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Open data
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Basic information
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Title | Structure of the Tau-PAM4 Type 1 amyloid fibril | |||||||||
![]() | Final postprocess, sharpened, helical symmetrised map of the acetyl-TauPAM4 2PF fibril form | |||||||||
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![]() | amyloid / tau / helical / cross-beta / fibril / neurodegeneration / PROTEIN FIBRIL | |||||||||
Function / homology | ![]() plus-end-directed organelle transport along microtubule / axonal transport / histone-dependent DNA binding / neurofibrillary tangle assembly / positive regulation of diacylglycerol kinase activity / 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 / axonal transport / histone-dependent DNA binding / neurofibrillary tangle assembly / positive regulation of diacylglycerol kinase activity / 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 / regulation of long-term synaptic depression / negative regulation of kinase activity / negative regulation of tubulin deacetylation / generation of neurons / positive regulation of protein localization / regulation of chromosome organization / rRNA metabolic process / internal protein amino acid acetylation / regulation of mitochondrial fission / intracellular distribution of mitochondria / axonal transport of mitochondrion / axon development / central nervous system neuron development / regulation of microtubule polymerization / microtubule polymerization / minor groove of adenine-thymine-rich DNA binding / lipoprotein particle binding / dynactin binding / apolipoprotein binding / glial cell projection / negative regulation of mitochondrial membrane potential / protein polymerization / negative regulation of mitochondrial fission / axolemma / Caspase-mediated cleavage of cytoskeletal proteins / regulation of microtubule polymerization or depolymerization / positive regulation of axon extension / regulation of microtubule cytoskeleton organization / Activation of AMPK downstream of NMDARs / supramolecular fiber organization / regulation of cellular response to heat / stress granule assembly / cytoplasmic microtubule organization / regulation of calcium-mediated signaling / axon cytoplasm / positive regulation of microtubule polymerization / somatodendritic compartment / cellular response to brain-derived neurotrophic factor stimulus / synapse assembly / phosphatidylinositol binding / nuclear periphery / 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 / regulation of synaptic plasticity / PKR-mediated signaling / protein homooligomerization / memory / cytoplasmic ribonucleoprotein granule / SH3 domain binding / microtubule cytoskeleton organization / cellular response to reactive oxygen species / activation of cysteine-type endopeptidase activity involved in apoptotic process / microtubule cytoskeleton / neuron projection development / cell-cell signaling / protein-macromolecule adaptor activity / actin binding / cellular response to heat / single-stranded DNA binding / protein-folding chaperone binding / cell body / growth cone / microtubule binding / double-stranded DNA binding / microtubule / amyloid fibril formation / sequence-specific DNA binding / 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 | |||||||||
Biological species | synthetic construct (others) | |||||||||
Method | helical reconstruction / cryo EM / Resolution: 2.6 Å | |||||||||
![]() | Wilkinson 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 | ![]()
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![]() | ![]() 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 |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 27.2 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 18.3 KB 18.3 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 10.6 KB | Display | ![]() |
Images | ![]() | 66.3 KB | ||
Filedesc metadata | ![]() | 5.8 KB | ||
Others | ![]() ![]() | 80.8 MB 80.8 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Validation report
Summary document | ![]() | 1 MB | Display | ![]() |
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Full document | ![]() | 1 MB | Display | |
Data in XML | ![]() | 17.6 KB | Display | |
Data in CIF | ![]() | 23.1 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8oh2MC ![]() 8ohiC ![]() 8ohpC ![]() 8oi0C M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Annotation | Final postprocess, sharpened, helical symmetrised map of the acetyl-TauPAM4 2PF fibril form | ||||||||||||||||||||||||||||||||||||
Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 0.95 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: halfmap1
File | emd_16876_half_map_1.map | ||||||||||||
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Annotation | halfmap1 | ||||||||||||
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Density Histograms |
-Half map: halfmap2
File | emd_16876_half_map_2.map | ||||||||||||
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Annotation | halfmap2 | ||||||||||||
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Density Histograms |
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Sample components
-Entire : 2PF amyloid fibril assembly of Tau-PAM4 peptide
Entire | Name: 2PF amyloid fibril assembly of Tau-PAM4 peptide |
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Components |
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-Supramolecule #1: 2PF amyloid fibril assembly of Tau-PAM4 peptide
Supramolecule | Name: 2PF amyloid fibril assembly of Tau-PAM4 peptide / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 / Details: Synthesised peptide assembled into amyloid fibril |
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Source (natural) | Organism: synthetic construct (others) |
-Macromolecule #1: Microtubule-associated protein tau
Macromolecule | Name: 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 N-terminally acetylated and C-terminally amidated Number of copies: 36 / Enantiomer: LEVO |
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Source (natural) | Organism: synthetic construct (others) |
Molecular weight | Theoretical: 1.437622 KDa |
Sequence | String: (ACE)VQSKIGSLD NITH(NH2) UniProtKB: Microtubule-associated protein tau |
-Macromolecule #2: water
Macromolecule | Name: water / type: ligand / ID: 2 / Number of copies: 30 / Formula: HOH |
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Molecular weight | Theoretical: 18.015 Da |
Chemical component information | ![]() ChemComp-HOH: |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | helical reconstruction |
Aggregation state | filament |
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Sample preparation
Concentration | 2.5 mg/mL |
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Buffer | pH: 7 Details: Peptide resuspended in MilliQ water for aggregation reaction |
Grid | Model: EMS Lacey Carbon / Material: COPPER / Support film - Material: CARBON / Support film - topology: LACEY / Pretreatment - Type: PLASMA CLEANING / Pretreatment - Time: 60 sec. |
Vitrification | Cryogen name: ETHANE / Chamber humidity: 90 % / Chamber temperature: 279 K / Instrument: FEI VITROBOT MARK IV |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Specialist optics | Energy filter - Name: TFS Selectris / Energy filter - Slit width: 10 eV |
Image recording | Film 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: 1512 / Average exposure time: 5.0 sec. / Average electron dose: 39.0 e/Å2 Details: Movies were collected as 1539 EER frames compressed and re-grouped into 36 TIF fractions |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | C2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.6 µm / Nominal defocus min: 1.4000000000000001 µm / Nominal magnification: 130000 |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
-Atomic model buiding 1
Details | Initial model built manually in coot, no starting template |
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Refinement | Space: REAL / Protocol: AB INITIO MODEL / Overall B value: 54 / Target criteria: Cross-correlation coefficient |
Output model | ![]() PDB-8oh2: |