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Yorodumi- PDB-6tjx: Cryo-EM structure of TypeII tau filaments extracted from the brai... -
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-Basic information
Entry | Database: PDB / ID: 6tjx | |||||||||
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Title | Cryo-EM structure of TypeII tau filaments extracted from the brains of individuals with Corticobasal degeneration | |||||||||
Components | Microtubule-associated protein tau | |||||||||
Keywords | PROTEIN FIBRIL / tau protein / filament / cross-beta structure | |||||||||
Function / homology | Function and homology information 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 / negative regulation of mitochondrial fission ...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 / negative regulation of mitochondrial fission / 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 / positive regulation of protein localization / 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 / microtubule polymerization / minor groove of adenine-thymine-rich DNA binding / lipoprotein particle binding / dynactin binding / glial cell projection / apolipoprotein binding / negative regulation of mitochondrial membrane potential / protein polymerization / axolemma / Caspase-mediated cleavage of cytoskeletal proteins / regulation of microtubule polymerization or depolymerization / positive regulation of axon extension / regulation of microtubule cytoskeleton organization / Activation of AMPK downstream of NMDARs / cytoplasmic microtubule organization / supramolecular fiber organization / regulation of cellular response to heat / stress granule assembly / positive regulation of superoxide anion generation / regulation of calcium-mediated signaling / axon cytoplasm / positive regulation of microtubule polymerization / somatodendritic compartment / synapse assembly / cellular response to brain-derived neurotrophic factor stimulus / astrocyte activation / phosphatidylinositol binding / nuclear periphery / cellular response to nerve growth factor stimulus / protein phosphatase 2A binding / regulation of autophagy / response to lead ion / synapse organization / microglial cell activation / cellular response to reactive oxygen species / Hsp90 protein binding / PKR-mediated signaling / protein homooligomerization / regulation of synaptic plasticity / memory / activation of cysteine-type endopeptidase activity involved in apoptotic process / microtubule cytoskeleton organization / SH3 domain binding / cytoplasmic ribonucleoprotein granule / microtubule cytoskeleton / neuron projection development / cell-cell signaling / double-stranded DNA binding / protein-macromolecule adaptor activity / single-stranded DNA binding / actin binding / protein-folding chaperone binding / cellular response to heat / cell body / growth cone / microtubule binding / sequence-specific DNA binding / amyloid fibril formation / microtubule / learning or memory / dendritic spine / 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 Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | ELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3 Å | |||||||||
Authors | Zhang, W. / Murzin, A.G. / Falcon, B. / Shi, Y. / Goedert, M. / Scheres, S.H.W. | |||||||||
Funding support | United Kingdom, 2items
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Citation | Journal: 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 |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | Molecule: MolmilJmol/JSmol |
-Downloads & links
-Download
PDBx/mmCIF format | 6tjx.cif.gz | 141.5 KB | Display | PDBx/mmCIF format |
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PDB format | pdb6tjx.ent.gz | 98.8 KB | Display | PDB format |
PDBx/mmJSON format | 6tjx.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 6tjx_validation.pdf.gz | 1.1 MB | Display | wwPDB validaton report |
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Full document | 6tjx_full_validation.pdf.gz | 1.1 MB | Display | |
Data in XML | 6tjx_validation.xml.gz | 33.1 KB | Display | |
Data in CIF | 6tjx_validation.cif.gz | 48.3 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/tj/6tjx ftp://data.pdbj.org/pub/pdb/validation_reports/tj/6tjx | HTTPS FTP |
-Related structure data
Related structure data | 10514MC 6tjoC C: citing same article (ref.) M: map data used to model this data |
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Similar structure data | |
EM raw data | EMPIAR-10340 (Title: Cryo-EM reconstruction of tau filaments extracted from the brains of three individuals with Corticobasal degeneration Data size: 2.8 TB Data #1: Unaligned movies for Case 1 [micrographs - multiframe] Data #2: Unaligned movies for Case 2 [micrographs - multiframe] Data #3: Unaligned movies for Case 3 [micrographs - multiframe]) |
-Links
-Assembly
Deposited unit |
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-Components
#1: Protein | Mass: 45919.871 Da / Num. of mol.: 6 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P10636 |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: FILAMENT / 3D reconstruction method: helical reconstruction |
-Sample preparation
Component | Name: 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 | |||||||||||||||
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Molecular weight | Value: 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 solution | pH: 7.4 / Details: 20 mM Tris, pH 7.4, 100mM NaCl | |||||||||||||||
Buffer component |
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Specimen | Conc.: 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. | |||||||||||||||
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K / Details: Blot force: -12 ; Blot time: 4s |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2800 nm / Nominal defocus min: 1700 nm / Cs: 2.7 mm / C2 aperture diameter: 70 µm / Alignment procedure: ZEMLIN TABLEAU |
Specimen holder | Cryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Image recording | Average 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 optics | Energyfilter name: GIF Quantum LS / Energyfilter slit width: 20 eV |
Image scans | Sampling size: 5 µm / Width: 3838 / Height: 3710 / Movie frames/image: 40 / Used frames/image: 1-40 |
-Processing
EM software |
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Image processing | Details: Movie frames were gain-corrected, aligned, dose weighted and then summed into a single micrograph using MOTIONCOR2 (Zheng et al., 2017) | ||||||||||||||||||||||||||||||||||||||||||||
CTF correction | Details: Aligned, non-dose-weighted micrographs were used to estimate the contrast transfer function (CTF) using CTFFIND4.1 Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||||||||||||||||||||||
Helical symmerty | Angular rotation/subunit: -0.61 ° / Axial rise/subunit: 4.786 Å / Axial symmetry: C2 | ||||||||||||||||||||||||||||||||||||||||||||
Particle selection | Num. of particles selected: 129812 / Details: Manually picked | ||||||||||||||||||||||||||||||||||||||||||||
3D reconstruction | Resolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 20752 / Num. of class averages: 1 / Symmetry type: HELICAL | ||||||||||||||||||||||||||||||||||||||||||||
Atomic model building | B value: 25.75 / 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. |