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- PDB-8bgv: Tau Paired Helical Filament from Cellular Fraction of Alzheimer's... -

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Basic information

Entry
Database: PDB / ID: 8bgv
TitleTau Paired Helical Filament from Cellular Fraction of Alzheimer's disease brain
ComponentsMicrotubule-associated protein tauTau protein
KeywordsPROTEIN FIBRIL / AMYLOID
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 / regulation of microtubule cytoskeleton organization / supramolecular fiber organization / Activation of AMPK downstream of NMDARs / cytoplasmic microtubule organization / stress granule assembly / regulation of cellular response to heat / axon cytoplasm / regulation of calcium-mediated signaling / 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 / response to lead ion / synapse organization / microglial cell activation / Hsp90 protein binding / regulation of synaptic plasticity / PKR-mediated signaling / protein homooligomerization / cytoplasmic ribonucleoprotein granule / microtubule cytoskeleton organization / memory / cellular response to reactive oxygen species / SH3 domain binding / activation of cysteine-type endopeptidase activity involved in apoptotic process / neuron projection development / 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 / sequence-specific DNA binding / amyloid fibril formation / dendritic spine / learning or memory / neuron projection / nuclear speck / 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, tubulin-binding repeat / Microtubule-associated protein Tau / 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: 3.27 Å
AuthorsBehr, T.S. / Ryskeldi-Falcon, B.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MC_UP_1201/25 United Kingdom
CitationJournal: bioRxiv / Year: 2023
Title: Tau filaments are tethered within brain extracellular vesicles in Alzheimer's disease.
Authors: S L Fowler / T S Behr / E Turkes / P Maglio Cauhy / M S Foiani / A Schaler / G Crowley / S Bez / E Ficulle / E Tsefou / D P O'Brien / R Fischer / B Geary / P Gaur / C Miller / P D'Acunzo / E ...Authors: S L Fowler / T S Behr / E Turkes / P Maglio Cauhy / M S Foiani / A Schaler / G Crowley / S Bez / E Ficulle / E Tsefou / D P O'Brien / R Fischer / B Geary / P Gaur / C Miller / P D'Acunzo / E Levy / K E Duff / B Ryskeldi-Falcon
Abstract: The abnormal assembly of tau protein in neurons is the pathological hallmark of multiple neurodegenerative diseases, including Alzheimer's disease (AD). In addition, assembled tau associates with ...The abnormal assembly of tau protein in neurons is the pathological hallmark of multiple neurodegenerative diseases, including Alzheimer's disease (AD). In addition, assembled tau associates with extracellular vesicles (EVs) in the central nervous system of patients with AD, which is linked to its clearance and prion-like propagation between neurons. However, the identities of the assembled tau species and the EVs, as well as how they associate, are not known. Here, we combined quantitative mass spectrometry, cryo-electron tomography and single-particle cryo-electron microscopy to study brain EVs from AD patients. We found filaments of truncated tau enclosed within EVs enriched in endo-lysosomal proteins. We observed multiple filament interactions, including with molecules that tethered filaments to the EV limiting membrane, suggesting selective packaging. Our findings will guide studies into the molecular mechanisms of EV-mediated secretion of assembled tau and inform the targeting of EV-associated tau as potential therapeutic and biomarker strategies for AD.
History
DepositionOct 28, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 24, 2023Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
n: Microtubule-associated protein tau
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


Theoretical massNumber of molelcules
Total (without water)321,4397
Polymers321,4397
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Noncrystallographic symmetry (NCS)NCS oper:
IDCodeMatrixVector
1given(1), (1), (1)
2given(0.999271, -0.038179), (0.038179, 0.999271), (1)5.02958, -4.84109, -9.652
3given(0.999818, -0.019093), (0.019093, 0.999818), (1)2.49168, -2.44456, -4.826
4given(-0.999954, 0.009547), (-0.009547, -0.999954), (1)257.30002, 259.76825, -2.413
5given(-0.999954, -0.009547), (0.009547, -0.999954), (1)259.76825, 257.30002, 2.413
6given(0.999818, 0.019093), (-0.019093, 0.999818), (1)-2.44456, 2.49168, 4.826
7given(-0.99959, -0.028637), (0.028637, -0.99959), (1)262.1889, 254.7851, 7.239

