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- EMDB-41611: PHF1-Phosphomimetic Tau Filaments (Full-length, Cofactor-Free 0N4... -

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Basic information

Entry
Database: EMDB / ID: EMD-41611
TitlePHF1-Phosphomimetic Tau Filaments (Full-length, Cofactor-Free 0N4R Tau S396E, S400E, T403E, S404E)
Map data
Sample
  • Complex: PHF1-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 / axonal transport / histone-dependent DNA binding / neurofibrillary tangle assembly / positive regulation of diacylglycerol kinase activity / negative regulation of establishment of protein localization to mitochondrion / neurofibrillary tangle / positive regulation of protein localization to synapse / microtubule lateral binding / tubulin complex ...plus-end-directed organelle transport along microtubule / axonal transport / histone-dependent DNA binding / neurofibrillary tangle assembly / positive regulation of diacylglycerol kinase activity / negative regulation of establishment of protein localization to mitochondrion / neurofibrillary tangle / positive regulation of protein localization to synapse / microtubule lateral binding / tubulin complex / phosphatidylinositol bisphosphate binding / main axon / regulation of long-term synaptic depression / negative regulation of kinase activity / negative regulation of tubulin deacetylation / generation of neurons / regulation of chromosome organization / positive regulation of protein localization / rRNA metabolic process / internal protein amino acid acetylation / regulation of mitochondrial fission / intracellular distribution of mitochondria / axonal transport of mitochondrion / axon development / central nervous system neuron development / regulation of microtubule polymerization / microtubule polymerization / minor groove of adenine-thymine-rich DNA binding / lipoprotein particle binding / dynactin binding / glial cell projection / apolipoprotein binding / negative regulation of mitochondrial membrane potential / 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 / supramolecular fiber organization / Activation of AMPK downstream of NMDARs / stress granule assembly / regulation of cellular response to heat / cytoplasmic microtubule organization / regulation of calcium-mediated signaling / axon cytoplasm / positive regulation of microtubule polymerization / somatodendritic compartment / cellular response to brain-derived neurotrophic factor stimulus / synapse assembly / phosphatidylinositol binding / nuclear periphery / cellular response to nerve growth factor stimulus / positive regulation of superoxide anion generation / protein phosphatase 2A binding / regulation of autophagy / astrocyte activation / response to lead ion / synapse organization / microglial cell activation / Hsp90 protein binding / regulation of synaptic plasticity / PKR-mediated signaling / protein homooligomerization / memory / cytoplasmic ribonucleoprotein granule / cellular response to reactive oxygen species / microtubule cytoskeleton organization / SH3 domain binding / activation of cysteine-type endopeptidase activity involved in apoptotic process / microtubule cytoskeleton / neuron projection development / cell-cell signaling / protein-macromolecule adaptor activity / actin binding / cellular response to heat / single-stranded DNA binding / protein-folding chaperone binding / cell body / growth cone / microtubule binding / double-stranded DNA binding / microtubule / amyloid fibril formation / sequence-specific DNA binding / dendritic spine / learning or memory / nuclear speck / neuron projection / membrane raft / axon / negative regulation of gene expression / neuronal cell body / DNA damage response / dendrite / protein kinase binding / enzyme binding / mitochondrion / DNA binding
Similarity search - Function
: / Microtubule associated protein, tubulin-binding repeat / Microtubule-associated protein Tau / 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: 2.4 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_41611.png

Downloads & links

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Map

FileDownload / File: emd_41611.map.gz / Format: CCP4 / Size: 30.5 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 200 pix.
= 163.5 Å		0.82 Å/pix.
x 200 pix.
= 163.5 Å		0.82 Å/pix.
x 200 pix.
= 163.5 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.8175 Å
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Histogram (log scale)
Contour LevelBy AUTHOR: 0.01
Minimum - Maximum-0.019298736 - 0.043475207
Average (Standard dev.)0.00013879803 (±0.001859066)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions200200200
Spacing200200200
CellA=B=C: 163.5 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_41611_msk_1.map
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Mask #2

Fileemd_41611_msk_2.map
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Additional map: Original unmasked and unboxed map from 3D refinement...

Fileemd_41611_additional_1.map
AnnotationOriginal unmasked and unboxed map from 3D refinement and postprocessing in RELION
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Half map: Original unmasked and unboxed half-map 1 from 3D refinement

Fileemd_41611_half_map_1.map
AnnotationOriginal unmasked and unboxed half-map 1 from 3D refinement
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Half map: Original unmasked and unboxed half-map 2 from 3D refinement

Fileemd_41611_half_map_2.map
AnnotationOriginal unmasked and unboxed half-map 2 from 3D refinement
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Sample components

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Entire : PHF1-Phosphomimetic 0N4R Tau Fibrils

EntireName: PHF1-Phosphomimetic 0N4R Tau Fibrils
Components
  • Complex: PHF1-Phosphomimetic 0N4R Tau Fibrils
    • Protein or peptide: Microtubule-associated protein tau

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Supramolecule #1: PHF1-Phosphomimetic 0N4R Tau Fibrils

SupramoleculeName: PHF1-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: 5 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 40.227973 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MAEPRQEFEV MEDHAGTYGL GDRKDQGGYT MHQDQEGDTD AGLKAEEAGI GDTPSLEDEA AGHVTQARMV SKSKDGTGSD DKKAKGADG KTKIATPRGA APPGQKGQAN ATRIPAKTPP APKTPPSSGE PPKSGDRSGY SSPGSPGTPG SRSRTPSLPT P PTREPKKV ...String:
MAEPRQEFEV MEDHAGTYGL GDRKDQGGYT MHQDQEGDTD AGLKAEEAGI GDTPSLEDEA AGHVTQARMV SKSKDGTGSD DKKAKGADG KTKIATPRGA APPGQKGQAN ATRIPAKTPP APKTPPSSGE PPKSGDRSGY SSPGSPGTPG SRSRTPSLPT P PTREPKKV AVVRTPPKSP SSAKSRLQTA PVPMPDLKNV KSKIGSTENL KHQPGGGKVQ IINKKLDLSN VQSKCGSKDN IK HVPGGGS VQIVYKPVDL SKVTSKCGSL GNIHHKPGGG QVEVKSEKLD FKDRVQSKIG SLDNITHVPG GGNKKIETHK LTF RENAKA KTDHGAEIVY KEPVVEGDEE 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

Concentration1.6 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.
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 400 / 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: 50.7 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.4 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 4.79 Å
Applied symmetry - Helical parameters - Δ&Phi: -1.07 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 2.4 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 4.0) / Number images used: 132972
Segment selectionNumber selected: 3830683 / 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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