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- EMDB-51886: PAD12 0N3R tau PHF seeded by AD -

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Basic information

Entry
Database: EMDB / ID: EMD-51886
TitlePAD12 0N3R tau PHF seeded by AD
Map dataSharpened map
Sample
  • Complex: Amyloid filament of tau
    • Protein or peptide: Isoform Fetal-tau of Microtubule-associated protein tau
KeywordsAmyloid / alzheimer / 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 mitochondrial fission / regulation of microtubule-based movement / intracellular distribution of mitochondria / regulation of chromosome organization / 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 / protein polymerization / main axon / Caspase-mediated cleavage of cytoskeletal proteins / glial cell projection / regulation of microtubule polymerization or depolymerization / negative regulation of mitochondrial fission / axolemma / positive regulation of axon extension / neurofibrillary tangle assembly / regulation of cellular response to heat / positive regulation of microtubule polymerization / positive regulation of protein localization / Activation of AMPK downstream of NMDARs / positive regulation of superoxide anion generation / regulation of calcium-mediated signaling / cytoplasmic microtubule organization / cellular response to brain-derived neurotrophic factor stimulus / regulation of long-term synaptic depression / axon cytoplasm / supramolecular fiber organization / somatodendritic compartment / synapse assembly / astrocyte activation / nuclear periphery / phosphatidylinositol binding / protein phosphatase 2A binding / enzyme inhibitor activity / stress granule assembly / regulation of autophagy / regulation of microtubule cytoskeleton organization / cellular response to reactive oxygen species / microglial cell activation / cellular response to nerve growth factor stimulus / Hsp90 protein binding / memory / regulation of synaptic plasticity / SH3 domain binding / synapse organization / protein homooligomerization / PKR-mediated signaling / microtubule cytoskeleton organization / 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: 2.72 Å
AuthorsLovestam S / Scheres SHW / Goedert M
Funding support United Kingdom, 1 items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom) United Kingdom
CitationJournal: Elife / Year: 2026
Title: Twelve phosphomimetic mutations induce the assembly of recombinant full-length human tau into paired helical filaments.
Authors: Sofia Lövestam / Jane L Wagstaff / Taxiarchis Katsinelos / Jenny Shi / Stefan M V Freund / Michel Goedert / Sjors H W Scheres /
Abstract: The assembly of tau into amyloid filaments is associated with more than 20 neurodegenerative diseases, collectively termed tauopathies. Electron cryo-microscopy (cryo-EM) structures of brain-derived ...The assembly of tau into amyloid filaments is associated with more than 20 neurodegenerative diseases, collectively termed tauopathies. Electron cryo-microscopy (cryo-EM) structures of brain-derived tau filaments revealed that specific structures define different diseases, triggering a quest for the development of experimental model systems that replicate the structures of disease. Here, we describe 12 phosphomimetic serine/threonine-to-aspartate mutations in tau, which we term PAD12, that collectively induce the in vitro assembly of full-length three-repeat tau into filaments with the same structure as paired helical filaments extracted from the brains of individuals with Alzheimer's disease. Solution-state nuclear magnetic resonance spectroscopy suggests that phosphomimetic mutations in the carboxy-terminal domain of tau may facilitate filament formation by disrupting an intramolecular interaction between two IVYK motifs. PAD12 tau can be used for both nucleation-dependent and multiple rounds of seeded assembly in vitro, as well as for the seeding of tau biosensor cells. PAD12 tau can be assembled into paired helical filaments under various shaking conditions, with the resulting filaments being stable for extended periods of time. They can be labelled with fluorophores and biotin. Tau filaments extracted from the brains of individuals with Alzheimer's disease have been known to be made of hyperphosphorylated and abnormally phosphorylated full-length tau, but it was not known if the presence of this post-translational modification is more than a mere correlation. Our findings suggest that hyperphosphorylation of tau may be sufficient for the formation of the Alzheimer tau fold. PAD12 tau will be a useful tool for the study of molecular mechanisms of neurodegeneration.
History
DepositionOct 22, 2024-
Header (metadata) releaseDec 4, 2024-
Map releaseDec 4, 2024-
UpdateJun 3, 2026-
Current statusJun 3, 2026Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_51886.png

Downloads & links

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Map

FileDownload / File: emd_51886.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSharpened map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.74 Å/pix.
x 384 pix.
= 285.696 Å		0.74 Å/pix.
x 384 pix.
= 285.696 Å		0.74 Å/pix.
x 384 pix.
= 285.696 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.744 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.00968
Minimum - Maximum-0.028640691 - 0.050644256
Average (Standard dev.)0.00014195037 (±0.0024455304)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 285.696 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: Unsharpened map

Fileemd_51886_additional_1.map
AnnotationUnsharpened map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
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Histogram

Histogram (log scale)

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Half map: Half map 2

Fileemd_51886_half_map_1.map
AnnotationHalf map 2
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map 1

Fileemd_51886_half_map_2.map
AnnotationHalf map 1
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : Amyloid filament of tau

EntireName: Amyloid filament of tau
Components
  • Complex: Amyloid filament of tau
    • Protein or peptide: Isoform Fetal-tau of Microtubule-associated protein tau

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Supramolecule #1: Amyloid filament of tau

SupramoleculeName: Amyloid filament of tau / 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 / Number of copies: 6 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 37.073078 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MAEPRQEFEV MEDHAGTYGL GDRKDQGGYT MHQDQEGDTD AGLKAEEAGI GDTPSLEDEA AGHVTQARMV SKSKDGTGSD DKKAKGADG KTKIATPRGA APPGQKGQAN ATRIPAKTPP APKDPPSSGE PPKSGDRSGY SSPGDPGDPG SRSRDPDLPD P PTREPKKV ...String:
MAEPRQEFEV MEDHAGTYGL GDRKDQGGYT MHQDQEGDTD AGLKAEEAGI GDTPSLEDEA AGHVTQARMV SKSKDGTGSD DKKAKGADG KTKIATPRGA APPGQKGQAN ATRIPAKTPP APKDPPSSGE PPKSGDRSGY SSPGDPGDPG SRSRDPDLPD P PTREPKKV AVVRDPPKDP SSAKSRLQTA PVPMPDLKNV KSKIGSTENL KHQPGGGKVQ IVYKPVDLSK VTSKCGSLGN IH HKPGGGQ VEVKSEKLDF KDRVQSKIGS LDNITHVPGG GNKKIETHKL TFRENAKAKT DHGAEIVYKD PVVDGDDDPR 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

BufferpH: 7.28
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 30.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 2.42 Å
Applied symmetry - Helical parameters - Δ&Phi: 179.393 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 2.72 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 5) / Number images used: 125334
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER / Details: de novo
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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