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- EMDB-10514: Cryo-EM reconstruction of TypeII tau filaments extracted from the... -

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Entry
Database: EMDB / ID: EMD-10514
TitleCryo-EM reconstruction of TypeII tau filaments extracted from the brains of individuals with Corticobasal degeneration
Map dataCryo-EM structure of TypeII tau filaments extracted from the brains of individuals with Corticobasal degeneration
Sample
  • Complex: Tau filaments extracted from the Frontal cortex of a patient with corticobasal degeneration.
    • Protein or peptide: Microtubule-associated protein tau
Keywordstau protein / filament / cross-beta structure / PROTEIN FIBRIL
Function / homology
Function and homology information


plus-end-directed organelle transport along microtubule / histone-dependent DNA binding / : / negative regulation of establishment of protein localization to mitochondrion / neurofibrillary tangle assembly / positive regulation of protein localization to synapse / neurofibrillary tangle / microtubule lateral binding / axonal transport / main axon ...plus-end-directed organelle transport along microtubule / histone-dependent DNA binding / : / negative regulation of establishment of protein localization to mitochondrion / neurofibrillary tangle assembly / positive regulation of protein localization to synapse / neurofibrillary tangle / microtubule lateral binding / axonal transport / main axon / phosphatidylinositol bisphosphate binding / tubulin complex / regulation of long-term synaptic depression / negative regulation of kinase activity / negative regulation of tubulin deacetylation / generation of neurons / internal protein amino acid acetylation / regulation of chromosome organization / rRNA metabolic process / axonal transport of mitochondrion / regulation of mitochondrial fission / axon development / intracellular distribution of mitochondria / central nervous system neuron development / regulation of microtubule polymerization / microtubule polymerization / minor groove of adenine-thymine-rich DNA binding / lipoprotein particle binding / dynactin binding / negative regulation of mitochondrial membrane potential / apolipoprotein binding / : / glial cell projection / 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 / regulation of microtubule cytoskeleton organization / regulation of cellular response to heat / cytoplasmic microtubule organization / Activation of AMPK downstream of NMDARs / synapse assembly / positive regulation of protein localization / axon cytoplasm / regulation of calcium-mediated signaling / supramolecular fiber organization / stress granule assembly / somatodendritic compartment / cellular response to brain-derived neurotrophic factor stimulus / positive regulation of microtubule polymerization / phosphatidylinositol binding / nuclear periphery / positive regulation of superoxide anion generation / protein phosphatase 2A binding / regulation of autophagy / cellular response to reactive oxygen species / astrocyte activation / Hsp90 protein binding / microglial cell activation / synapse organization / cellular response to nerve growth factor stimulus / response to lead ion / PKR-mediated signaling / protein homooligomerization / regulation of synaptic plasticity / SH3 domain binding / memory / microtubule cytoskeleton organization / cytoplasmic ribonucleoprotein granule / neuron projection development / microtubule cytoskeleton / cell-cell signaling / single-stranded DNA binding / protein-folding chaperone binding / actin binding / cell body / cellular response to heat / growth cone / double-stranded DNA binding / microtubule binding / protein-macromolecule adaptor activity / sequence-specific DNA binding / microtubule / amyloid fibril formation / dendritic spine / learning or memory / neuron projection / nuclear speck / 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
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)
Methodhelical reconstruction / cryo EM / Resolution: 3.0 Å
AuthorsZhang W / Murzin AG / Falcon B / Shi Y / Goedert M / Scheres SHW
Funding support United Kingdom, 2 items
OrganizationGrant numberCountry
Medical Research Council (United Kingdom)MC_UP_A025_1013 United Kingdom
Medical Research Council (United Kingdom)MC_U105184291 United Kingdom
CitationJournal: Nature / Year: 2020
Title: Novel tau filament fold in corticobasal degeneration.
Authors: Wenjuan Zhang / Airi Tarutani / Kathy L Newell / Alexey G Murzin / Tomoyasu Matsubara / Benjamin Falcon / Ruben Vidal / Holly J Garringer / Yang Shi / Takeshi Ikeuchi / Shigeo Murayama / ...Authors: Wenjuan Zhang / Airi Tarutani / Kathy L Newell / Alexey G Murzin / Tomoyasu Matsubara / Benjamin Falcon / Ruben Vidal / Holly J Garringer / Yang Shi / Takeshi Ikeuchi / Shigeo Murayama / Bernardino Ghetti / Masato Hasegawa / Michel Goedert / Sjors H W Scheres /
Abstract: Corticobasal degeneration (CBD) is a neurodegenerative tauopathy-a class of disorders in which the tau protein forms insoluble inclusions in the brain-that is characterized by motor and cognitive ...Corticobasal degeneration (CBD) is a neurodegenerative tauopathy-a class of disorders in which the tau protein forms insoluble inclusions in the brain-that is characterized by motor and cognitive disturbances. The H1 haplotype of MAPT (the tau gene) is present in cases of CBD at a higher frequency than in controls, and genome-wide association studies have identified additional risk factors. By histology, astrocytic plaques are diagnostic of CBD; by SDS-PAGE, so too are detergent-insoluble, 37 kDa fragments of tau. Like progressive supranuclear palsy, globular glial tauopathy and argyrophilic grain disease, CBD is characterized by abundant filamentous tau inclusions that are made of isoforms with four microtubule-binding repeats. This distinguishes such '4R' tauopathies from Pick's disease (the filaments of which are made of three-repeat (3R) tau isoforms) and from Alzheimer's disease and chronic traumatic encephalopathy (CTE) (in which both 3R and 4R isoforms are found in the filaments). Here we use cryo-electron microscopy to analyse the structures of tau filaments extracted from the brains of three individuals with CBD. These filaments were identical between cases, but distinct from those seen in Alzheimer's disease, Pick's disease and CTE. The core of a CBD filament comprises residues lysine 274 to glutamate 380 of tau, spanning the last residue of the R1 repeat, the whole of the R2, R3 and R4 repeats, and 12 amino acids after R4. The core adopts a previously unseen four-layered fold, which encloses a large nonproteinaceous density. This density is surrounded by the side chains of lysine residues 290 and 294 from R2 and lysine 370 from the sequence after R4.
History
DepositionNov 27, 2019-
Header (metadata) releaseFeb 5, 2020-
Map releaseFeb 5, 2020-
UpdateMay 22, 2024-
Current statusMay 22, 2024Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.0166
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by cylindrical radius
  • Surface level: 0.0166
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6tjx
  • Surface level: 0.0166
  • Imaged by UCSF Chimera
  • Download
  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-6tjx
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_10514.png

