+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-3743 | ||||||||||||||||||||||||
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Title | Straight filament in Alzheimer's disease brain | ||||||||||||||||||||||||
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Sample |
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Keywords | TAU / AMYLOID / CROSS-BETA / BETA-HELIX / PROTEIN FIBRIL | ||||||||||||||||||||||||
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 / tubulin complex ...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 / regulation of long-term synaptic depression / negative regulation of kinase activity / 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 / axon development / intracellular distribution of mitochondria / central nervous system neuron development / regulation of microtubule polymerization / microtubule polymerization / lipoprotein particle binding / minor groove of adenine-thymine-rich DNA binding / dynactin binding / glial cell projection / negative regulation of mitochondrial membrane potential / apolipoprotein binding / protein polymerization / axolemma / negative regulation of mitochondrial fission / 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 / positive regulation of protein localization / regulation of cellular response to heat / cytoplasmic microtubule organization / stress granule assembly / supramolecular fiber organization / regulation of calcium-mediated signaling / axon cytoplasm / somatodendritic compartment / positive regulation of microtubule polymerization / 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 / microglial cell activation / synapse organization / Hsp90 protein binding / protein homooligomerization / PKR-mediated signaling / regulation of synaptic plasticity / memory / activation of cysteine-type endopeptidase activity involved in apoptotic process / microtubule cytoskeleton organization / SH3 domain binding / cellular response to reactive oxygen species / cytoplasmic ribonucleoprotein granule / microtubule cytoskeleton / neuron projection development / cell-cell signaling / protein-macromolecule adaptor activity / protein-folding chaperone binding / single-stranded DNA binding / actin binding / cellular response to heat / cell body / 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 / dendrite / DNA damage response / protein kinase binding / enzyme binding / mitochondrion / DNA binding Similarity search - Function | ||||||||||||||||||||||||
Biological species | Homo sapiens (human) | ||||||||||||||||||||||||
Method | helical reconstruction / cryo EM / Resolution: 3.4 Å | ||||||||||||||||||||||||
Authors | Fitzpatrick AWP / Falcon B / He S | ||||||||||||||||||||||||
Funding support | United Kingdom, United States, 7 items
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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 | EM map: SurfViewMolmilJmol/JSmol |
Supplemental images |
-Downloads & links
-EMDB archive
Map data | emd_3743.map.gz | 4.8 MB | EMDB map data format | |
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Header (meta data) | emd-3743-v30.xml emd-3743.xml | 18.9 KB 18.9 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_3743_fsc.xml | 9.6 KB | Display | FSC data file |
Images | emd_3743.png | 111.9 KB | ||
Filedesc metadata | emd-3743.cif.gz | 5.9 KB | ||
Others | emd_3743_half_map_1.map.gz emd_3743_half_map_2.map.gz | 30.4 MB 30.4 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-3743 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-3743 | HTTPS FTP |
-Validation report
Summary document | emd_3743_validation.pdf.gz | 353.6 KB | Display | EMDB validaton report |
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Full document | emd_3743_full_validation.pdf.gz | 352.7 KB | Display | |
Data in XML | emd_3743_validation.xml.gz | 15.6 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-3743 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-3743 | HTTPS FTP |
-Related structure data
Related structure data | 5o3tMC 3741C 3742C 3744C 5o3lC 5o3oC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_3743.map.gz / Format: CCP4 / Size: 75.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.04 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Half map: #1
File | emd_3743_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #2
File | emd_3743_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : Tau
Entire | Name: Tau |
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Components |
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-Supramolecule #1: Tau
Supramolecule | Name: Tau / type: tissue / ID: 1 / Parent: 0 / Macromolecule list: all |
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Source (natural) | Organism: Homo sapiens (human) |
-Macromolecule #1: Microtubule-associated protein tau
Macromolecule | Name: Microtubule-associated protein tau / type: protein_or_peptide / ID: 1 / Number of copies: 10 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 7.940141 KDa |
Sequence | String: VQIVYKPVDL SKVTSKCGSL GNIHHKPGGG QVEVKSEKLD FKDRVQSKIG SLDNITHVPG GGNKKIETHK LTF UniProtKB: Microtubule-associated protein tau |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | helical reconstruction |
Aggregation state | tissue |
-Sample preparation
Concentration | 1.0 mg/mL |
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Buffer | pH: 7.4 / Details: 20 mM Tris-HCl pH 7.4 containing 100 mM NaCl |
Grid | Model: Quantifoil Au R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 60 sec. |
Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV |
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. |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Specialist optics | Energy filter - Name: GIF Quantum / Energy filter - Lower energy threshold: -10 eV / Energy filter - Upper energy threshold: 10 eV |
Image recording | Film or detector model: GATAN K2 QUANTUM (4k x 4k) / Detector mode: SUPER-RESOLUTION / Digitization - Dimensions - Width: 3710 pixel / Digitization - Dimensions - Height: 3710 pixel / Number grids imaged: 1 / Number real images: 1560 / Average exposure time: 0.2 sec. / Average electron dose: 1.2 e/Å2 Details: images were collected in movie-mode at 5 frames per second |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | C2 aperture diameter: 70.0 µm / Calibrated defocus max: 3.0 µm / Calibrated defocus min: 0.9 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 3.0 µm / Nominal defocus min: 0.9 µm |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
+Image processing
-Atomic model buiding 1
Initial model | PDB ID: Chain - Chain ID: A / Chain - Residue range: 226-242 / Chain - Source name: PDB / Chain - Initial model type: experimental model |
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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. |
Refinement | Space: RECIPROCAL / Protocol: AB INITIO MODEL / Overall B value: 114 / Target criteria: Fourier shell correlation |
Output model | PDB-5o3t: |