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- EMDB-41610: AT8-Phosphomimetic Tau Filaments (Full-length, Cofactor-Free 0N4R... -

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Basic information

Entry
Database: EMDB / ID: EMD-41610
TitleAT8-Phosphomimetic Tau Filaments (Full-length, Cofactor-Free 0N4R Tau S202E, T205E, S208E)
Map data
Sample
  • Complex: AT8-Phosphomimetic 0N4R Tau Fibrils
    • Protein or peptide: Microtubule-associated protein tau
KeywordsTau / Amyloid Fibril / Phosphomimetic / 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: 2.6 Å
AuthorsEl Mammeri N / Dregni AJ / Duan P / Hong M
Funding support United States, 3 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Aging (NIH/NIA)AG059661 United States
National Institutes of Health/National Institute on Aging (NIH/NIA)AG069418 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM132079 United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2024
Title: Structures of AT8 and PHF1 phosphomimetic tau: Insights into the posttranslational modification code of tau aggregation.
Authors: Nadia El Mammeri / Aurelio J Dregni / Pu Duan / Mei Hong /
Abstract: The microtubule-associated protein tau aggregates into amyloid fibrils in Alzheimer's disease and other neurodegenerative diseases. In these tauopathies, tau is hyperphosphorylated, suggesting that ...The microtubule-associated protein tau aggregates into amyloid fibrils in Alzheimer's disease and other neurodegenerative diseases. In these tauopathies, tau is hyperphosphorylated, suggesting that this posttranslational modification (PTM) may induce tau aggregation. Tau is also phosphorylated in normal developing brains. To investigate how tau phosphorylation induces amyloid fibrils, here we report the atomic structures of two phosphomimetic full-length tau fibrils assembled without anionic cofactors. We mutated key Ser and Thr residues to Glu in two regions of the protein. One construct contains three Glu mutations at the epitope of the anti-phospho-tau antibody AT8 (AT8-3E tau), whereas the other construct contains four Glu mutations at the epitope of the antibody PHF1 (PHF1-4E tau). Solid-state NMR data show that both phosphomimetic tau mutants form homogeneous fibrils with a single set of chemical shifts. The AT8-3E tau rigid core extends from the R3 repeat to the C terminus, whereas the PHF1-4E tau rigid core spans R2, R3, and R4 repeats. Cryoelectron microscopy data show that AT8-3E tau forms a triangular multi-layered core, whereas PHF1-4E tau forms a triple-stranded core. Interestingly, a construct combining all seven Glu mutations exhibits the same conformation as PHF1-4E tau. Scalar-coupled NMR data additionally reveal the dynamics and shape of the fuzzy coat surrounding the rigid cores. These results demonstrate that specific PTMs induce structurally specific tau aggregates, and the phosphorylation code of tau contains redundancy.
History
DepositionAug 14, 2023-
Header (metadata) releaseJun 26, 2024-
Map releaseJun 26, 2024-
UpdateJun 26, 2024-
Current statusJun 26, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_41610.png

Downloads & links

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Map

FileDownload / File: emd_41610.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
0.82 Å/pix.
x 512 pix.
= 418.56 Å		0.82 Å/pix.
x 512 pix.
= 418.56 Å		0.82 Å/pix.
x 512 pix.
= 418.56 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.8175 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.01
Minimum - Maximum-0.020028474 - 0.042604864
Average (Standard dev.)0.00005746898 (±0.0011272127)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 418.56 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_41610_msk_1.map
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Additional map: Unmasked final map

Fileemd_41610_additional_1.map
AnnotationUnmasked final map
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Half map: #1

Fileemd_41610_half_map_1.map
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Half map: #2

Fileemd_41610_half_map_2.map
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Sample components

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Entire : AT8-Phosphomimetic 0N4R Tau Fibrils

EntireName: AT8-Phosphomimetic 0N4R Tau Fibrils
Components
  • Complex: AT8-Phosphomimetic 0N4R Tau Fibrils
    • Protein or peptide: Microtubule-associated protein tau

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Supramolecule #1: AT8-Phosphomimetic 0N4R Tau Fibrils

SupramoleculeName: AT8-Phosphomimetic 0N4R Tau Fibrils / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Microtubule-associated protein tau

MacromoleculeName: Microtubule-associated protein tau / type: protein_or_peptide / ID: 1 / Details: Using numbering from 2N4R Tau / Number of copies: 6 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 40.185934 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MAEPRQEFEV MEDHAGTYGL GDRKDQGGYT MHQDQEGDTD AGLKAEEAGI GDTPSLEDEA AGHVTQARMV SKSKDGTGSD DKKAKGADG KTKIATPRGA APPGQKGQAN ATRIPAKTPP APKTPPSSGE PPKSGDRSGY SSPGEPGEPG ERSRTPSLPT P PTREPKKV ...String:
MAEPRQEFEV MEDHAGTYGL GDRKDQGGYT MHQDQEGDTD AGLKAEEAGI GDTPSLEDEA AGHVTQARMV SKSKDGTGSD DKKAKGADG KTKIATPRGA APPGQKGQAN ATRIPAKTPP APKTPPSSGE PPKSGDRSGY SSPGEPGEPG ERSRTPSLPT P PTREPKKV AVVRTPPKSP SSAKSRLQTA PVPMPDLKNV KSKIGSTENL KHQPGGGKVQ IINKKLDLSN VQSKCGSKDN IK HVPGGGS VQIVYKPVDL SKVTSKCGSL GNIHHKPGGG QVEVKSEKLD FKDRVQSKIG SLDNITHVPG GGNKKIETHK LTF RENAKA KTDHGAEIVY KSPVVSGDTS PRHLSNVSST GSIDMVDSPQ LATLADEVSA SLAKQGL

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

Concentration0.4 mg/mL
BufferpH: 6.8
Component:
ConcentrationFormulaName
300.0 mMNaClSodium Chloride
5.0 mMDTTDithiothreitol
50.0 mMK2HPO4Potassium Phosphate Dibasic

Details: 50 mM K2HPO4 buffer, pH 6.8, containing 300 mM NaCl, 5 mM DTT, and 1x cOmplete protease inhibitor cocktail tablet (Roche) per 40 ml fibrillization buffer.
GridMaterial: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 60 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 48.7 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.75 µm / Nominal defocus min: 0.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 4.8 Å
Applied symmetry - Helical parameters - Δ&Phi: -0.7 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 2.6 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 4.0) / Number images used: 21767
Segment selectionNumber selected: 675445 / Software - Name: RELION (ver. 4.0)
Software - details: Start-end coordinates manually picked in relion 4.0.
Details: Manual Selection of Start-End Coordinates
Startup modelType of model: NONE
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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