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- EMDB-45588: Alzheimer's Disease Seeded 0N3R Tau Fibrils -

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Basic information

Entry
Database: EMDB / ID: EMD-45588
TitleAlzheimer's Disease Seeded 0N3R Tau Fibrils
Map data
Sample
  • Complex: Amyloid Fibril of 0N3R Tau Seeded with Alzheimer's Disease Tau from Human Brain
    • Protein or peptide: Isoform Fetal-tau of Microtubule-associated protein tau
KeywordsTau / Amyloid / Cross-beta / Seeded-Fibril / PROTEIN 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 / axon development / axonal transport of mitochondrion / rRNA metabolic process / central nervous system neuron development / regulation of microtubule-based movement / 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 / axolemma / positive regulation of axon extension / neurofibrillary tangle assembly / protein polymerization / negative regulation of mitochondrial fission / positive regulation of microtubule polymerization / regulation of cellular response to heat / Activation of AMPK downstream of NMDARs / positive regulation of protein localization / positive regulation of superoxide anion generation / cellular response to brain-derived neurotrophic factor stimulus / cytoplasmic microtubule organization / regulation of long-term synaptic depression / axon cytoplasm / supramolecular fiber organization / synapse assembly / somatodendritic compartment / astrocyte activation / nuclear periphery / phosphatidylinositol binding / protein phosphatase 2A binding / stress granule assembly / enzyme inhibitor activity / 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 / SH3 domain binding / synapse organization / regulation of autophagy / protein homooligomerization / microtubule cytoskeleton organization / 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 / growth cone / protein-folding chaperone binding / actin binding / cell body / double-stranded DNA binding / sequence-specific DNA binding / microtubule binding / amyloid fibril formation / dendritic spine / microtubule / 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)
Methodhelical reconstruction / cryo EM / Resolution: 2.97 Å
AuthorsDuan P / Dregni AJ / Xu H / Changolkar L / Lee VM-Y / Hong M
Funding support United States, 1 items
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, 2024-
Header (metadata) releaseSep 11, 2024-
Map releaseSep 11, 2024-
UpdateOct 2, 2024-
Current statusOct 2, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_45588.png

Downloads & links

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Map

FileDownload / File: emd_45588.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.06 Å/pix.
x 384 pix.
= 407.04 Å		1.06 Å/pix.
x 384 pix.
= 407.04 Å		1.06 Å/pix.
x 384 pix.
= 407.04 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.06 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.02
Minimum - Maximum-0.044383056 - 0.08219245
Average (Standard dev.)0.000036552505 (±0.0014237214)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 407.03998 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_45588_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Amyloid Fibril of 0N3R Tau Seeded with Alzheimer's Disease Tau fr...

EntireName: Amyloid Fibril of 0N3R Tau Seeded with Alzheimer's Disease Tau from Human Brain
Components
  • Complex: Amyloid Fibril of 0N3R Tau Seeded with Alzheimer's Disease Tau from Human Brain
    • Protein or peptide: Isoform Fetal-tau of Microtubule-associated protein tau

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Supramolecule #1: Amyloid Fibril of 0N3R Tau Seeded with Alzheimer's Disease Tau fr...

SupramoleculeName: Amyloid Fibril of 0N3R Tau Seeded with Alzheimer's Disease Tau from Human Brain
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Isoform Fetal-tau of Microtubule-associated protein tau

MacromoleculeName: Isoform Fetal-tau of Microtubule-associated protein tau
type: protein_or_peptide / ID: 1 / Details: Using Numbering From 2N4R Tau / Number of copies: 6 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 36.821121 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MAEPRQEFEV MEDHAGTYGL GDRKDQGGYT MHQDQEGDTD AGLKAEEAGI GDTPSLEDEA AGHVTQARMV SKSKDGTGSD DKKAKGADG KTKIATPRGA APPGQKGQAN ATRIPAKTPP APKTPPSSGE PPKSGDRSGY SSPGSPGTPG SRSRTPSLPT P PTREPKKV ...String:
MAEPRQEFEV MEDHAGTYGL GDRKDQGGYT MHQDQEGDTD AGLKAEEAGI GDTPSLEDEA AGHVTQARMV SKSKDGTGSD DKKAKGADG KTKIATPRGA APPGQKGQAN ATRIPAKTPP APKTPPSSGE PPKSGDRSGY SSPGSPGTPG SRSRTPSLPT P PTREPKKV AVVRTPPKSP SSAKSRLQTA PVPMPDLKNV KSKIGSTENL KHQPGGGKVQ IVYKPVDLSK VTSKCGSLGN IH HKPGGGQ VEVKSEKLDF KDRVQSKIGS LDNITHVPGG GNKKIETHKL TFRENAKAKT DHGAEIVYKS PVVSGDTSPR HLS NVSSTG SIDMVDSPQL ATLADEVSAS LAKQGL

UniProtKB: Microtubule-associated protein tau

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statefilament

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Sample preparation

Concentration1.6 mg/mL
BufferpH: 7.4
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK I

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number grids imaged: 1 / Number real images: 9021 / Average exposure time: 1.55 sec. / Average electron dose: 44.4 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 100.0 µm / Illumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.2 µm / Nominal magnification: 81000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 2.369 Å
Applied symmetry - Helical parameters - Δ&Phi: 179.49 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 2.97 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 4.0) / Number images used: 30112
Segment selectionNumber selected: 1164000 / Software - Name: RELION (ver. 4.0)
Software - details: Autopicking with Topaz done in RELION using -f -t -7
Startup modelType of model: EMDB MAP
EMDB ID:

23894

Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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