+Open data
-Basic information
Entry | Database: PDB / ID: 5o3l | ||||||||||||||||||||||||
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Title | Paired helical filament in Alzheimer's disease brain | ||||||||||||||||||||||||
Components | Microtubule-associated protein tauTau protein | ||||||||||||||||||||||||
Keywords | STRUCTURAL PROTEIN / TAU / AMYLOID / CROSS-BETA / BETA-HELIX | ||||||||||||||||||||||||
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 / 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 / lipoprotein particle binding / dynactin binding / glial cell projection / negative regulation of mitochondrial membrane potential / 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 / Activation of AMPK downstream of NMDARs / regulation of microtubule cytoskeleton organization / supramolecular fiber organization / stress granule assembly / regulation of cellular response to heat / cytoplasmic microtubule organization / regulation of calcium-mediated signaling / positive regulation of microtubule polymerization / axon cytoplasm / somatodendritic compartment / cellular response to brain-derived neurotrophic factor stimulus / 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 / response to lead ion / synapse organization / microglial cell activation / Hsp90 protein binding / regulation of synaptic plasticity / PKR-mediated signaling / protein homooligomerization / memory / cellular response to reactive oxygen species / microtubule cytoskeleton organization / SH3 domain binding / cytoplasmic ribonucleoprotein granule / activation of cysteine-type endopeptidase activity involved in apoptotic process / neuron projection development / microtubule cytoskeleton / cell-cell signaling / protein-macromolecule adaptor activity / actin binding / single-stranded DNA binding / cellular response to heat / cell body / protein-folding chaperone binding / growth cone / microtubule binding / double-stranded DNA binding / microtubule / sequence-specific DNA binding / 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 Similarity search - Function | ||||||||||||||||||||||||
Biological species | Homo sapiens (human) | ||||||||||||||||||||||||
Method | ELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3.4 Å | ||||||||||||||||||||||||
Authors | Fitzpatrick, A.W.P. / Falcon, B. / He, S. / Murzin, A.G. / Murshudov, G. / Garringer, H.G. / Crowther, R.A. / Ghetti, B. / Goedert, M. / Scheres, S.H.W. | ||||||||||||||||||||||||
Funding support | United Kingdom, United States, 7items
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Citation | Journal: Nature / Year: 2017 Title: Cryo-EM structures of tau filaments from Alzheimer's disease. Authors: Anthony W P Fitzpatrick / Benjamin Falcon / Shaoda He / Alexey G Murzin / Garib Murshudov / Holly J Garringer / R Anthony Crowther / Bernardino Ghetti / Michel Goedert / Sjors H W Scheres / Abstract: Alzheimer's disease is the most common neurodegenerative disease, and there are no mechanism-based therapies. The disease is defined by the presence of abundant neurofibrillary lesions and neuritic ...Alzheimer's disease is the most common neurodegenerative disease, and there are no mechanism-based therapies. The disease is defined by the presence of abundant neurofibrillary lesions and neuritic plaques in the cerebral cortex. Neurofibrillary lesions comprise paired helical and straight tau filaments, whereas tau filaments with different morphologies characterize other neurodegenerative diseases. No high-resolution structures of tau filaments are available. Here we present cryo-electron microscopy (cryo-EM) maps at 3.4-3.5 Å resolution and corresponding atomic models of paired helical and straight filaments from the brain of an individual with Alzheimer's disease. Filament cores are made of two identical protofilaments comprising residues 306-378 of tau protein, which adopt a combined cross-β/β-helix structure and define the seed for tau aggregation. Paired helical and straight filaments differ in their inter-protofilament packing, showing that they are ultrastructural polymorphs. These findings demonstrate that cryo-EM allows atomic characterization of amyloid filaments from patient-derived material, and pave the way for investigation of a range of neurodegenerative diseases. | ||||||||||||||||||||||||
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 | 5o3l.cif.gz | 233.3 KB | Display | PDBx/mmCIF format |
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PDB format | pdb5o3l.ent.gz | 190.8 KB | Display | PDB format |
PDBx/mmJSON format | 5o3l.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/o3/5o3l ftp://data.pdbj.org/pub/pdb/validation_reports/o3/5o3l | HTTPS FTP |
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-Related structure data
Related structure data | 3741MC 3742C 3743C 3744C 5o3oC 5o3tC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
#1: Protein | Mass: 7940.141 Da / Num. of mol.: 10 / Fragment: UNP Residues 623-695 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Organ: 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: Structure of Paired Helical Filaments from Alzheimer's Disease Brain Type: TISSUE / Entity ID: all / Source: NATURAL |
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Source (natural) | Organism: Homo sapiens (human) |
Buffer solution | pH: 7.4 / Details: 20 mM Tris-HCl pH 7.4 containing 100 mM NaCl |
Specimen | Conc.: 1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES Details: Sarkosyl-insoluble material was extracted from grey matter of frontal and temporal cortex from the patients brain, as described in the Methods section of the paper. |
Specimen support | Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil Au R1.2/1.3 |
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277.15 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: 3000 nm / Nominal defocus min: 900 nm / Calibrated defocus min: 900 nm / Calibrated defocus max: 3000 nm / Cs: 2.7 mm / C2 aperture diameter: 70 µm / Alignment procedure: COMA FREE |
Specimen holder | Cryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Image recording | Average exposure time: 0.2 sec. / Electron dose: 1.2 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 QUANTUM (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 1560 Details: images were collected in movie-mode at 5 frames per second |
EM imaging optics | Energyfilter name: GIF Quantum / Energyfilter upper: 10 eV / Energyfilter lower: -10 eV |
Image scans | Width: 3710 / Height: 3710 / Movie frames/image: 50 |
-Processing
EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||||||||||||||
Helical symmerty | Angular rotation/subunit: 179.4 ° / Axial rise/subunit: 2.36 Å / Axial symmetry: C1 | ||||||||||||||||||||||||||||||||||||
Particle selection | Num. of particles selected: 214757 | ||||||||||||||||||||||||||||||||||||
3D reconstruction | Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 23086 / Num. of class averages: 1 / Symmetry type: HELICAL | ||||||||||||||||||||||||||||||||||||
Atomic model building | B value: 105 / Protocol: AB INITIO MODEL / Space: RECIPROCAL / Target criteria: Fourier shell correlation Details: Fourier-space refinement of the complete atomic model against the paired helical filament and straight filament maps was performed in REFMAC. A stack of three consecutive monomers from each ...Details: Fourier-space refinement of the complete atomic model against the paired helical filament and straight filament maps was performed in REFMAC. A stack of three consecutive monomers from each of the protofilaments was refined to preserve nearest-neighbour interactions for the middle chain. | ||||||||||||||||||||||||||||||||||||
Atomic model building | PDB-ID: 2RNM Pdb chain-ID: A / Accession code: 2RNM / Pdb chain residue range: 226-242 / Source name: PDB / Type: experimental model |