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- PDB-8q96: P301S Tau Filaments from the Brains of Tg2541 Transgenic Mouse Line -

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Basic information

Entry
Database: PDB / ID: 8q96
TitleP301S Tau Filaments from the Brains of Tg2541 Transgenic Mouse Line
Components
  • (Unknown protein) x 2
  • Isoform Tau-E of Microtubule-associated protein tau
KeywordsPROTEIN FIBRIL / P301S tau / Frontotemporal dementia and parkinsonism linked to chromosome 17 / Transgenic mice / Electron cryo-microscopy
Function / homology
Function and homology information


Caspase-mediated cleavage of cytoskeletal proteins / negative regulation of intracellular transport / positive regulation of long-term synaptic depression / regulation of microtubule-based movement / PKR-mediated signaling / axon extension / axo-dendritic transport / adult walking behavior / mitochondrion transport along microtubule / negative regulation of establishment of protein localization to mitochondrion ...Caspase-mediated cleavage of cytoskeletal proteins / negative regulation of intracellular transport / positive regulation of long-term synaptic depression / regulation of microtubule-based movement / PKR-mediated signaling / axon extension / axo-dendritic transport / adult walking behavior / mitochondrion transport along microtubule / negative regulation of establishment of protein localization to mitochondrion / neurofibrillary tangle / positive regulation of protein localization to synapse / microtubule lateral binding / tubulin complex / main axon / negative regulation of tubulin deacetylation / intrinsic apoptotic signaling pathway in response to oxidative stress / positive regulation of protein localization / intracellular distribution of mitochondria / microtubule polymerization / axoneme / lipoprotein particle binding / glial cell projection / negative regulation of mitochondrial membrane potential / apolipoprotein binding / protein polymerization / negative regulation of mitochondrial fission / axolemma / intracellular transport / regulation of microtubule polymerization or depolymerization / positive regulation of axon extension / mRNA transport / supramolecular fiber organization / regulation of microtubule cytoskeleton organization / axonal growth cone / regulation of cellular response to heat / regulation of calcium-mediated signaling / positive regulation of microtubule polymerization / somatodendritic compartment / synapse assembly / heat shock protein binding / axonogenesis / nuclear periphery / response to nutrient / positive regulation of superoxide anion generation / protein phosphatase 2A binding / response to organic substance / regulation of autophagy / synapse organization / response to lead ion / neuron migration / Hsp90 protein binding / protein homooligomerization / cytoplasmic side of plasma membrane / cytoplasmic ribonucleoprotein granule / memory / microtubule cytoskeleton organization / positive regulation of neuron projection development / SH3 domain binding / neuron projection development / microtubule cytoskeleton / cell body / growth cone / protein-folding chaperone binding / microtubule binding / microtubule / amyloid fibril formation / postsynaptic density / learning or memory / neuron projection / nuclear speck / membrane raft / axon / negative regulation of gene expression / neuronal cell body / dendrite / DNA damage response / protein-containing complex binding / protein kinase binding / enzyme binding / DNA binding / extracellular region / identical protein binding / nucleus / plasma membrane / cytosol / cytoplasm
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 speciesMus musculus (house mouse)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3.09 Å
AuthorsSchweighauser, M. / Murzin, A.G. / Macdonald, J. / Lavenir, I. / Crowther, R.A. / Scheres, S.H.W. / Goedert, M.
Funding support United Kingdom, 2items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MC-UP-A025-1013 United Kingdom
Medical Research Council (MRC, United Kingdom)MC-U105184291 United Kingdom
CitationJournal: Acta Neuropathol Commun / Year: 2023
Title: Cryo-EM structures of tau filaments from the brains of mice transgenic for human mutant P301S Tau.
Authors: Manuel Schweighauser / Alexey G Murzin / Jennifer Macdonald / Isabelle Lavenir / R Anthony Crowther / Sjors H W Scheres / Michel Goedert /
Abstract: Mice transgenic for human mutant P301S tau are widely used as models for human tauopathies. They develop neurodegeneration and abundant filamentous inclusions made of human mutant four-repeat tau. ...Mice transgenic for human mutant P301S tau are widely used as models for human tauopathies. They develop neurodegeneration and abundant filamentous inclusions made of human mutant four-repeat tau. Here we used electron cryo-microscopy (cryo-EM) to determine the structures of tau filaments from the brains of Tg2541 and PS19 mice. Both lines express human P301S tau (0N4R for Tg2541 and 1N4R for PS19) on mixed genetic backgrounds and downstream of different promoters (murine Thy1 for Tg2541 and murine Prnp for PS19). The structures of tau filaments from Tg2541 and PS19 mice differ from each other and those of wild-type tau filaments from human brains. The structures of tau filaments from the brains of humans with mutations P301L, P301S or P301T in MAPT are not known. Filaments from the brains of Tg2541 and PS19 mice share a substructure at the junction of repeats 2 and 3, which comprises residues I297-V312 of tau and includes the P301S mutation. The filament core from the brainstem of Tg2541 mice consists of residues K274-H329 of tau and two disconnected protein densities. Two non-proteinaceous densities are also in evidence. The filament core from the cerebral cortex of line PS19 extends from residues G271-P364 of tau. One strong non-proteinaceous density is also present. Unlike the tau filaments from human brains, the sequences following repeat 4 are missing from the cores of tau filaments from the brains of Tg2541 and PS19 mice.
History
DepositionAug 19, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 11, 2023Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Isoform Tau-E of Microtubule-associated protein tau
B: Unknown protein
C: Unknown protein
D: Isoform Tau-E of Microtubule-associated protein tau
E: Unknown protein
F: Unknown protein
G: Isoform Tau-E of Microtubule-associated protein tau
H: Unknown protein
I: Unknown protein
J: Isoform Tau-E of Microtubule-associated protein tau
K: Unknown protein
L: Unknown protein


