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- PDB-8bgs: Tau Paired Helical Filament from Extracellular Vesicles from Alzh... -

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Basic information

Entry
Database: PDB / ID: 8bgs
TitleTau Paired Helical Filament from Extracellular Vesicles from Alzheimer's disease brain
ComponentsMicrotubule-associated protein tau
KeywordsPROTEIN FIBRIL / AMYLOID
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: 3.16 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
Revision 1.1Jul 24, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond / em_admin / Item: _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
r: 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
Water00
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(-0.99957, 0.029317), (-0.029317, -0.99957), (1)264.80197, 272.68246, -7.062
3given(0.999809, -0.019546), (0.019546, 0.999809), (1)2.65272, -2.60136, -4.708
4given(-0.999952, 0.009774), (-0.009774, -0.999952), (1)267.47998, 270.10715, -2.354
5given(-0.999952, -0.009774), (0.009774, -0.999952), (1)270.10715, 267.47998, 2.354
6given(0.999809, 0.019546), (-0.019546, 0.999809), (1)-2.60136, 2.65272, 4.708
7given(0.999236, 0.039085), (-0.039085, 0.999236), (1)-5.15038, 5.35578, 9.416

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Components

#1: Protein
Microtubule-associated protein tau / 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 extracellular vesicles that were isolated from the brain of an individual who had Alzheimer's disease.
Entity ID: all / Source: NATURAL
Source (natural)Organism: Homo sapiens (human) / Cellular location: Extracellular vesicle / Organ: Brain / Organelle: Extracellular vesicle / 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 FIELD / Nominal defocus max: 2200 nm / Nominal defocus min: 1400 nm
Image recordingElectron dose: 38.7 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: REFMAC / Version: 5.8.0387 / Classification: refinement
CTF correctionType: NONE
Helical symmertyAngular rotation/subunit: 174.439 ° / Axial rise/subunit: 2.354 Å / Axial symmetry: C1
3D reconstructionResolution: 3.16 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 18041 / Symmetry type: HELICAL
RefinementResolution: 3.16→159.6 Å / Cor.coef. Fo:Fc: 0.812 / SU B: 26.307 / SU ML: 0.424 / ESU R: 0.18
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflection
Rwork0.47182 --
obs0.47182 41782 100 %
Solvent computationSolvent model: PARAMETERS FOR MASK CACLULATION
Displacement parametersBiso mean: 69.65 Å2
Refinement stepCycle: 1 / Total: 574
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0070.012583
ELECTRON MICROSCOPYr_bond_other_d00.016583
ELECTRON MICROSCOPYr_angle_refined_deg1.591.657780
ELECTRON MICROSCOPYr_angle_other_deg0.6321.6011356
ELECTRON MICROSCOPYr_dihedral_angle_1_deg11.579574
ELECTRON MICROSCOPYr_dihedral_angle_2_deg2.93352
ELECTRON MICROSCOPYr_dihedral_angle_3_deg12.03710116
ELECTRON MICROSCOPYr_dihedral_angle_4_deg
ELECTRON MICROSCOPYr_chiral_restr0.0810.288
ELECTRON MICROSCOPYr_gen_planes_refined0.0060.02653
ELECTRON MICROSCOPYr_gen_planes_other0.0030.02115
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_it7.5235.637299
ELECTRON MICROSCOPYr_mcbond_other7.5155.637299
ELECTRON MICROSCOPYr_mcangle_it11.6868.476372
ELECTRON MICROSCOPYr_mcangle_other11.6728.499373
ELECTRON MICROSCOPYr_scbond_it10.3587.763284
ELECTRON MICROSCOPYr_scbond_other10.3427.816285
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other17.85710.823409
ELECTRON MICROSCOPYr_long_range_B_refined24.95574.12566
ELECTRON MICROSCOPYr_long_range_B_other24.93374.53567
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
LS refinement shellResolution: 3.162→3.245 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork0.728 3084 -
obs--100 %

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