Downloads & links

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Map

FileDownload / File: emd_10514.map.gz / Format: CCP4 / Size: 137.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM structure of TypeII tau filaments extracted from the brains of individuals with Corticobasal degeneration
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.15 Å/pix.
x 330 pix.
= 379.5 Å		1.15 Å/pix.
x 330 pix.
= 379.5 Å		1.15 Å/pix.
x 330 pix.
= 379.5 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.15 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0166 / Movie #1: 0.0166
Minimum - Maximum-0.043242417 - 0.09686032
Average (Standard dev.)0.00059157796 (±0.0043819784)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions330330330
Spacing330330330
CellA=B=C: 379.5 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.151.151.15
M x/y/z330330330
origin x/y/z0.0000.0000.000
length x/y/z379.500379.500379.500
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS330330330
D min/max/mean-0.0430.0970.001

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Supplemental data

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Mask #1

Fileemd_10514_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map1

Fileemd_10514_half_map_1.map
AnnotationHalf map1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map2

Fileemd_10514_half_map_2.map
AnnotationHalf map2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Tau filaments extracted from the Frontal cortex of a patient with...

EntireName: Tau filaments extracted from the Frontal cortex of a patient with corticobasal degeneration.
Components
  • Complex: Tau filaments extracted from the Frontal cortex of a patient with corticobasal degeneration.
    • Protein or peptide: Microtubule-associated protein tau

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Supramolecule #1: Tau filaments extracted from the Frontal cortex of a patient with...

