+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-16883 | |||||||||
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Title | Structure of the Fmoc-Tau-PAM4 Type 3 amyloid fibril | |||||||||
Map data | Final postprocessed, sharpened, helical symmetrised map of the Fmoc-TauPAM4 fibril morphology IIa | |||||||||
Sample |
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Keywords | amyloid / 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 / apolipoprotein binding / microtubule polymerization / lipoprotein particle binding / minor groove of adenine-thymine-rich DNA binding / dynactin binding / negative regulation of mitochondrial membrane potential / glial cell projection / 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 / protein homooligomerization / PKR-mediated signaling / regulation of synaptic plasticity / : / memory / SH3 domain binding / microtubule cytoskeleton organization / cytoplasmic ribonucleoprotein granule / cellular response to reactive oxygen species / microtubule cytoskeleton / neuron projection development / cell-cell signaling / protein-folding chaperone binding / single-stranded DNA binding / actin binding / cellular response to heat / protein-macromolecule adaptor activity / double-stranded DNA binding / growth cone / cell body / 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 | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | helical reconstruction / cryo EM / Resolution: 2.7 Å | |||||||||
Authors | 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 | Belgium, 1 items
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Citation | Journal: 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 |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_16883.map.gz | 20.8 MB | EMDB map data format | |
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Header (meta data) | emd-16883-v30.xml emd-16883.xml | 18.6 KB 18.6 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_16883_fsc.xml | 10.6 KB | Display | FSC data file |
Images | emd_16883.png | 78 KB | ||
Filedesc metadata | emd-16883.cif.gz | 6 KB | ||
Others | emd_16883_half_map_1.map.gz emd_16883_half_map_2.map.gz | 80.7 MB 80.7 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-16883 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-16883 | HTTPS FTP |
-Validation report
Summary document | emd_16883_validation.pdf.gz | 817.9 KB | Display | EMDB validaton report |
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Full document | emd_16883_full_validation.pdf.gz | 817.5 KB | Display | |
Data in XML | emd_16883_validation.xml.gz | 17.9 KB | Display | |
Data in CIF | emd_16883_validation.cif.gz | 23.7 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-16883 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-16883 | HTTPS FTP |
-Related structure data
Related structure data | 8ohpMC 8oh2C 8ohiC 8oi0C M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_16883.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
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Annotation | Final postprocessed, sharpened, helical symmetrised map of the Fmoc-TauPAM4 fibril morphology IIa | ||||||||||||||||||||||||||||||||||||
Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 0.94 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: halfmap2
File | emd_16883_half_map_1.map | ||||||||||||
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Annotation | halfmap2 | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: halfmap1
File | emd_16883_half_map_2.map | ||||||||||||
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Annotation | halfmap1 | ||||||||||||
Projections & Slices |
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Density Histograms |
-Sample components
-Entire : Amyloid fibril form 2a of Tau-PAM4 peptide adducted with the Fmoc...
Entire | Name: Amyloid fibril form 2a of Tau-PAM4 peptide adducted with the Fmoc protection group |
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Components |
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-Supramolecule #1: Amyloid fibril form 2a of Tau-PAM4 peptide adducted with the Fmoc...
Supramolecule | Name: 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 |
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Source (natural) | Organism: Homo sapiens (human) |
-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 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 |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 1.652269 KDa |
Sequence | String: (VP1)VQSKIGSLD NITH(NH2) UniProtKB: Microtubule-associated protein tau |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | helical reconstruction |
Aggregation state | filament |
-Sample preparation
Concentration | 0.6 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 / Mesh: 300 / 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 |
-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: 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 beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | C2 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 stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
+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: 48 / Target criteria: Cross-correlation coefficient |
Output model | PDB-8ohp: |