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- PDB-8azu: Paired helical tau filaments from high-spin supernatants of aqueo... -

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Basic information

Entry
Database: PDB / ID: 8azu
TitlePaired helical tau filaments from high-spin supernatants of aqueous extracts from Alzheimer's disease brains | PHF Tau
ComponentsMicrotubule-associated protein tauTau protein
KeywordsPROTEIN FIBRIL / amyloid / filaments / tau / PHF / cryo-EM
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 / axon cytoplasm / regulation of calcium-mediated signaling / positive regulation of microtubule polymerization / 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 / cytoplasmic ribonucleoprotein granule / memory / microtubule cytoskeleton organization / 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 / cell body / cellular response to heat / actin binding / protein-folding chaperone binding / growth cone / double-stranded DNA binding / microtubule 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
: / 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: 3.1 Å
AuthorsYang, Y. / Stern, M.A. / Meunier, L.A. / Liu, W. / Cai, Y.Q. / Ericsson, M. / Liu, L. / Selkoe, J.D. / Goedert, M. / Scheres, H.W.S.
Funding support United Kingdom, 3items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MC_UP_1201/25 United Kingdom
Medical Research Council (MRC, United Kingdom)MC_UP_A025_1013 United Kingdom
Medical Research Council (MRC, United Kingdom)MC_U105184291 United Kingdom
CitationJournal: Neuron / Year: 2023
Title: Abundant Aβ fibrils in ultracentrifugal supernatants of aqueous extracts from Alzheimer's disease brains.
Authors: Andrew M Stern / Yang Yang / Shanxue Jin / Keitaro Yamashita / Angela L Meunier / Wen Liu / Yuqi Cai / Maria Ericsson / Lei Liu / Michel Goedert / Sjors H W Scheres / Dennis J Selkoe /
Abstract: Soluble oligomers of amyloid β-protein (Aβ) have been defined as aggregates in supernatants following ultracentrifugation of aqueous extracts from Alzheimer's disease (AD) brains and are believed ...Soluble oligomers of amyloid β-protein (Aβ) have been defined as aggregates in supernatants following ultracentrifugation of aqueous extracts from Alzheimer's disease (AD) brains and are believed to be upstream initiators of synaptic dysfunction, but little is known about their structures. We now report the unexpected presence of Aβ fibrils in synaptotoxic high-speed supernatants from AD brains extracted by soaking in an aqueous buffer. The fibrils did not appear to form during preparation, and their counts by EM correlated with Aβ ELISA quantification. Cryo-EM structures of aqueous Aβ fibrils were identical to those from sarkosyl-insoluble homogenates. The fibrils in aqueous extracts were labeled by lecanemab, an Aβ aggregate-directed antibody reported to improve AD cognitive outcomes. Lecanemab provided protection against aqueous fibril synaptotoxicity. We conclude that fibrils are abundant in aqueous extracts from AD brains and have the same structures as those from plaques. These findings have implications for AD pathogenesis and drug design.
History
DepositionSep 6, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 24, 2023Provider: repository / Type: Initial release
Revision 1.1Jul 19, 2023Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.page_first

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
C: Microtubule-associated protein tau


Theoretical massNumber of molelcules
Total (without water)45,9201
Polymers45,9201
Non-polymers00
Water0
1
C: Microtubule-associated protein tau
x 6


Theoretical massNumber of molelcules
Total (without water)275,5196
Polymers275,5196
Non-polymers00
Water0
TypeNameSymmetry operationNumber
point symmetry operation5
identity operation1_555x,y,z1
Noncrystallographic symmetry (NCS)NCS oper:
IDCodeMatrixVector
1given(1), (1), (1)
2generate(-0.999544, 0.030207), (-0.030207, -0.999544), (1)209.47438, 215.90051, -7.17939
3generate(0.999797, -0.02014), (0.02014, 0.999797), (1)2.1638, -2.12065, -4.78626
4generate(-0.999949, 0.01007), (-0.01007, -0.999949), (1)211.65942, 213.80176, -2.39313
5generate(-0.999949, -0.01007), (0.01007, -0.999949), (1)213.80176, 211.65942, 2.39313
6generate(0.999797, 0.02014), (-0.02014, 0.999797), (1)-2.12065, 2.1638, 4.78626
7generate(0.999189, 0.040271), (-0.040271, 0.999189), (1)-4.19729, 4.36987, 9.57252

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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.: 1 / 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: FILAMENT / 3D reconstruction method: helical reconstruction