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Components

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


Mass: 45919.871 Da / Num. of mol.: 7 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Organ: Brain / Tissue: Brain / References: UniProt: P10636

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Experimental details

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Experiment

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

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Sample preparation

ComponentName: Tau Paired Helical Filament / Type: TISSUE
Details: Tau Paired Helical Filament extracted from the cellular fraction of the brain of an individual who had Alzheimer's disease.
Entity ID: all / Source: NATURAL
Source (natural)Organism: Homo sapiens (human) / Cellular location: Cytoplasm / Organ: Brain / Organelle: Cytoplasm / Tissue: Brain
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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 FIELDBright-field microscopy / Nominal defocus max: 2400 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: REFMAC / Version: 5.8.0387 / Classification: refinement
CTF correctionType: NONE
Helical symmertyAngular rotation/subunit: 174.454 ° / Axial rise/subunit: 2.413 Å / Axial symmetry: C1
3D reconstructionResolution: 3.27 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 9347 / Symmetry type: HELICAL
RefinementResolution: 3.27→155.12 Å / Cor.coef. Fo:Fc: 0.779 / SU B: 27.188 / SU ML: 0.42 / ESU R: 0.173
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflection
Rwork0.47739 --
obs0.47739 50303 100 %
Solvent computationSolvent model: PARAMETERS FOR MASK CACLULATION
Displacement parametersBiso mean: 66.433 Å2
Refinement stepCycle: 1 / Total: 587
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0070.012596
ELECTRON MICROSCOPYr_bond_other_d00.016592
ELECTRON MICROSCOPYr_angle_refined_deg1.5381.657797
ELECTRON MICROSCOPYr_angle_other_deg0.61.6021378
ELECTRON MICROSCOPYr_dihedral_angle_1_deg11.099576
ELECTRON MICROSCOPYr_dihedral_angle_2_deg4.27552
ELECTRON MICROSCOPYr_dihedral_angle_3_deg10.62310118
ELECTRON MICROSCOPYr_dihedral_angle_4_deg
ELECTRON MICROSCOPYr_chiral_restr0.070.289
ELECTRON MICROSCOPYr_gen_planes_refined0.0070.02671
ELECTRON MICROSCOPYr_gen_planes_other0.0030.02117
ELECTRON MICROSCOPYr_nbd_refined
ELECTRON MICROSCOPYr_nbd_other
ELECTRON MICROSCOPYr_nbtor_refined
ELECTRON MICROSCOPYr_nbtor_other
ELECTRON MICROSCOPYr_xyhbond_nbd_refined
ELECTRON MICROSCOPYr_xyhbond_nbd_other
ELECTRON MICROSCOPYr_metal_ion_refined
ELECTRON MICROSCOPYr_metal_ion_other
ELECTRON MICROSCOPYr_symmetry_vdw_refined
ELECTRON MICROSCOPYr_symmetry_vdw_other
ELECTRON MICROSCOPYr_symmetry_hbond_refined
ELECTRON MICROSCOPYr_symmetry_hbond_other
ELECTRON MICROSCOPYr_symmetry_metal_ion_refined
ELECTRON MICROSCOPYr_symmetry_metal_ion_other
ELECTRON MICROSCOPYr_mcbond_it7.4225.457307
ELECTRON MICROSCOPYr_mcbond_other7.4185.457307
ELECTRON MICROSCOPYr_mcangle_it12.058.149382
ELECTRON MICROSCOPYr_mcangle_other12.0358.207383
ELECTRON MICROSCOPYr_scbond_it10.2027.42289
ELECTRON MICROSCOPYr_scbond_other10.1837.35288
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other17.61710.326416
ELECTRON MICROSCOPYr_long_range_B_refined22.87164.13571
ELECTRON MICROSCOPYr_long_range_B_other22.99365.12572
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
LS refinement shellResolution: 3.273→3.358 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork0.751 3745 -
obs--100 %

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