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- PDB-6tjo: Cryo-EM structure of TypeI tau filaments extracted from the brain... -

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Basic information

Entry
Database: PDB / ID: 6tjo
TitleCryo-EM structure of TypeI tau filaments extracted from the brains of individuals with Corticobasal degeneration
ComponentsMicrotubule-associated protein tauTau protein
KeywordsPROTEIN FIBRIL / tau protein / filament / cross-beta structure
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 / cellular response to reactive oxygen species / SH3 domain binding / 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)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsZhang, W. / Murzin, A.G. / Falcon, B. / Shi, Y. / Goedert, M. / Scheres, S.H.W.
Funding support United Kingdom, 2items
OrganizationGrant numberCountry
Medical Research Council (United Kingdom)MC_UP_A025_1013 United Kingdom
Medical Research Council (United Kingdom)MC_U105184291 United Kingdom
CitationJournal: Nature / Year: 2020
Title: Novel tau filament fold in corticobasal degeneration.
Authors: Wenjuan Zhang / Airi Tarutani / Kathy L Newell / Alexey G Murzin / Tomoyasu Matsubara / Benjamin Falcon / Ruben Vidal / Holly J Garringer / Yang Shi / Takeshi Ikeuchi / Shigeo Murayama / ...Authors: Wenjuan Zhang / Airi Tarutani / Kathy L Newell / Alexey G Murzin / Tomoyasu Matsubara / Benjamin Falcon / Ruben Vidal / Holly J Garringer / Yang Shi / Takeshi Ikeuchi / Shigeo Murayama / Bernardino Ghetti / Masato Hasegawa / Michel Goedert / Sjors H W Scheres /
Abstract: Corticobasal degeneration (CBD) is a neurodegenerative tauopathy-a class of disorders in which the tau protein forms insoluble inclusions in the brain-that is characterized by motor and cognitive ...Corticobasal degeneration (CBD) is a neurodegenerative tauopathy-a class of disorders in which the tau protein forms insoluble inclusions in the brain-that is characterized by motor and cognitive disturbances. The H1 haplotype of MAPT (the tau gene) is present in cases of CBD at a higher frequency than in controls, and genome-wide association studies have identified additional risk factors. By histology, astrocytic plaques are diagnostic of CBD; by SDS-PAGE, so too are detergent-insoluble, 37 kDa fragments of tau. Like progressive supranuclear palsy, globular glial tauopathy and argyrophilic grain disease, CBD is characterized by abundant filamentous tau inclusions that are made of isoforms with four microtubule-binding repeats. This distinguishes such '4R' tauopathies from Pick's disease (the filaments of which are made of three-repeat (3R) tau isoforms) and from Alzheimer's disease and chronic traumatic encephalopathy (CTE) (in which both 3R and 4R isoforms are found in the filaments). Here we use cryo-electron microscopy to analyse the structures of tau filaments extracted from the brains of three individuals with CBD. These filaments were identical between cases, but distinct from those seen in Alzheimer's disease, Pick's disease and CTE. The core of a CBD filament comprises residues lysine 274 to glutamate 380 of tau, spanning the last residue of the R1 repeat, the whole of the R2, R3 and R4 repeats, and 12 amino acids after R4. The core adopts a previously unseen four-layered fold, which encloses a large nonproteinaceous density. This density is surrounded by the side chains of lysine residues 290 and 294 from R2 and lysine 370 from the sequence after R4.
History
DepositionNov 26, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 5, 2020Provider: repository / Type: Initial release
Revision 1.1Feb 26, 2020Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID
Revision 1.2Apr 22, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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Structure visualization

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Assembly

Deposited unit
A: Microtubule-associated protein tau
B: Microtubule-associated protein tau
C: Microtubule-associated protein tau


Theoretical massNumber of molelcules
Total (without water)137,7603
Polymers137,7603
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: microscopy, Both Negative-stain and Cryo-EM images showed the twist along the helical axis.
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area17250 Å2
ΔGint-60 kcal/mol
Surface area17840 Å2
MethodPISA

