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- PDB-8ohi: Structure of the Fmoc-Tau-PAM4 Type 2 amyloid fibril -

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Basic information

Entry
Database: PDB / ID: 8ohi
TitleStructure of the Fmoc-Tau-PAM4 Type 2 amyloid fibril
ComponentsMicrotubule-associated protein tauTau protein
KeywordsPROTEIN FIBRIL / amyloid / tau / helical / cross-beta / fibril / neurodegeneration / Fmoc
Function / homology
Function and homology information


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 / regulation of chromosome organization / positive regulation of protein localization / rRNA metabolic process / internal protein amino acid acetylation / regulation of mitochondrial fission / lipoprotein particle binding / 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 / negative regulation of mitochondrial membrane potential / dynactin binding / glial cell projection / apolipoprotein binding / 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 / supramolecular fiber organization / Activation of AMPK downstream of NMDARs / regulation of microtubule cytoskeleton organization / stress granule assembly / cytoplasmic microtubule organization / regulation of cellular response to heat / regulation of calcium-mediated signaling / axon cytoplasm / positive regulation of microtubule polymerization / cellular response to brain-derived neurotrophic factor stimulus / somatodendritic compartment / 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 / synapse organization / microglial cell activation / response to lead ion / Hsp90 protein binding / regulation of synaptic plasticity / PKR-mediated signaling / protein homooligomerization / cytoplasmic ribonucleoprotein granule / memory / microtubule cytoskeleton organization / cellular response to reactive oxygen species / SH3 domain binding / neuron projection development / activation of cysteine-type endopeptidase activity involved in apoptotic process / microtubule cytoskeleton / protein-macromolecule adaptor activity / single-stranded DNA binding / cell-cell signaling / cellular response to heat / cell body / actin binding / growth cone / protein-folding chaperone binding / double-stranded DNA binding / microtubule binding / microtubule / amyloid fibril formation / sequence-specific DNA binding / dendritic spine / learning or memory / neuron projection / nuclear speck / membrane raft / axon / negative regulation of gene expression / dendrite / neuronal cell body / DNA damage response / protein kinase binding / enzyme binding / mitochondrion / DNA binding
Similarity search - Function
: / Microtubule associated protein, tubulin-binding repeat / Microtubule-associated protein Tau / 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 speciessynthetic construct (others)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 2.8 Å
AuthorsWilkinson, 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
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, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 21, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Microtubule-associated protein tau
B: Microtubule-associated protein tau
C: Microtubule-associated protein tau
D: Microtubule-associated protein tau
E: Microtubule-associated protein tau
F: Microtubule-associated protein tau
G: Microtubule-associated protein tau
H: Microtubule-associated protein tau
I: Microtubule-associated protein tau
J: Microtubule-associated protein tau
K: Microtubule-associated protein tau
L: Microtubule-associated protein tau
M: Microtubule-associated protein tau
N: Microtubule-associated protein tau
O: Microtubule-associated protein tau
P: Microtubule-associated protein tau
Q: Microtubule-associated protein tau
R: Microtubule-associated protein tau


Theoretical massNumber of molelcules
Total (without water)29,74118
Polymers29,74118
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: assay for oligomerization, ThT fluorescence assay, electron microscopy, Negative stain EM, microscopy, Atomic force microscopy, light scattering, FTIR
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein/peptide
Microtubule-associated protein tau / Tau protein / Neurofibrillary tangle protein / Paired helical filament-tau / PHF-tau


Mass: 1652.269 Da / Num. of mol.: 18 / 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 supposed to be N-terminally acetylated but 10% (by mass spec) was ...Details: 13-residue peptide of the PAM4 motif of Tau, corresponding to residues 350-362 of the Tau repeat domain. The peptide is supposed to be N-terminally acetylated but 10% (by mass spec) was still adducted to the Fmoc protection group from synthesis. The peptide in the fibrils is dominated by this impurity. The peptide is also C-terminally amidated.
Source: (synth.) synthetic construct (others) / References: UniProt: P10636
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: FILAMENT / 3D reconstruction method: helical reconstruction

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Sample preparation

ComponentName: Amyloid fibril form 1a of Tau-PAM4 peptide adducted with the Fmoc protection group
Type: COMPLEX / Details: Synthesised peptide assembled into amyloid fibril / Entity ID: all / Source: NATURAL
Molecular weightExperimental value: NO
Source (natural)Organism: synthetic construct (others)
Buffer solutionpH: 7
Details: Peptide resuspended in MilliQ water for aggregation reaction
SpecimenConc.: 0.6 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: EMS Lacey Carbon
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 90 % / Chamber temperature: 279 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal magnification: 130000 X / Nominal defocus max: 2400 nm / Nominal defocus min: 1200 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm / Alignment procedure: COMA FREE
Specimen holderSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 5 sec. / Electron dose: 32 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 1957
Details: Movies were collected as 1204 EER frames compressed and re-grouped into 35 TIF fractions
EM imaging opticsEnergyfilter name: TFS Selectris / Energyfilter slit width: 10 eV
Image scansWidth: 4096 / Height: 4096

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Processing

EM software
IDNameVersionCategory
1crYOLO1.8particle selection
2EPU3image acquisition
4CTFFIND4.14CTF correction
7Coot0.8.9model fitting
9RELION4initial Euler assignment
10RELION4final Euler assignment
11RELION4classification
12RELION43D reconstruction
13PHENIX1.17.1:model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: -1.45 ° / Axial rise/subunit: 4.8 Å / Axial symmetry: C1
Particle selectionNum. of particles selected: 520390
3D reconstructionResolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 11255 / Symmetry type: HELICAL
Atomic model buildingB value: 48 / Protocol: AB INITIO MODEL / Space: REAL / Target criteria: Cross-correlation coefficient
Details: Initial model built manually in coot, no starting template
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0062142
ELECTRON MICROSCOPYf_angle_d0.532916
ELECTRON MICROSCOPYf_dihedral_angle_d8.611972
ELECTRON MICROSCOPYf_chiral_restr0.047324
ELECTRON MICROSCOPYf_plane_restr0.002360

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