+Open data
-Basic information
Entry | Database: PDB / ID: 6hre | ||||||||||||||||||
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Title | Paired helical filament from sporadic Alzheimer's disease brain | ||||||||||||||||||
Components | Microtubule-associated protein tauTau protein | ||||||||||||||||||
Keywords | PROTEIN FIBRIL / Tau / helical / filament / fibril / amyloid / Alzheimer's disease / PHF / paired helical filament / NFT / neurofibrillary tangly | ||||||||||||||||||
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 / cytoplasmic microtubule organization / regulation of microtubule cytoskeleton organization / stress granule assembly / 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 | ||||||||||||||||||
Biological species | Homo sapiens (human) | ||||||||||||||||||
Method | ELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3.2 Å | ||||||||||||||||||
Authors | Falcon, B. / Zhang, W. / Schweighauser, M. / Murzin, A.G. / Vidal, R. / Garringer, H.J. / Ghetti, B. / Scheres, S.H.W. / Goedert, M. | ||||||||||||||||||
Funding support | United Kingdom, United States, 5items
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Citation | Journal: Acta Neuropathol / Year: 2018 Title: Tau filaments from multiple cases of sporadic and inherited Alzheimer's disease adopt a common fold. Authors: Benjamin Falcon / Wenjuan Zhang / Manuel Schweighauser / Alexey G Murzin / Ruben Vidal / Holly J Garringer / Bernardino Ghetti / Sjors H W Scheres / Michel Goedert / Abstract: The ordered assembly of tau protein into abnormal filaments is a defining characteristic of Alzheimer's disease (AD) and other neurodegenerative disorders. It is not known if the structures of tau ...The ordered assembly of tau protein into abnormal filaments is a defining characteristic of Alzheimer's disease (AD) and other neurodegenerative disorders. It is not known if the structures of tau filaments vary within, or between, the brains of individuals with AD. We used a combination of electron cryo-microscopy (cryo-EM) and immuno-gold negative-stain electron microscopy (immuno-EM) to determine the structures of paired helical filaments (PHFs) and straight filaments (SFs) from the frontal cortex of 17 cases of AD (15 sporadic and 2 inherited) and 2 cases of atypical AD (posterior cortical atrophy). The high-resolution structures of PHFs and SFs from the frontal cortex of 3 cases of AD, 2 sporadic and 1 inherited, were determined by cryo-EM. We also used immuno-EM to study the PHFs and SFs from a number of cortical and subcortical brain regions. PHFs outnumbered SFs in all AD cases. By cryo-EM, PHFs and SFs were made of two C-shaped protofilaments with a combined cross-β/β-helix structure, as described previously for one case of AD. The higher resolution structures obtained here showed two additional amino acids at each end of the protofilament. The immuno-EM findings, which indicated the presence of repeats 3 and 4, but not of the N-terminal regions of repeats 1 and 2, of tau in the filament cores of all AD cases, were consistent with the cryo-EM results. These findings show that there is no significant variation in tau filament structures between individuals with AD. This knowledge will be crucial for understanding the mechanisms that underlie tau filament formation and for developing novel diagnostics and therapies. | ||||||||||||||||||
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 | 6hre.cif.gz | 121.5 KB | Display | PDBx/mmCIF format |
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PDB format | pdb6hre.ent.gz | 86 KB | Display | PDB format |
PDBx/mmJSON format | 6hre.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/hr/6hre ftp://data.pdbj.org/pub/pdb/validation_reports/hr/6hre | HTTPS FTP |
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-Related structure data
Related structure data | 0259MC 0260C 6hrfC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | |
EM raw data | EMPIAR-10230 (Title: Cryo electron microscopy of tau filaments from sporadic Alzheimer's disease brain Data size: 27.0 Data #1: Dose-weighted micrographs of tau filaments from sporadic Alzheimer's disease brain (case 2) [micrographs - single frame]) |
-Links
-Assembly
Deposited unit |
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1 |
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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) / Plasmid details: Post-mortem / Tissue: Brain / References: UniProt: P10636 |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: TISSUE / 3D reconstruction method: helical reconstruction |
-Sample preparation
Component | Name: Tau filaments extracted from the frontotemporal cortex of a patient with sporadic Alzheimer's disease Type: TISSUE / Entity ID: all / Source: NATURAL | ||||||||||||
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Source (natural) | Organism: Homo sapiens (human) / Organ: Brain / Tissue: Frontotemporal cortex | ||||||||||||
Buffer solution | pH: 7.4 | ||||||||||||
Buffer component |
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Specimen | Conc.: 0.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: Dispersed filaments | ||||||||||||
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K |
-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 FIELDBright-field microscopy / Nominal defocus max: 2800 nm / Nominal defocus min: 1700 nm / Cs: 2.7 mm |
Image recording | Electron dose: 1.2 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 QUANTUM (4k x 4k) |
EM imaging optics | Energyfilter name: GIF Quantum LS |
-Processing
EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
Helical symmerty | Angular rotation/subunit: 179.45 ° / Axial rise/subunit: 2.37 Å / Axial symmetry: C1 | ||||||||||||||||||||||||
3D reconstruction | Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 95917 / Symmetry type: HELICAL | ||||||||||||||||||||||||
Atomic model building | B value: 72.8 / Protocol: AB INITIO MODEL / Space: RECIPROCAL / Target criteria: Fourier shell correlation Details: Fourier-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- ...Details: Fourier-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. |