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- EMDB-16883: Structure of the Fmoc-Tau-PAM4 Type 3 amyloid fibril -

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Basic information

Entry
Database: EMDB / ID: EMD-16883
TitleStructure of the Fmoc-Tau-PAM4 Type 3 amyloid fibril
Map dataFinal postprocessed, sharpened, helical symmetrised map of the Fmoc-TauPAM4 fibril morphology IIa
Sample
  • Complex: Amyloid fibril form 2a of Tau-PAM4 peptide adducted with the Fmoc protection group
    • Protein or peptide: Microtubule-associated protein tau
Keywordsamyloid / tau / helical / cross-beta / fibril / neurodegeneration / Fmoc / PROTEIN FIBRIL
Function / homology
Function and homology information


plus-end-directed organelle transport along microtubule / histone-dependent DNA binding / neurofibrillary tangle assembly / positive regulation of diacylglycerol kinase activity / axonal transport / 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 / histone-dependent DNA binding / neurofibrillary tangle assembly / positive regulation of diacylglycerol kinase activity / axonal transport / 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 / negative regulation of kinase activity / regulation of long-term synaptic depression / negative regulation of tubulin deacetylation / generation of neurons / rRNA metabolic process / internal protein amino acid acetylation / regulation of chromosome organization / regulation of mitochondrial fission / axonal transport of mitochondrion / intracellular distribution of mitochondria / axon development / central nervous system neuron development / regulation of microtubule polymerization / microtubule polymerization / lipoprotein particle binding / minor groove of adenine-thymine-rich DNA binding / dynactin binding / negative regulation of mitochondrial membrane potential / glial cell projection / apolipoprotein binding / protein polymerization / axolemma / negative regulation of mitochondrial fission / regulation of microtubule polymerization or depolymerization / Caspase-mediated cleavage of cytoskeletal proteins / positive regulation of axon extension / regulation of microtubule cytoskeleton organization / Activation of AMPK downstream of NMDARs / regulation of cellular response to heat / positive regulation of protein localization / cytoplasmic microtubule organization / stress granule assembly / supramolecular fiber organization / regulation of calcium-mediated signaling / axon cytoplasm / somatodendritic compartment / positive regulation of microtubule polymerization / synapse assembly / cellular response to brain-derived neurotrophic factor stimulus / nuclear periphery / phosphatidylinositol binding / 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 / microglial cell activation / synapse organization / Hsp90 protein binding / PKR-mediated signaling / protein homooligomerization / regulation of synaptic plasticity / : / memory / microtubule cytoskeleton organization / SH3 domain binding / cytoplasmic ribonucleoprotein granule / cellular response to reactive oxygen species / microtubule cytoskeleton / neuron projection development / cell-cell signaling / single-stranded DNA binding / protein-folding chaperone binding / actin binding / cellular response to heat / protein-macromolecule adaptor activity / growth cone / cell body / double-stranded DNA binding / microtubule binding / sequence-specific DNA binding / microtubule / amyloid fibril formation / dendritic spine / learning or memory / nuclear speck / 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
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: 2.7 Å
AuthorsWilkinson M / Louros N / Tsaka G / Ramakers M / Morelli C / Garcia T / Gallardo RU / D'Haeyer S / Goossens V / Audenaert D ...Wilkinson M / Louros N / Tsaka G / Ramakers M / Morelli C / Garcia T / Gallardo RU / D'Haeyer S / Goossens V / Audenaert D / Thal DR / Ranson NA / Radford SE / Rousseau F / Schymkowitz J
Funding support Belgium, 1 items
OrganizationGrant numberCountry
Research Foundation - Flanders (FWO) Belgium
CitationJournal: Nat Commun / Year: 2024
Title: Local structural preferences in shaping tau amyloid polymorphism.
Authors: Nikolaos Louros / Martin Wilkinson / Grigoria Tsaka / Meine Ramakers / Chiara Morelli / Teresa Garcia / Rodrigo Gallardo / Sam D'Haeyer / Vera Goossens / Dominique Audenaert / Dietmar Rudolf ...Authors: Nikolaos Louros / Martin Wilkinson / Grigoria Tsaka / Meine Ramakers / Chiara Morelli / Teresa Garcia / Rodrigo Gallardo / Sam D'Haeyer / Vera Goossens / Dominique Audenaert / Dietmar Rudolf Thal / Ian R Mackenzie / Rosa Rademakers / Neil A Ranson / Sheena E Radford / Frederic Rousseau / Joost Schymkowitz /
Abstract: Tauopathies encompass a group of neurodegenerative disorders characterised by diverse tau amyloid fibril structures. The persistence of polymorphism across tauopathies suggests that distinct ...Tauopathies encompass a group of neurodegenerative disorders characterised by diverse tau amyloid fibril structures. The persistence of polymorphism across tauopathies suggests that distinct pathological conditions dictate the adopted polymorph for each disease. However, the extent to which intrinsic structural tendencies of tau amyloid cores contribute to fibril polymorphism remains uncertain. Using a combination of experimental approaches, we here identify a new amyloidogenic motif, PAM4 (Polymorphic Amyloid Motif of Repeat 4), as a significant contributor to tau polymorphism. Calculation of per-residue contributions to the stability of the fibril cores of different pathologic tau structures suggests that PAM4 plays a central role in preserving structural integrity across amyloid polymorphs. Consistent with this, cryo-EM structural analysis of fibrils formed from a synthetic PAM4 peptide shows that the sequence adopts alternative structures that closely correspond to distinct disease-associated tau strains. Furthermore, in-cell experiments revealed that PAM4 deletion hampers the cellular seeding efficiency of tau aggregates extracted from Alzheimer's disease, corticobasal degeneration, and progressive supranuclear palsy patients, underscoring PAM4's pivotal role in these tauopathies. Together, our results highlight the importance of the intrinsic structural propensity of amyloid core segments to determine the structure of tau in cells, and in propagating amyloid structures in disease.
History
DepositionMar 21, 2023-
Header (metadata) releaseFeb 21, 2024-
Map releaseFeb 21, 2024-
UpdateNov 6, 2024-
Current statusNov 6, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

