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- EMDB-18874: Cofactor-free Tau 4R2N isoform -

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Basic information

Entry
Database: EMDB / ID: EMD-18874
TitleCofactor-free Tau 4R2N isoform
Map dataAutomatically sharpened and masked map
Sample
  • Complex: In vitro assembled MAPT P-10636 4R2N isoform
    • Protein or peptide: Microtubule-associated protein tau
KeywordsTau / ClearTau / fibrils / aggregation / co-factor-free / heparin-free / 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 / microtubule lateral binding / main axon / axonal transport / tubulin complex / positive regulation of protein localization to synapse / phosphatidylinositol bisphosphate binding ...plus-end-directed organelle transport along microtubule / histone-dependent DNA binding / negative regulation of establishment of protein localization to mitochondrion / neurofibrillary tangle / microtubule lateral binding / main axon / axonal transport / tubulin complex / positive regulation of protein localization to synapse / phosphatidylinositol bisphosphate binding / negative regulation of tubulin deacetylation / generation of neurons / regulation of chromosome organization / rRNA metabolic process / axonal transport of mitochondrion / regulation of mitochondrial fission / axon development / regulation of long-term synaptic depression / central nervous system neuron development / intracellular distribution of mitochondria / regulation of microtubule polymerization / microtubule polymerization / lipoprotein particle binding / minor groove of adenine-thymine-rich DNA binding / negative regulation of mitochondrial membrane potential / dynactin binding / apolipoprotein binding / axolemma / protein polymerization / glial cell projection / negative regulation of mitochondrial fission / Caspase-mediated cleavage of cytoskeletal proteins / regulation of microtubule polymerization or depolymerization / positive regulation of axon extension / neurofibrillary tangle assembly / Activation of AMPK downstream of NMDARs / regulation of cellular response to heat / supramolecular fiber organization / synapse assembly / positive regulation of protein localization / cellular response to brain-derived neurotrophic factor stimulus / somatodendritic compartment / regulation of calcium-mediated signaling / cytoplasmic microtubule organization / positive regulation of microtubule polymerization / axon cytoplasm / stress granule assembly / phosphatidylinositol binding / regulation of microtubule cytoskeleton organization / nuclear periphery / protein phosphatase 2A binding / positive regulation of superoxide anion generation / cellular response to reactive oxygen species / astrocyte activation / Hsp90 protein binding / microglial cell activation / response to lead ion / cellular response to nerve growth factor stimulus / synapse organization / PKR-mediated signaling / protein homooligomerization / regulation of synaptic plasticity / SH3 domain binding / memory / microtubule cytoskeleton organization / cytoplasmic ribonucleoprotein granule / neuron projection development / cell-cell signaling / single-stranded DNA binding / protein-folding chaperone binding / actin binding / cellular response to heat / microtubule cytoskeleton / cell body / growth cone / double-stranded DNA binding / protein-macromolecule adaptor activity / microtubule binding / dendritic spine / sequence-specific DNA binding / amyloid fibril formation / microtubule / learning or memory / neuron projection / regulation of autophagy / membrane raft / axon / negative regulation of gene expression / neuronal cell body / dendrite / DNA damage response / protein kinase binding / enzyme binding / mitochondrion / DNA binding / RNA binding / extracellular region / identical protein binding / nucleus / plasma membrane
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: 3.1 Å
AuthorsLimorenko G / Tatli M / Kolla R / Nazarov S / Weil MT / Schondorf DC / Geist D / Reinhardt P / Ehrnhoefer DE / Stahlberg H ...Limorenko G / Tatli M / Kolla R / Nazarov S / Weil MT / Schondorf DC / Geist D / Reinhardt P / Ehrnhoefer DE / Stahlberg H / Gasparini L / Lashuel HA
Funding support1 items
OrganizationGrant numberCountry
Other government
CitationJournal: Nat Commun / Year: 2023
Title: Fully co-factor-free ClearTau platform produces seeding-competent Tau fibrils for reconstructing pathological Tau aggregates.
Authors: Galina Limorenko / Meltem Tatli / Rajasekhar Kolla / Sergey Nazarov / Marie-Theres Weil / David C Schöndorf / Daniela Geist / Peter Reinhardt / Dagmar E Ehrnhoefer / Henning Stahlberg / ...Authors: Galina Limorenko / Meltem Tatli / Rajasekhar Kolla / Sergey Nazarov / Marie-Theres Weil / David C Schöndorf / Daniela Geist / Peter Reinhardt / Dagmar E Ehrnhoefer / Henning Stahlberg / Laura Gasparini / Hilal A Lashuel /
Abstract: Tau protein fibrillization is implicated in the pathogenesis of several neurodegenerative diseases collectively known as Tauopathies. For decades, investigating Tau fibrillization in vitro has ...Tau protein fibrillization is implicated in the pathogenesis of several neurodegenerative diseases collectively known as Tauopathies. For decades, investigating Tau fibrillization in vitro has required the addition of polyanions or other co-factors to induce its misfolding and aggregation, with heparin being the most commonly used. However, heparin-induced Tau fibrils exhibit high morphological heterogeneity and a striking structural divergence from Tau fibrils isolated from Tauopathies patients' brains at ultra- and macro-structural levels. To address these limitations, we developed a quick, cheap, and effective method for producing completely co-factor-free fibrils from all full-length Tau isoforms and mixtures thereof. We show that Tau fibrils generated using this ClearTau method - ClearTau fibrils - exhibit amyloid-like features, possess seeding activity in biosensor cells and hiPSC-derived neurons, retain RNA-binding capacity, and have morphological properties and structures more reminiscent of the properties of the brain-derived Tau fibrils. We present the proof-of-concept implementation of the ClearTau platform for screening Tau aggregation-modifying compounds. We demonstrate that these advances open opportunities to investigate the pathophysiology of disease-relevant Tau aggregates and will facilitate the development of Tau pathology-targeting and modifying therapies and PET tracers that can distinguish between different Tauopathies.
History
DepositionNov 10, 2023-
Header (metadata) releaseDec 6, 2023-
Map releaseDec 6, 2023-
SupersessionJan 24, 2024ID: EMD-18874
UpdateJul 9, 2025-
Current statusJul 9, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_18874.png