SupramoleculeName: Tau filaments extracted from the Frontal cortex of a patient with corticobasal degeneration.
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Details: Corticobasal degeneration (CBD) is characterised by abundant filamentous tau inclusions that are made of isoforms with four microtubule-binding repeats (4R).
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 460 KDa

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Macromolecule #1: Microtubule-associated protein tau

MacromoleculeName: Microtubule-associated protein tau / type: protein_or_peptide / ID: 1 / Number of copies: 6 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 45.919871 KDa
SequenceString: MAEPRQEFEV MEDHAGTYGL GDRKDQGGYT MHQDQEGDTD AGLKESPLQT PTEDGSEEPG SETSDAKSTP TAEDVTAPLV DEGAPGKQA AAQPHTEIPE GTTAEEAGIG DTPSLEDEAA GHVTQARMVS KSKDGTGSDD KKAKGADGKT KIATPRGAAP P GQKGQANA ...String:
MAEPRQEFEV MEDHAGTYGL GDRKDQGGYT MHQDQEGDTD AGLKESPLQT PTEDGSEEPG SETSDAKSTP TAEDVTAPLV DEGAPGKQA AAQPHTEIPE GTTAEEAGIG DTPSLEDEAA GHVTQARMVS KSKDGTGSDD KKAKGADGKT KIATPRGAAP P GQKGQANA TRIPAKTPPA PKTPPSSGEP PKSGDRSGYS SPGSPGTPGS RSRTPSLPTP PTREPKKVAV VRTPPKSPSS AK SRLQTAP VPMPDLKNVK SKIGSTENLK HQPGGGKVQI INKKLDLSNV QSKCGSKDNI KHVPGGGSVQ IVYKPVDLSK VTS KCGSLG NIHHKPGGGQ VEVKSEKLDF KDRVQSKIGS LDNITHVPGG GNKKIETHKL TFRENAKAKT DHGAEIVYKS PVVS GDTSP RHLSNVSSTG SIDMVDSPQL ATLADEVSAS LAKQGL

UniProtKB: Microtubule-associated protein tau

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statefilament

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Sample preparation

Concentration2.0 mg/mL
BufferpH: 7.4
Component:
ConcentrationFormulaName
0.02 mol/LTristris(hydroxymethyl)aminomethane
0.1 mol/LNaClsodium chloride

Details: 20 mM Tris, pH 7.4, 100mM NaCl
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV / Details: Blot force: -12 ; Blot time: 4s.
DetailsThe tau filaments were extracted from the Frontal cortex of a patient with corticobasal degeneration by using sarkosyl and ultracentrifuge.

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Specialist opticsEnergy filter - Name: GIF Quantum LS / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Digitization - Dimensions - Width: 3838 pixel / Digitization - Dimensions - Height: 3710 pixel / Digitization - Frames/image: 1-40 / Number grids imaged: 1 / Number real images: 2567 / Average exposure time: 10.0 sec. / Average electron dose: 1.346 e/Å2
Details: Images were collected in movie-mode at 40 frames every 10 seconds
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.8000000000000003 µm / Nominal defocus min: 1.7 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

DetailsMovie frames were gain-corrected, aligned, dose weighted and then summed into a single micrograph using MOTIONCOR2 (Zheng et al., 2017)
Final reconstructionNumber classes used: 1
Applied symmetry - Helical parameters - Δz: 4.786 Å
Applied symmetry - Helical parameters - Δ&Phi: -0.61 °
Applied symmetry - Helical parameters - Axial symmetry: C2 (2 fold cyclic)
Resolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.0) / Number images used: 20752
Segment selectionNumber selected: 129812 / Software - Name: RELION (ver. 3.0) / Details: Manually picked
Startup modelType of model: OTHER
Details: An initial 3D reference was reconstructed from the 2D class averages de novo.
Final angle assignmentType: NOT APPLICABLE / Software - Name: RELION (ver. 3.0)
FSC plot (resolution estimation)

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Atomic model buiding 1

DetailsA stack of three consecutive monomers was refined to preserve nearest-neighbour interactions for the middle chain. Because most residues adopted cross strand conformation, hydrogen-bond restraints were imposed to preserve a parallel, in-register hydrogen bonding pattern in earlier stages of Fourier-space refinements. Local symmetry restraints were imposed to keep all beta strand rungs identical. Side-chain clashes were detected using MOLPROBITY, and corrected by iterative cycles of real-space refinement in COOT and Fourier-space refinement in REFMAC and PHENIX. For each refined structure, separate model refinements were performed against a single half-map, and the resulting model was compared to the other half-map to confirm the absence of overfitting.
RefinementSpace: RECIPROCAL / Protocol: AB INITIO MODEL / Overall B value: 25.75 / Target criteria: Fourier shell correlation
Output model

PDB-6tjx:
Cryo-EM structure of TypeII tau filaments extracted from the brains of individuals with Corticobasal degeneration

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