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- PDB-5o3t: Straight filament in Alzheimer's disease brain -

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Basic information

Entry
Database: PDB / ID: 5o3t
TitleStraight filament in Alzheimer's disease brain
ComponentsMicrotubule-associated protein tau
KeywordsPROTEIN FIBRIL / TAU / AMYLOID / CROSS-BETA / BETA-HELIX
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 / negative regulation of kinase activity / regulation of long-term synaptic depression / 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 / intracellular distribution of mitochondria / axon development / central nervous system neuron development / regulation of microtubule polymerization / microtubule polymerization / lipoprotein particle binding / minor groove of adenine-thymine-rich DNA binding / dynactin binding / negative regulation of mitochondrial membrane potential / glial cell projection / apolipoprotein binding / protein polymerization / axolemma / negative regulation of mitochondrial fission / regulation of microtubule polymerization or depolymerization / Caspase-mediated cleavage of cytoskeletal proteins / positive regulation of axon extension / regulation of microtubule cytoskeleton organization / Activation of AMPK downstream of NMDARs / regulation of cellular response to heat / positive regulation of protein localization / cytoplasmic microtubule organization / stress granule assembly / supramolecular fiber organization / regulation of calcium-mediated signaling / axon cytoplasm / somatodendritic compartment / positive regulation of microtubule polymerization / synapse assembly / cellular response to brain-derived neurotrophic factor stimulus / nuclear periphery / phosphatidylinositol binding / 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 / PKR-mediated signaling / protein homooligomerization / regulation of synaptic plasticity / : / memory / microtubule cytoskeleton organization / SH3 domain binding / cytoplasmic ribonucleoprotein granule / cellular response to reactive oxygen species / microtubule cytoskeleton / neuron projection development / cell-cell signaling / single-stranded DNA binding / protein-folding chaperone binding / actin binding / cellular response to heat / protein-macromolecule adaptor activity / growth cone / cell body / double-stranded DNA binding / microtubule binding / sequence-specific DNA binding / microtubule / 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
Microtubule-associated protein Tau / Microtubule associated protein, tubulin-binding repeat / : / 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: 3.4 Å
AuthorsFitzpatrick, 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
OrganizationGrant numberCountry
Medical Research Council (United Kingdom)MC_UP_A025_1013 United Kingdom
Medical Research Council (United Kingdom)MC_U105184291 United Kingdom
Medical Research Council (United Kingdom)MC_UP_A025_1012 United Kingdom
European UnionMarie Curie International Outgoing Fellowship United Kingdom
European UnionJoint Programme-Neurodegeneration Research United Kingdom
European UnionHorizon 2020 IMPRiND United Kingdom
National Institutes of HealthP30-AG010133 United States
CitationJournal: 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
DepositionMay 24, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 26, 2017Provider: repository / Type: Initial release
Revision 1.1Aug 2, 2017Group: Data collection / Source and taxonomy / Structure summary
Category: em_imaging_optics / entity ...em_imaging_optics / entity / entity_src_gen / entity_src_nat
Item: _em_imaging_optics.energyfilter_name / _entity.src_method
Revision 1.2May 15, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / em_3d_fitting_list / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id / _em_3d_fitting_list.source_name / _em_3d_fitting_list.type

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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
D: Microtubule-associated protein tau
E: Microtubule-associated protein tau
F: Microtubule-associated protein tau
G: Microtubule-associated protein tau
H: Microtubule-associated protein tau
I: Microtubule-associated protein tau
J: Microtubule-associated protein tau


Theoretical massNumber of molelcules
Total (without water)79,40110
Polymers79,40110
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: mass spectrometry
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area51090 Å2
ΔGint-228 kcal/mol
Surface area31680 Å2
MethodPISA

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Components

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


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) / References: UniProt: P10636

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Experimental details

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Experiment

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

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Sample preparation

ComponentName: Tau / Type: TISSUE / Entity ID: all / Source: NATURAL
Source (natural)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4 / Details: 20 mM Tris-HCl pH 7.4 containing 100 mM NaCl
SpecimenConc.: 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 supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil Au R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277.15 K

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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 FIELD / 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 holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage 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 opticsEnergyfilter name: GIF Quantum / Energyfilter upper: 10 eV / Energyfilter lower: -10 eV
Image scansWidth: 3710 / Height: 3710 / Movie frames/image: 50

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Processing

EM software
IDNameVersionCategory
1RELION2particle selection
4GctfCTF correction
7Cootmodel fitting
9RELION2initial Euler assignment
10RELION2final Euler assignment
11RELION2classification
12RELION23D reconstruction
13REFMACmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: -1.05 ° / Axial rise/subunit: 4.74 Å / Axial symmetry: C1
Particle selectionNum. of particles selected: 84701
3D reconstructionResolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 24689 / Num. of class averages: 1 / Symmetry type: HELICAL
Atomic model buildingB value: 114 / 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 buildingPDB-ID: 2RNM

2rnm


Pdb chain-ID: A / Accession code: 2RNM / Pdb chain residue range: 226-242 / Source name: PDB / Type: experimental model

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