+Open data
-Basic information
Entry | Database: PDB / ID: 8oh2 | ||||||
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Title | Structure of the Tau-PAM4 Type 1 amyloid fibril | ||||||
Components | Microtubule-associated protein tau | ||||||
Keywords | PROTEIN FIBRIL / amyloid / tau / helical / cross-beta / fibril / neurodegeneration | ||||||
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 / regulation of long-term synaptic depression / negative regulation of kinase activity / 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 / axon development / intracellular distribution of mitochondria / central nervous system neuron development / regulation of microtubule polymerization / microtubule polymerization / lipoprotein particle binding / minor groove of adenine-thymine-rich DNA binding / dynactin binding / glial cell projection / negative regulation of mitochondrial membrane potential / apolipoprotein binding / protein polymerization / axolemma / negative regulation of mitochondrial fission / 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 / positive regulation of protein localization / regulation of cellular response to heat / cytoplasmic microtubule organization / stress granule assembly / supramolecular fiber organization / regulation of calcium-mediated signaling / axon cytoplasm / somatodendritic compartment / positive regulation of microtubule polymerization / 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 / protein homooligomerization / PKR-mediated signaling / regulation of synaptic plasticity / memory / activation of cysteine-type endopeptidase activity involved in apoptotic process / microtubule cytoskeleton organization / SH3 domain binding / cellular response to reactive oxygen species / cytoplasmic ribonucleoprotein granule / microtubule cytoskeleton / neuron projection development / cell-cell signaling / protein-macromolecule adaptor activity / protein-folding chaperone binding / single-stranded DNA binding / actin binding / cellular response to heat / cell body / growth cone / microtubule binding / double-stranded DNA binding / microtubule / sequence-specific DNA binding / amyloid fibril formation / dendritic spine / learning or memory / nuclear speck / neuron projection / membrane raft / axon / negative regulation of gene expression / neuronal cell body / dendrite / DNA damage response / protein kinase binding / enzyme binding / mitochondrion / DNA binding Similarity search - Function | ||||||
Biological species | synthetic construct (others) | ||||||
Method | ELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 2.6 Å | ||||||
Authors | Wilkinson, M. / Louros, N. / Tsaka, G. / Ramakers, M. / Morelli, C. / Garcia, T. / Gallardo, R.U. / D'Haeyer, S. / Goossens, V. / Audenaert, D. ...Wilkinson, M. / Louros, N. / Tsaka, G. / Ramakers, M. / Morelli, C. / Garcia, T. / Gallardo, R.U. / D'Haeyer, S. / Goossens, V. / Audenaert, D. / Thal, D.R. / Ranson, N.A. / Radford, S.E. / Rousseau, F. / Schymkowitz, J. | ||||||
Funding support | Belgium, 1items
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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
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8oh2.cif.gz | 90.9 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8oh2.ent.gz | 72.8 KB | Display | PDB format |
PDBx/mmJSON format | 8oh2.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8oh2_validation.pdf.gz | 1.4 MB | Display | wwPDB validaton report |
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Full document | 8oh2_full_validation.pdf.gz | 1.4 MB | Display | |
Data in XML | 8oh2_validation.xml.gz | 28.8 KB | Display | |
Data in CIF | 8oh2_validation.cif.gz | 42.2 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/oh/8oh2 ftp://data.pdbj.org/pub/pdb/validation_reports/oh/8oh2 | HTTPS FTP |
-Related structure data
Related structure data | 16876MC 8ohiC 8ohpC 8oi0C M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
#1: Protein/peptide | Mass: 1437.622 Da / Num. of mol.: 36 / Source method: obtained synthetically 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 Source: (synth.) synthetic construct (others) / References: UniProt: P10636 #2: Water | ChemComp-HOH / | Has ligand of interest | N | |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: FILAMENT / 3D reconstruction method: helical reconstruction |
-Sample preparation
Component | Name: 2PF amyloid fibril assembly of Tau-PAM4 peptide / Type: COMPLEX / Details: Synthesised peptide assembled into amyloid fibril / Entity ID: #1 / Source: NATURAL |
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Molecular weight | Experimental value: NO |
Source (natural) | Organism: synthetic construct (others) |
Buffer solution | pH: 7 Details: Peptide resuspended in MilliQ water for aggregation reaction |
Specimen | Conc.: 2.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Specimen support | Grid material: COPPER / Grid type: EMS Lacey Carbon |
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 90 % / Chamber temperature: 279 K |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD / Nominal magnification: 130000 X / Nominal defocus max: 2600 nm / Nominal defocus min: 1400 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm / Alignment procedure: COMA FREE |
Specimen holder | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Image recording | Average exposure time: 5 sec. / Electron dose: 39 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 1512 Details: Movies were collected as 1539 EER frames compressed and re-grouped into 36 TIF fractions |
EM imaging optics | Energyfilter name: TFS Selectris / Energyfilter slit width: 10 eV |
Image scans | Width: 4096 / Height: 4096 |
-Processing
EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||||||||||||||||||
Helical symmerty | Angular rotation/subunit: -0.68 ° / Axial rise/subunit: 4.86 Å / Axial symmetry: C1 | ||||||||||||||||||||||||||||||||||||||||
3D reconstruction | Resolution: 2.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 17820 / Symmetry type: HELICAL | ||||||||||||||||||||||||||||||||||||||||
Atomic model building | B value: 54 / Protocol: AB INITIO MODEL / Space: REAL / Target criteria: Cross-correlation coefficient Details: Initial model built manually in coot, no starting template | ||||||||||||||||||||||||||||||||||||||||
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