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Sample preparation

ComponentName: Paired helical tau filament in soluble high-molecular weight aggregate fractions extracted from the Alzheimer's disease brain
Type: TISSUE / Entity ID: all / Source: NATURAL
Source (natural)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
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: 5.8.0350 / Classification: refinement / Contact author: Garib N. Murshudov / Contact author email: garib[at]mrc-lmb.cam.ac.uk / Date: May 11, 2022
Description: (un)restrained refinement or idealisation of macromolecular structures
EM software
IDNameCategoryDetails
7Cootmodel fitting
12RELION3D reconstruction
13REFMACmodel refinementServalcat
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: 179.4 ° / Axial rise/subunit: 2.4 Å / Axial symmetry: C1
3D reconstructionResolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 44535 / Symmetry type: HELICAL
Atomic model buildingPDB-ID: 6HRE

6hre

RefinementResolution: 3.1→136.284 Å / Cor.coef. Fo:Fc: 0.871 / WRfactor Rwork: 0.413 / SU B: 13.241 / SU ML: 0.236 / Average fsc free: 0 / Average fsc overall: 0.8206 / Average fsc work: 0.8206 / ESU R: 0.144
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rwork0.413 47394 -
all0.413 --
Rfree--0 %
obs--100 %
Solvent computationSolvent model: NONE
Displacement parametersBiso mean: 89.734 Å2
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0070.012577
ELECTRON MICROSCOPYr_bond_other_d00.016563
ELECTRON MICROSCOPYr_angle_refined_deg1.4741.638772
ELECTRON MICROSCOPYr_angle_other_deg0.5771.5791322
ELECTRON MICROSCOPYr_dihedral_angle_1_deg12.505573
ELECTRON MICROSCOPYr_dihedral_angle_2_deg4.466102
ELECTRON MICROSCOPYr_dihedral_angle_3_deg12.41610115
ELECTRON MICROSCOPYr_dihedral_angle_6_deg14.8041022
ELECTRON MICROSCOPYr_chiral_restr0.0650.287
ELECTRON MICROSCOPYr_gen_planes_refined0.0070.02630
ELECTRON MICROSCOPYr_gen_planes_other0.0040.0298
ELECTRON MICROSCOPYr_nbd_refined0.1730.264
ELECTRON MICROSCOPYr_symmetry_nbd_other0.1540.2419
ELECTRON MICROSCOPYr_nbtor_refined0.1580.2257
ELECTRON MICROSCOPYr_symmetry_nbtor_other0.0770.2352
ELECTRON MICROSCOPYr_xyhbond_nbd_refined0.1750.23
ELECTRON MICROSCOPYr_symmetry_nbd_refined0.2220.223
ELECTRON MICROSCOPYr_nbd_other0.1660.2142
ELECTRON MICROSCOPYr_symmetry_xyhbond_nbd_refined0.0780.26
ELECTRON MICROSCOPYr_mcbond_it9.8947.668295
ELECTRON MICROSCOPYr_mcbond_other9.8857.667295
ELECTRON MICROSCOPYr_mcangle_it14.55711.545367
ELECTRON MICROSCOPYr_mcangle_other14.53711.577368
ELECTRON MICROSCOPYr_scbond_it12.0710.076282
ELECTRON MICROSCOPYr_scbond_other12.0510.129283
ELECTRON MICROSCOPYr_scangle_it20.39514.175405
ELECTRON MICROSCOPYr_scangle_other20.3714.233406
ELECTRON MICROSCOPYr_lrange_it26.209104.473541
ELECTRON MICROSCOPYr_lrange_other26.202104.894542
LS refinement shell

Refine-ID: ELECTRON MICROSCOPY / Num. reflection Rfree: 0 / Total num. of bins used: 20 / % reflection obs: 100 %

Resolution (Å)Rfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc workWRfactor Rwork
3.1-3.181.04134531.04134530.611.041
3.18-3.2680.65634300.65634300.6860.656
3.268-3.3620.5833450.5833450.7340.58
3.362-3.4660.50931660.50931660.7990.509
3.466-3.5790.46932540.46932540.8040.469
3.579-3.7050.42229440.42229440.8380.422
3.705-3.8450.39529640.39529640.8480.395
3.845-4.0010.37327930.37327930.8550.373
4.001-4.1790.37927050.37927050.8630.379
4.179-4.3830.38125510.38125510.8630.381
4.383-4.620.36724830.36724830.9260.367
4.62-4.90.37722790.37722790.9010.377
4.9-5.2370.33721990.33721990.9470.337
5.237-5.6560.3320040.3320040.8970.33
5.656-6.1950.33318710.33318710.90.333
6.195-6.9250.38316910.38316910.8580.383
6.925-7.9920.40814930.40814930.7990.408
7.992-9.780.47612600.47612600.780.476
9.78-13.7960.4129660.4129660.8910.412
13.796-136.2840.4765430.4765430.9570.476

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