization / cytoplasmic ribonucleoprotein granule / cellular response to reactive oxygen species / microtubule cytoskeleton / neuron projection development / cell-cell signaling / protein-folding chaperone binding / single-stranded DNA binding / actin binding / cellular response to heat / protein-macromolecule adaptor activity / double-stranded DNA binding / growth cone / cell body / microtubule binding / sequence-specific DNA binding / microtubule / amyloid fibril formation / dendritic spine / learning or memory / nuclear speck / neuron projection / membrane raft / axon / negative regulation of gene expression / neuronal cell body / DNA damage response / dendrite / protein kinase binding / enzyme binding / mitochondrion / DNA binding

Domain/homology:

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.

Component:

Microtubule-associated protein tau

• Biological species: Homo sapiens (human)
• Method: helical reconstruction / cryo EM / Resolution: 3.4 Å
• Authors: Falcon B / Zivanov J

Funding support

United Kingdom, United States, 6 items

Organization	Grant number	Country
Medical Research Council (United Kingdom)	MC_UP_A025_1013	United Kingdom
Medical Research Council (United Kingdom)	MC_U105184291	United Kingdom
European Union	Joint Programme- Neurodegeneration Research REfrAME	United Kingdom
Innovative Medicines Initiative	116060	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

• Citation: Journal: 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 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

Deposition	Feb 7, 2019	-
Header (metadata) release	Mar 27, 2019	-
Map release	Mar 27, 2019	-
Update	Jul 10, 2024	-
Current status	Jul 10, 2024	Processing site: PDBe / Status: Released

Map

• File: Download / File: emd_0528.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
• Voxel size: X=Y=Z: 1.15 Å

Density

Contour Level	By AUTHOR: 0.02 / Movie #1: 0.02
Minimum - Maximum	-0.0412029 - 0.090029605
Average (Standard dev.)	0.0015025522 (±0.0049414746)

• Symmetry: Space group: 1

Details

EMDB XML:

Map geometry	Axis order X Y Z Origin 0 0 0 Dimensions 256 256 256 Spacing 256 256 256
Cell	A=B=C: 294.4 Å α=β=γ: 90.0 °

CCP4 map header:

mode	Image stored as Reals
Å/pix. X/Y/Z	1.15	1.15	1.15
M x/y/z	256	256	256
origin x/y/z	0.000	0.000	0.000
length x/y/z	294.400	294.400	294.400
α/β/γ	90.000	90.000	90.000
MAP C/R/S	1	2	3
start NC/NR/NS	0	0	0
NC/NR/NS	256	256	256
D min/max/mean	-0.041	0.090	0.002

Supplemental data

Mask #1

• File: emd_0528_msk_1.map

Half map: Half map 1

• File: emd_0528_half_map_1.map
• Annotation: Half map 1

Half map: Half map 2

• File: emd_0528_half_map_2.map
• Annotation: Half map 2

Sample components

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

• Entire: Name: 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 tau

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

• Supramolecule: Name: 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

Macromolecule #1: Microtubule-associated protein tau

• Macromolecule: Name: Microtubule-associated protein tau / type: protein_or_peptide / ID: 1 / Number of copies: 6 / Enantiomer: LEVO
• Source (natural): Organism: Homo sapiens (human) / Organ: Brain / Tissue: Temporal cortex
• Molecular weight: Theoretical: 45.919871 KDa

Sequence

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

Experimental details

Structure determination

• Method: cryo EM
• Processing: helical reconstruction
• Aggregation state: tissue

Sample preparation

• Concentration: 0.5 mg/mL

Buffer

pH: 7.4 / Component:

Concentration	Formula
20.0 mM	Tris-HCl
100.0 mM	NaCl

• Vitrification: Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV

Electron microscopy

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

Image processing

• Final reconstruction: Applied 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
• Startup model: Type of model: OTHER / Details: De novo
• Final angle assignment: Type: NOT APPLICABLE

Atomic model buiding 1

• Details: Fourier-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.
• Refinement: Space: RECIPROCAL / Overall B value: 51.7 / Target criteria: Fourier shell correlation

Output model

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