Theoretical massNumber of molelcules
Total (without water)31,48112
Polymers31,48112
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein
Isoform Tau-E of Microtubule-associated protein tau


Mass: 5961.934 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / Organ: Brain / Strain: Tg2541 / Tissue: Brainstem / References: UniProt: P10637
#2: Protein/peptide
Unknown protein


Mass: 1039.273 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / Organ: Brain / Strain: Tg2541 / Tissue: Brainstem
#3: Protein/peptide
Unknown protein


Mass: 869.063 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / Organ: Brain / Strain: Tg2541 / Tissue: Brainstem

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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: P301S Tau Protein Filament (Tg2541) / Type: TISSUE
Details: Human P301S tau filaments extracted from the brains of transgenic mouse line Tg2541
Entity ID: all / Source: NATURAL
Source (natural)Organism: Mus musculus (house mouse) / Strain: Tg2541 / Organ: Brain / Tissue: Brainstem
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 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: 105000 X / Nominal defocus max: 2400 nm / Nominal defocus min: 1800 nm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN
Image recordingElectron dose: 34.2 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

EM software
IDNameVersionCategory
1RELION4.1particle selection
2EPUimage acquisition
4CTFFIND4.1CTF correction
9Servalcatmodel refinement
13RELION4.13D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: -0.83 ° / Axial rise/subunit: 4.75 Å / Axial symmetry: C1
3D reconstructionResolution: 3.09 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 22760 / Symmetry type: HELICAL
RefinementResolution: 3.09→94.3 Å / Cor.coef. Fo:Fc: 0.873 / SU B: 15.854 / SU ML: 0.269 / ESU R: 0.163
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflection
Rwork0.37736 --
obs0.37736 28827 100 %
Solvent computationSolvent model: PARAMETERS FOR MASK CACLULATION
Displacement parametersBiso mean: 44.677 Å2
Refinement stepCycle: 1 / Total: 525
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0060.011526
ELECTRON MICROSCOPYr_bond_other_d0.0010.016502
ELECTRON MICROSCOPYr_angle_refined_deg1.1431.61706
ELECTRON MICROSCOPYr_angle_other_deg0.521.61144
ELECTRON MICROSCOPYr_dihedral_angle_1_deg7.256575
ELECTRON MICROSCOPYr_dihedral_angle_2_deg
ELECTRON MICROSCOPYr_dihedral_angle_3_deg12.5931088
ELECTRON MICROSCOPYr_dihedral_angle_4_deg
ELECTRON MICROSCOPYr_chiral_restr0.0490.289
ELECTRON MICROSCOPYr_gen_planes_refined0.0050.02600
ELECTRON MICROSCOPYr_gen_planes_other0.0020.0296
ELECTRON MICROSCOPYr_nbd_refined
ELECTRON MICROSCOPYr_nbd_other
ELECTRON MICROSCOPYr_nbtor_refined
ELECTRON MICROSCOPYr_nbtor_other
ELECTRON MICROSCOPYr_xyhbond_nbd_refined
ELECTRON MICROSCOPYr_xyhbond_nbd_other
ELECTRON MICROSCOPYr_metal_ion_refined
ELECTRON MICROSCOPYr_metal_ion_other
ELECTRON MICROSCOPYr_symmetry_vdw_refined
ELECTRON MICROSCOPYr_symmetry_vdw_other
ELECTRON MICROSCOPYr_symmetry_hbond_refined
ELECTRON MICROSCOPYr_symmetry_hbond_other
ELECTRON MICROSCOPYr_symmetry_metal_ion_refined
ELECTRON MICROSCOPYr_symmetry_metal_ion_other
ELECTRON MICROSCOPYr_mcbond_it5.1894.33309
ELECTRON MICROSCOPYr_mcbond_other5.1824.325309
ELECTRON MICROSCOPYr_mcangle_it8.497.698381
ELECTRON MICROSCOPYr_mcangle_other8.5147.71382
ELECTRON MICROSCOPYr_scbond_it7.7015.33217
ELECTRON MICROSCOPYr_scbond_other7.6845.337218
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other12.7769.17326
ELECTRON MICROSCOPYr_long_range_B_refined16.2639.08477
ELECTRON MICROSCOPYr_long_range_B_other16.29139.13478
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
LS refinement shellResolution: 3.09→3.17 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork0.984 2153 -
obs--100 %

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