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- PDB-8q92: P301S Tau Filaments from the Brains of PS19 Transgenic Mouse Line -

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Basic information

Entry
Database: PDB / ID: 8q92
TitleP301S Tau Filaments from the Brains of PS19 Transgenic Mouse Line
ComponentsMicrotubule-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


plus-end-directed organelle transport along microtubule / histone-dependent DNA binding / negative regulation of protein localization to mitochondrion / neurofibrillary tangle / microtubule lateral binding / axonal transport / tubulin complex / positive regulation of protein localization to synapse / phosphatidylinositol bisphosphate binding / generation of neurons ...plus-end-directed organelle transport along microtubule / histone-dependent DNA binding / negative regulation of protein localization to mitochondrion / neurofibrillary tangle / microtubule lateral binding / axonal transport / tubulin complex / positive regulation of protein localization to synapse / phosphatidylinositol bisphosphate binding / generation of neurons / rRNA metabolic process / axonal transport of mitochondrion / regulation of mitochondrial fission / axon development / regulation of microtubule-based movement / regulation of chromosome organization / intracellular distribution of mitochondria / central nervous system neuron development / minor groove of adenine-thymine-rich DNA binding / lipoprotein particle binding / microtubule polymerization / negative regulation of mitochondrial membrane potential / regulation of microtubule polymerization / dynactin binding / apolipoprotein binding / protein polymerization / main axon / axolemma / Caspase-mediated cleavage of cytoskeletal proteins / regulation of microtubule polymerization or depolymerization / negative regulation of mitochondrial fission / glial cell projection / neurofibrillary tangle assembly / positive regulation of axon extension / positive regulation of microtubule polymerization / regulation of cellular response to heat / Activation of AMPK downstream of NMDARs / positive regulation of protein localization / positive regulation of superoxide anion generation / supramolecular fiber organization / cellular response to brain-derived neurotrophic factor stimulus / regulation of long-term synaptic depression / cytoplasmic microtubule organization / regulation of calcium-mediated signaling / somatodendritic compartment / axon cytoplasm / synapse assembly / astrocyte activation / phosphatidylinositol binding / nuclear periphery / enzyme inhibitor activity / protein phosphatase 2A binding / stress granule assembly / regulation of microtubule cytoskeleton organization / regulation of autophagy / cellular response to reactive oxygen species / microglial cell activation / cellular response to nerve growth factor stimulus / Hsp90 protein binding / protein homooligomerization / PKR-mediated signaling / SH3 domain binding / regulation of synaptic plasticity / synapse organization / response to lead ion / microtubule cytoskeleton organization / memory / cytoplasmic ribonucleoprotein granule / neuron projection development / cell-cell signaling / single-stranded DNA binding / cellular response to heat / growth cone / protein-folding chaperone binding / microtubule cytoskeleton / actin binding / cell body / double-stranded DNA binding / microtubule binding / sequence-specific DNA binding / amyloid fibril formation / dendritic spine / microtubule / protein-macromolecule adaptor activity / learning or memory / neuron projection / membrane raft / negative regulation of gene expression / axon / neuronal cell body / DNA damage response / dendrite / protein kinase binding / enzyme binding / mitochondrion / DNA binding / RNA binding / extracellular region / identical protein binding / nucleus
Similarity search - Function
Microtubule-associated protein Tau / Microtubule associated protein, tubulin-binding repeat / 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 speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3.05 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: Microtubule-associated protein tau
B: Microtubule-associated protein tau
C: Microtubule-associated protein tau


Theoretical massNumber of molelcules
Total (without water)29,9023
Polymers29,9023
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area15120 Å2
ΔGint-52 kcal/mol
Surface area14510 Å2
MethodPISA

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Components

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


Mass: 9967.430 Da / Num. of mol.: 3 / Mutation: P301S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Strain: Transgenic PS19 / Tissue: Cerebral Cortex / Gene: MAPT, MAPTL, MTBT1, TAU / Organ: Brain / Production host: Mus musculus (house mouse) / References: UniProt: P10636

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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 (PS19) / Type: TISSUE
Details: Human P301S tau filaments extracted from the brains of transgenic mouse line PS19
Entity ID: all / Source: NATURAL
Source (natural)Organism: Mus musculus (house mouse) / Strain: PS19 / Organ: Brain / Tissue: Cerebral Cortex
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
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 FIELD / Nominal magnification: 96000 X / Nominal defocus max: 2400 nm / Nominal defocus min: 1500 nm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN
Image recordingElectron dose: 30 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM software
IDNameVersionCategory
1RELION4.1particle selection
2EPUimage acquisition
4CTFFIND4.1CTF correction
12RELION4.13D reconstruction
13Servalcatmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: -0.98 ° / Axial rise/subunit: 4.71 Å / Axial symmetry: C1
3D reconstructionResolution: 3.05 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 36951 / Symmetry type: HELICAL
RefinementResolution: 3.05→138.43 Å / Cor.coef. Fo:Fc: 0.761 / SU B: 20.147 / SU ML: 0.342 / ESU R: 0.228
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflection
Rwork0.47778 --
obs0.47778 31365 100 %
Solvent computationSolvent model: PARAMETERS FOR MASK CACLULATION
Displacement parametersBiso mean: 53.879 Å2
Refinement stepCycle: 1 / Total: 697
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0060.012705
ELECTRON MICROSCOPYr_bond_other_d0.0010.016710
ELECTRON MICROSCOPYr_angle_refined_deg1.1961.638942
ELECTRON MICROSCOPYr_angle_other_deg0.5561.6031653
ELECTRON MICROSCOPYr_dihedral_angle_1_deg6.955593
ELECTRON MICROSCOPYr_dihedral_angle_2_deg2.06551
ELECTRON MICROSCOPYr_dihedral_angle_3_deg15.110142
ELECTRON MICROSCOPYr_dihedral_angle_4_deg
ELECTRON MICROSCOPYr_chiral_restr0.080.2107
ELECTRON MICROSCOPYr_gen_planes_refined0.0060.02796
ELECTRON MICROSCOPYr_gen_planes_other0.0020.02132
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_it5.0774.785375
ELECTRON MICROSCOPYr_mcbond_other5.0674.786375
ELECTRON MICROSCOPYr_mcangle_it8.0718.606467
ELECTRON MICROSCOPYr_mcangle_other8.0688.62468
ELECTRON MICROSCOPYr_scbond_it8.0655.828330
ELECTRON MICROSCOPYr_scbond_other8.0535.842331
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other13.86810.127476
ELECTRON MICROSCOPYr_long_range_B_refined18.52945.04684
ELECTRON MICROSCOPYr_long_range_B_other18.51845.17685
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
LS refinement shellResolution: 3.05→3.129 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork0.867 2264 -
obs--100 %

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