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- PDB-9cgz: Alzheimer's Disease Seeded Mixed 0N4R and 0N3R Tau Fibrils -

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Basic information

Entry
Database: PDB / ID: 9cgz
TitleAlzheimer's Disease Seeded Mixed 0N4R and 0N3R Tau Fibrils
ComponentsIsoform Fetal-tau of Microtubule-associated protein tau
KeywordsPROTEIN FIBRIL / Tau / Amyloid / Cross-beta / Seeded-Fibril
Function / homology
Function and homology information


plus-end-directed organelle transport along microtubule / histone-dependent DNA binding / negative regulation of protein localization to mitochondrion / neurofibrillary tangle / microtubule lateral binding / axonal transport / tubulin complex / positive regulation of protein localization to synapse / phosphatidylinositol bisphosphate binding / generation of neurons ...plus-end-directed organelle transport along microtubule / histone-dependent DNA binding / negative regulation of protein localization to mitochondrion / neurofibrillary tangle / microtubule lateral binding / axonal transport / tubulin complex / positive regulation of protein localization to synapse / phosphatidylinositol bisphosphate binding / generation of neurons / rRNA metabolic process / axonal transport of mitochondrion / regulation of mitochondrial fission / axon development / regulation of chromosome organization / regulation of microtubule-based movement / central nervous system neuron development / intracellular distribution of mitochondria / minor groove of adenine-thymine-rich DNA binding / lipoprotein particle binding / microtubule polymerization / negative regulation of mitochondrial membrane potential / regulation of microtubule polymerization / dynactin binding / apolipoprotein binding / main axon / protein polymerization / axolemma / glial cell projection / Caspase-mediated cleavage of cytoskeletal proteins / regulation of microtubule polymerization or depolymerization / negative regulation of mitochondrial fission / neurofibrillary tangle assembly / positive regulation of axon extension / regulation of cellular response to heat / synapse assembly / Activation of AMPK downstream of NMDARs / regulation of long-term synaptic depression / positive regulation of superoxide anion generation / positive regulation of protein localization / cellular response to brain-derived neurotrophic factor stimulus / supramolecular fiber organization / cytoplasmic microtubule organization / regulation of calcium-mediated signaling / somatodendritic compartment / axon cytoplasm / positive regulation of microtubule polymerization / astrocyte activation / phosphatidylinositol binding / enzyme inhibitor activity / nuclear periphery / stress granule assembly / protein phosphatase 2A binding / regulation of microtubule cytoskeleton organization / cellular response to reactive oxygen species / Hsp90 protein binding / microglial cell activation / cellular response to nerve growth factor stimulus / synapse organization / PKR-mediated signaling / regulation of synaptic plasticity / protein homooligomerization / response to lead ion / SH3 domain binding / microtubule cytoskeleton organization / memory / regulation of autophagy / cytoplasmic ribonucleoprotein granule / neuron projection development / cell-cell signaling / single-stranded DNA binding / protein-folding chaperone binding / cellular response to heat / microtubule cytoskeleton / growth cone / actin binding / cell body / double-stranded DNA binding / protein-macromolecule adaptor activity / microtubule binding / sequence-specific DNA binding / dendritic spine / amyloid fibril formation / microtubule / learning or memory / neuron projection / membrane raft / axon / negative regulation of gene expression / neuronal cell body / DNA damage response / dendrite / protein kinase binding / enzyme binding / mitochondrion / DNA binding / RNA binding / extracellular region / identical protein binding / nucleus
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: 2.69 Å
AuthorsDuan, P. / Dregni, A.J. / Xu, H. / Changolkar, L. / Lee, V.M.-Y. / Hong, M.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Aging (NIH/NIA)AG059661 United States
CitationJournal: J Biol Chem / Year: 2024
Title: Alzheimer's disease seeded tau forms paired helical filaments yet lacks seeding potential.
Authors: Pu Duan / Aurelio J Dregni / Hong Xu / Lakshmi Changolkar / Virginia M-Y Lee / Edward B Lee / Mei Hong /
Abstract: Alzheimer's disease (AD) and many other neurodegenerative diseases are characterized by pathological aggregation of the protein tau. These tau aggregates spread in a stereotypical spatiotemporal ...Alzheimer's disease (AD) and many other neurodegenerative diseases are characterized by pathological aggregation of the protein tau. These tau aggregates spread in a stereotypical spatiotemporal pattern in the brain of each disease, suggesting that the misfolded tau can recruit soluble monomers to adopt the same pathological structure. To investigate whether recruited tau indeed adopts the same structure and properties as the original seed, here we template recombinant full-length 0N3R tau, 0N4R tau, and an equimolar mixture of the two using sarkosyl-insoluble tau extracted from AD brain and determine the structures of the resulting fibrils using cryoelectron microscopy. We show that these cell-free amplified tau fibrils adopt the same molecular structure as the AD paired-helical filament (PHF) tau but are unable to template additional monomers. Therefore, the PHF structure alone is insufficient for defining the pathological properties of AD tau, and other biochemical components such as tau posttranslational modifications, other proteins, polyanionic cofactors, and salt are required for the prion-like serial propagation of tauopathies.
History
DepositionJul 1, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 11, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 2, 2024Group: Data collection / Database references / Category: citation / em_admin
Item: _citation.journal_volume / _citation.title / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Isoform Fetal-tau of Microtubule-associated protein tau
B: Isoform Fetal-tau of Microtubule-associated protein tau
C: Isoform Fetal-tau of Microtubule-associated protein tau
D: Isoform Fetal-tau of Microtubule-associated protein tau
E: Isoform Fetal-tau of Microtubule-associated protein tau
F: Isoform Fetal-tau of Microtubule-associated protein tau


Theoretical massNumber of molelcules
Total (without water)220,9276
Polymers220,9276
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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


Mass: 36821.121 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Details: Mixture of 0N4R and 0N3R monomers templated by Alzheimer's Disease Seeds
Source: (gene. exp.) Homo sapiens (human) / Gene: MAPT, MAPTL, MTBT1, TAU / Production host: Escherichia coli (E. coli) / 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: Amyloid Fibril of Mixed 0N4R and 0N3R Tau Seeded with Alzheimer's Disease Tau from Human Brain
Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.4
SpecimenConc.: 1.6 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK I / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 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: SPOT SCAN
Electron lensMode: BRIGHT FIELD / Nominal magnification: 81000 X / Nominal defocus max: 2000 nm / Nominal defocus min: 200 nm / Cs: 2.7 mm / C2 aperture diameter: 100 µm
Specimen holderSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 2.25 sec. / Electron dose: 45.7 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 7917

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Processing

EM software
IDNameVersionCategoryDetails
1RELION4particle selectionAutopicking with Topaz done in RELION using -f -t -7
9ISOLDEmodel refinement
13RELION43D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: 179.51 ° / Axial rise/subunit: 2.376 Å / Axial symmetry: C1
Particle selectionNum. of particles selected: 2966238
3D reconstructionResolution: 2.69 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 55886 / Symmetry type: HELICAL

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