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- PDB-9r2f: Tau filaments seeded by AD homogenate using 0N3R C322A -

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Basic information

Entry
Database: PDB / ID: 9r2f
TitleTau filaments seeded by AD homogenate using 0N3R C322A
ComponentsIsoform Fetal-tau of Microtubule-associated protein tau
KeywordsPROTEIN FIBRIL / MAPT / Tau / Alzheimer's Disease / RT-QuiC
Function / homology
Function and homology information


plus-end-directed organelle transport along microtubule / histone-dependent DNA binding / neurofibrillary tangle / microtubule lateral binding / axonal transport / tubulin complex / positive regulation of protein localization to synapse / phosphatidylinositol bisphosphate binding / generation of neurons / axonal transport of mitochondrion ...plus-end-directed organelle transport along microtubule / histone-dependent DNA binding / neurofibrillary tangle / microtubule lateral binding / axonal transport / tubulin complex / positive regulation of protein localization to synapse / phosphatidylinositol bisphosphate binding / generation of neurons / axonal transport of mitochondrion / axon development / rRNA metabolic process / central nervous system neuron development / regulation of microtubule-based movement / negative regulation of protein localization to mitochondrion / regulation of mitochondrial fission / regulation of chromosome organization / 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 / regulation of calcium-mediated signaling / main axon / Caspase-mediated cleavage of cytoskeletal proteins / glial cell projection / regulation of microtubule polymerization or depolymerization / neurofibrillary tangle assembly / negative regulation of mitochondrial fission / protein polymerization / positive regulation of axon extension / axolemma / positive regulation of microtubule polymerization / regulation of cellular response to heat / positive regulation of superoxide anion generation / Activation of AMPK downstream of NMDARs / cytoplasmic microtubule organization / cellular response to brain-derived neurotrophic factor stimulus / regulation of long-term synaptic depression / axon cytoplasm / positive regulation of protein localization / supramolecular fiber organization / synapse assembly / somatodendritic compartment / astrocyte activation / nuclear periphery / phosphatidylinositol binding / protein phosphatase 2A binding / enzyme inhibitor activity / stress granule assembly / SH3 domain binding / cellular response to reactive oxygen species / regulation of microtubule cytoskeleton organization / memory / microglial cell activation / cellular response to nerve growth factor stimulus / regulation of synaptic plasticity / Hsp90 protein binding / microtubule cytoskeleton organization / regulation of autophagy / synapse organization / protein homooligomerization / PKR-mediated signaling / response to lead ion / neuron projection development / cytoplasmic ribonucleoprotein granule / microtubule cytoskeleton / cell-cell signaling / cellular response to heat / single-stranded DNA binding / actin binding / protein-folding chaperone binding / growth cone / double-stranded DNA binding / cell body / microtubule / sequence-specific DNA binding / amyloid fibril formation / microtubule binding / dendritic spine / learning or memory / protein-macromolecule adaptor activity / neuron projection / membrane raft / negative regulation of gene expression / axon / 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: 2.8 Å
AuthorsLovestam, S. / Scheres, H.W.S.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom) United Kingdom
CitationJournal: FEBS Lett / Year: 2025
Title: Serial amplification of tau filaments using Alzheimer's brain homogenates and C322A or C322S recombinant tau.
Authors: Alessia Santambrogio / Sofia Lövestam / Michael A Metrick / Thomas Löhr / Peifeng Xu / Nicholas C T Gallagher / Bernardino Ghetti / Byron Caughey / Sjors H W Scheres / Michele Vendruscolo /
Abstract: The assembly of tau into amyloid filaments is a hallmark of Alzheimer's disease (AD) and other tauopathies. Cryo-EM revealed the existence of disease-specific tau folds, which are challenging to ...The assembly of tau into amyloid filaments is a hallmark of Alzheimer's disease (AD) and other tauopathies. Cryo-EM revealed the existence of disease-specific tau folds, which are challenging to replicate in vitro. We studied three full-length recombinant 0N3R tau forms (the wild-type and the C322A and C322S variants) using an RT-QuIC assay with brain homogenate seeding. C322A tau formed filaments resembling AD paired helical filaments (PHFs) but with a more open C-shaped core. C322S tau yielded structurally distinct filaments with an ordered C-terminal region. Both mutants seeded further aggregation, whereas the wild-type showed poor reproducibility and mainly unfolded aggregates. These results highlight the importance of optimised conditions to produce disease-relevant tau filaments and aid the development of targeted therapies. Impact statement We investigated the seeded assembly of 0N3R tau and its two mutational variants C322A and C322S, using Alzheimer's disease brain homogenates in a real-time quaking-induced conversion (RT-QuIC) assay. The C322A variant formed filaments partially resembling the AD PHF structure, showing the importance of optimised conditions to produce disease-relevant tau filaments.
History
DepositionApr 30, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 11, 2025Provider: repository / Type: Initial release
Revision 1.0Jun 11, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
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Revision 1.0Jun 11, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Jun 11, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
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Revision 1.1Oct 22, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Revision 1.1Oct 22, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / Category: citation / citation_author / em_admin
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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)46,8546
Polymers46,8546
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: 7808.945 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAPT, MAPTL, MTBT1, TAU / Production host: Escherichia coli (E. coli) / References: UniProt: P10636
Has protein modificationN

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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: Microtubule associate tau protein assembled into an amyloid filament
Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.2
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 200 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK III / Cryogen name: ETHANE / Humidity: 100 %

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS 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: 500 nm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM software
IDNameVersionCategory
2EPUimage acquisition
13RELION53D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: 179.6 ° / Axial rise/subunit: 2.417 Å / Axial symmetry: C1
3D reconstructionResolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 61103 / Algorithm: BACK PROJECTION / Symmetry type: HELICAL

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