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

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Basic information

Entry
Database: PDB / ID: 8r3t
TitleCofactor-free Tau 4R2N isoform
ComponentsMicrotubule-associated protein tau
KeywordsPROTEIN FIBRIL / Tau / ClearTau / fibrils / aggregation / co-factor-free / heparin-free
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 / axon development / axonal transport of mitochondrion / rRNA metabolic process / central nervous system neuron development / regulation of mitochondrial fission / regulation of microtubule-based movement / intracellular distribution of mitochondria / regulation of chromosome organization / 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 / main axon / Caspase-mediated cleavage of cytoskeletal proteins / glial cell projection / regulation of microtubule polymerization or depolymerization / negative regulation of mitochondrial fission / axolemma / positive regulation of axon extension / neurofibrillary tangle assembly / protein polymerization / positive regulation of microtubule polymerization / regulation of cellular response to heat / positive regulation of protein localization / Activation of AMPK downstream of NMDARs / positive regulation of superoxide anion generation / regulation of calcium-mediated signaling / cytoplasmic microtubule organization / cellular response to brain-derived neurotrophic factor stimulus / regulation of long-term synaptic depression / axon cytoplasm / supramolecular fiber organization / synapse assembly / somatodendritic compartment / astrocyte activation / nuclear periphery / phosphatidylinositol binding / protein phosphatase 2A binding / stress granule assembly / enzyme inhibitor activity / regulation of autophagy / regulation of microtubule cytoskeleton organization / cellular response to reactive oxygen species / microglial cell activation / cellular response to nerve growth factor stimulus / Hsp90 protein binding / regulation of synaptic plasticity / memory / SH3 domain binding / synapse organization / protein homooligomerization / microtubule cytoskeleton organization / PKR-mediated signaling / response to lead ion / neuron projection development / cytoplasmic ribonucleoprotein granule / microtubule cytoskeleton / cell-cell signaling / cellular response to heat / single-stranded DNA binding / growth cone / protein-folding chaperone binding / actin binding / cell body / double-stranded DNA binding / sequence-specific DNA binding / microtubule binding / amyloid fibril formation / dendritic spine / microtubule / learning or memory / protein-macromolecule adaptor activity / 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: 3.1 Å
AuthorsLimorenko, G. / Tatli, M. / Kolla, R. / Nazarov, S. / Weil, M.T. / Schondorf, D.C. / Geist, D. / Reinhardt, P. / Ehrnhoefer, D.E. / Stahlberg, H. ...Limorenko, G. / Tatli, M. / Kolla, R. / Nazarov, S. / Weil, M.T. / Schondorf, D.C. / Geist, D. / Reinhardt, P. / Ehrnhoefer, D.E. / Stahlberg, H. / Gasparini, L. / Lashuel, H.A.
Funding support1items
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, 2023Deposition site: PDBE / Processing site: PDBE
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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


Theoretical massNumber of molelcules
Total (without water)275,5196
Polymers275,5196
Non-polymers00
Water00
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
Microtubule-associated protein tau / Neurofibrillary tangle protein / Paired helical filament-tau / PHF-tau


Mass: 45919.871 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Details: ClearTau full-length Tau 4R2N isoform fibrils, PK-digested post-fibrillization
Source: (gene. exp.) Homo sapiens (human) / Gene: MAPT, MAPTL, MTBT1, TAU
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: P10636
Has protein modificationY

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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: In vitro assembled MAPT P-10636 4R2N isoform / Type: COMPLEX
Details: ClearTau 4R2N isoform fibrils, PK-digested post-fibrillization
Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 9 kDa/nm / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
Plasmid: pT7-7
Buffer solutionpH: 7.4
Buffer component
IDConc.NameFormulaBuffer-ID
1137 mMsodium chlorideNaCl1
22.7 mMpotasium chlorideKCl1
34.3 mMdisodium phosphateNa2HPO1
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid type: Quantifoil R2/1
VitrificationCryogen name: ETHANE

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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 defocus max: 2500 nm / Nominal defocus min: 600 nm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 40 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM software
IDNameVersionCategory
1RELION4.0-beta-2particle selection
2EPUimage acquisition
4CTFFIND4.1CTF correction
9PHENIXmodel refinement
10RELION4.0-beta-2initial Euler assignment
11RELION4.0-beta-2final Euler assignment
12RELION4.0-beta-2classification
13RELION4.0-beta-23D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: -0.88 ° / Axial rise/subunit: 4.72 Å / Axial symmetry: C1
3D reconstructionResolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 15869 / Num. of class averages: 1 / Symmetry type: HELICAL
Atomic model buildingB value: 33 / Protocol: AB INITIO MODEL / Space: REAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0092664
ELECTRON MICROSCOPYf_angle_d1.0343558
ELECTRON MICROSCOPYf_dihedral_angle_d12.744354
ELECTRON MICROSCOPYf_chiral_restr0.062414
ELECTRON MICROSCOPYf_plane_restr0.004444

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