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Components

#1: Protein Microtubule-associated protein tau / Tau protein / Neurofibrillary tangle protein / Paired helical filament-tau / PHF-tau


Mass: 45919.871 Da / Num. of mol.: 3 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P10636

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: FILAMENT / 3D reconstruction method: helical reconstruction

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Sample preparation

ComponentName: Tau filaments extracted from the Frontal cortex of a patient with corticobasal degeneration.
Type: COMPLEX
Details: Corticobasal degeneration (CBD) is characterised by abundant filamentous tau inclusions that are made of isoforms with four microtubule-binding repeats (4R).
Entity ID: all / Source: NATURAL
Molecular weightValue: 0.46 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli) / Strain: BL21(DE3) / Plasmid: pRK172
Buffer solutionpH: 7.4 / Details: 20 mM Tris, pH 7.4, 100mM NaCl
Buffer component
IDConc.NameFormulaBuffer-ID
10.02 mol/Ltris(hydroxymethyl)aminomethaneTris1
20.1 mol/Lsodium chlorideNaClSodium chloride1
SpecimenConc.: 2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: The tau filaments were extracted from the Frontal cortex of a patient with corticobasal degeneration by using sarkosyl and ultracentrifuge.
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K / Details: Blot force: -12 ; Blot time: 4s

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2800 nm / Nominal defocus min: 1700 nm / Cs: 2.7 mm / C2 aperture diameter: 70 µm / Alignment procedure: ZEMLIN TABLEAU
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 10 sec. / Electron dose: 1.346 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 2567
Details: Images were collected in movie-mode at 40 frames every 10 seconds
EM imaging opticsEnergyfilter name: GIF Quantum LS / Energyfilter slit width: 20 eV
Image scansSampling size: 5 µm / Width: 3838 / Height: 3710 / Movie frames/image: 40 / Used frames/image: 1-40

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Processing

EM software
IDNameVersionCategory
1RELION3particle selection
2EPU1.10.0.77RELimage acquisition
4CTFFIND4.1CTF correction
7Coot0.8.9.1model fitting
9RELION3initial Euler assignment
10RELION3final Euler assignment
11RELION3classification
12RELION33D reconstruction
13REFMAC5.8.0256model refinement
14PHENIXdev-2919model refinement
Image processingDetails: Movie frames were gain-corrected, aligned, dose weighted and then summed into a single micrograph using MOTIONCOR2 (Zheng et al., 2017)
CTF correctionDetails: Aligned, non-dose-weighted micrographs were used to estimate the contrast transfer function (CTF) using CTFFIND4.1
Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: -0.845 ° / Axial rise/subunit: 4.786 Å / Axial symmetry: C1
Particle selectionNum. of particles selected: 135646 / Details: Manually picked
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 24073 / Num. of class averages: 3 / Symmetry type: HELICAL
Atomic model buildingB value: 26.63 / Protocol: AB INITIO MODEL / Space: RECIPROCAL / Target criteria: Fourier shell correlation
Details: A stack of three consecutive monomers was refined to preserve nearest-neighbour interactions for the middle chain. Because most residues adopted cross strand conformation, hydrogen-bond ...Details: A stack of three consecutive monomers was refined to preserve nearest-neighbour interactions for the middle chain. Because most residues adopted cross strand conformation, hydrogen-bond restraints were imposed to preserve a parallel, in-register hydrogen bonding pattern in earlier stages of Fourier-space refinements. Local symmetry restraints were imposed to keep all beta strand rungs identical. Side-chain clashes were detected using MOLPROBITY, and corrected by iterative cycles of real-space refinement in COOT and Fourier-space refinement in REFMAC and PHENIX. For each refined structure, separate model refinements were performed against a single half-map, and the resulting model was compared to the other half-map to confirm the absence of overfitting.

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