Downloads & links

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Map

FileDownload / File: emd_18874.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationAutomatically sharpened and masked map
Projections & slices

Image control

Size
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.73 Å/pix.
x 384 pix.
= 278.784 Å		0.73 Å/pix.
x 384 pix.
= 278.784 Å		0.73 Å/pix.
x 384 pix.
= 278.784 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.726 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0072
Minimum - Maximum-0.015234422 - 0.031466186
Average (Standard dev.)0.000023706252 (±0.0005815435)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 278.784 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_18874_msk_1.map
Projections & Slices
AxesZYX

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Additional map: Refined map

Fileemd_18874_additional_1.map
AnnotationRefined map
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Half map: Half map1

Fileemd_18874_half_map_1.map
AnnotationHalf map1
Projections & Slices
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Histogram

Histogram (log scale)

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Half map: Half map2

Fileemd_18874_half_map_2.map
AnnotationHalf map2
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Sample components

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Entire : In vitro assembled MAPT P-10636 4R2N isoform

EntireName: In vitro assembled MAPT P-10636 4R2N isoform
Components
  • Complex: In vitro assembled MAPT P-10636 4R2N isoform
    • Protein or peptide: Microtubule-associated protein tau

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Supramolecule #1: In vitro assembled MAPT P-10636 4R2N isoform

SupramoleculeName: In vitro assembled MAPT P-10636 4R2N isoform / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Details: ClearTau 4R2N isoform fibrils, PK-digested post-fibrillization
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 9 kDa/nm

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Macromolecule #1: Microtubule-associated protein tau

MacromoleculeName: Microtubule-associated protein tau / type: protein_or_peptide / ID: 1
Details: ClearTau full-length Tau 4R2N isoform fibrils, PK-digested post-fibrillization
Number of copies: 6 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 45.919871 KDa
Recombinant expressionOrganism: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
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

BufferpH: 7.4
Component:
ConcentrationFormulaName
137.0 mMNaClsodium chloride
2.7 mMKClpotasium chloride
4.3 mMNa2HPOdisodium phosphate
GridModel: Quantifoil R2/1 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 23 sec.
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.6 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

Final reconstructionNumber classes used: 1
Applied symmetry - Helical parameters - Δz: 4.72 Å
Applied symmetry - Helical parameters - Δ&Phi: -0.88 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 4.0-beta-2) / Number images used: 15869
CTF correctionSoftware - Name: CTFFIND (ver. 4.1) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER / Details: IniModel2D was used for the initial model creation
Final angle assignmentType: NOT APPLICABLE / Software - Name: RELION (ver. 4.0-beta-2)
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: AB INITIO MODEL / Overall B value: 33
Output model

PDB-8r3t:
Cofactor-free Tau 4R2N isoform

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