Downloads & links

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Map

FileDownload / File: emd_16883.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationFinal postprocessed, sharpened, helical symmetrised map of the Fmoc-TauPAM4 fibril morphology IIa
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.94 Å/pix.
x 300 pix.
= 282. Å
0.94 Å/pix.
x 300 pix.
= 282. Å
0.94 Å/pix.
x 300 pix.
= 282. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.94 Å
Density
Contour LevelBy AUTHOR: 0.013
Minimum - Maximum-0.022152433 - 0.05096678
Average (Standard dev.)0.00025926903 (±0.002446436)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 282.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: halfmap2

Fileemd_16883_half_map_1.map
Annotationhalfmap2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Half map: halfmap1

Fileemd_16883_half_map_2.map
Annotationhalfmap1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Sample components

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Entire : Amyloid fibril form 2a of Tau-PAM4 peptide adducted with the Fmoc...

EntireName: Amyloid fibril form 2a of Tau-PAM4 peptide adducted with the Fmoc protection group
Components
  • Complex: Amyloid fibril form 2a of Tau-PAM4 peptide adducted with the Fmoc protection group
    • Protein or peptide: Microtubule-associated protein tau

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Supramolecule #1: Amyloid fibril form 2a of Tau-PAM4 peptide adducted with the Fmoc...

SupramoleculeName: Amyloid fibril form 2a of Tau-PAM4 peptide adducted with the Fmoc protection group
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all / Details: Synthesised peptide assembled into amyloid fibril
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Microtubule-associated protein tau

MacromoleculeName: Microtubule-associated protein tau / type: protein_or_peptide / ID: 1
Details: 13-residue peptide of the PAM4 motif of Tau, corresponding to residues 350-362 of the Tau repeat domain. The peptide is C-terminally amidated and should have been N-terminally acetylated but ...Details: 13-residue peptide of the PAM4 motif of Tau, corresponding to residues 350-362 of the Tau repeat domain. The peptide is C-terminally amidated and should have been N-terminally acetylated but 10% of the peptide (by mass spec) was still adducted to the Fmoc protection group from peptide synthesis. This contaminant species dominated fibril assembly
Number of copies: 24 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 1.652269 KDa
SequenceString:
(VP1)VQSKIGSLD NITH(NH2)

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

Concentration0.6 mg/mL
BufferpH: 7
Details: Peptide resuspended in MilliQ water for aggregation reaction
GridModel: EMS Lacey Carbon / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: LACEY / Pretreatment - Type: PLASMA CLEANING / Pretreatment - Time: 60 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 90 % / Chamber temperature: 279 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Specialist opticsEnergy filter - Name: TFS Selectris / Energy filter - Slit width: 10 eV
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Digitization - Dimensions - Width: 4096 pixel / Digitization - Dimensions - Height: 4096 pixel / Number grids imaged: 1 / Number real images: 1957 / Average exposure time: 5.0 sec. / Average electron dose: 32.0 e/Å2
Details: Movies were collected as 1204 EER frames compressed and re-grouped into 35 TIF fractions
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.4 µm / Nominal defocus min: 1.2 µm / Nominal magnification: 130000
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: 4.8 Å
Applied symmetry - Helical parameters - Δ&Phi: -1.05 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 4.0) / Number images used: 11319
Segment selectionNumber selected: 520390 / Software - Name: crYOLO (ver. 1.8)
Startup modelType of model: INSILICO MODEL
In silico model: Initial model generated from a single 2D class average from within the data
Final angle assignmentType: NOT APPLICABLE / Software - Name: RELION (ver. 4.0)
FSC plot (resolution estimation)

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Atomic model buiding 1

DetailsInitial model built manually in coot, no starting template
RefinementSpace: REAL / Protocol: AB INITIO MODEL / Overall B value: 48 / Target criteria: Cross-correlation coefficient
Output model

PDB-8ohp:
Structure of the Fmoc-Tau-PAM4 Type 3 amyloid fibril

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