- EMDB-28721: CryoEM structure of synthetic tau repeat R1R2 with two acetylated... -
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Open data
ID or keywords:
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Basic information
Entry
Database: EMDB / ID: EMD-28721
Title
CryoEM structure of synthetic tau repeat R1R2 with two acetylated lysines at positions 274 and 280
Map data
Sample
Complex: Acetylated tau repeat 1 and 2 fragment (AcR1R2)
Protein or peptide: Acetylated tau repeat 1 and 2 fragment (AcR1R2)
Keywords
Amyloid motif / acetylation / tau / repeat domain / post-translational modification / 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 / apolipoprotein binding / glial cell projection / 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 / Activation of AMPK downstream of NMDARs / supramolecular fiber organization / regulation of cellular response to heat / stress granule assembly / 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 / microtubule cytoskeleton organization / cellular response to reactive oxygen species / 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 / single-stranded DNA binding / cellular response to heat / 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
National Institutes of Health/National Cancer Institute (NIH/NCI)
1U01CA242115
United States
Welch Foundation
I-1928-20200401
United States
Chan Zuckerberg Initiative
2018-191983
United States
Citation
Journal: Structure / Year: 2023 Title: Disease-associated patterns of acetylation stabilize tau fibril formation. Authors: Li Li / Binh A Nguyen / Vishruth Mullapudi / Yang Li / Lorena Saelices / Lukasz A Joachimiak / Abstract: Assembly of tau into beta-sheet-rich amyloids dictates the pathology of a diversity of diseases. Lysine acetylation has been proposed to drive tau amyloid assembly, but no direct mechanism has ...Assembly of tau into beta-sheet-rich amyloids dictates the pathology of a diversity of diseases. Lysine acetylation has been proposed to drive tau amyloid assembly, but no direct mechanism has emerged. Using tau fragments, we identify patterns of acetylation that flank amyloidogenic motifs on the tau fragments that promote rapid fibril assembly. We determined a 3.9 Å cryo-EM amyloid fibril structure assembled from an acetylated tau fragment uncovering how lysine acetylation can mediate gain-of-function interactions. Comparison of the structure to an ex vivo tauopathy fibril reveals regions of structural similarity. Finally, we show that fibrils encoding disease-associated patterns of acetylation are active in cell-based tau aggregation assays. Our data uncover the dual role of lysine residues in limiting tau aggregation while their acetylation leads to stabilizing pro-aggregation interactions. Design of tau sequence with specific acetylation patterns may lead to controllable tau aggregation to direct folding of tau into distinct amyloid folds.
Entire : Acetylated tau repeat 1 and 2 fragment (AcR1R2)
Entire
Name: Acetylated tau repeat 1 and 2 fragment (AcR1R2)
Components
Complex: Acetylated tau repeat 1 and 2 fragment (AcR1R2)
Protein or peptide: Acetylated tau repeat 1 and 2 fragment (AcR1R2)
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Supramolecule #1: Acetylated tau repeat 1 and 2 fragment (AcR1R2)
Supramolecule
Name: Acetylated tau repeat 1 and 2 fragment (AcR1R2) / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all Details: Synthetic tau repeat R1R2 with two acetylated lysines at position 274 and 280
Source (natural)
Organism: Homo sapiens (human) / Synthetically produced: Yes
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Macromolecule #1: Acetylated tau repeat 1 and 2 fragment (AcR1R2)
Macromolecule
Name: Acetylated tau repeat 1 and 2 fragment (AcR1R2) / type: protein_or_peptide / ID: 1 / Details: (ALY): Acetylated lysine / Enantiomer: LEVO
Source (natural)
Organism: Homo sapiens (human)
Sequence
String:
TENLKHQPGG G(ALY)VQIIN(ALY)
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Experimental details
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Structure determination
Method
cryo EM
Processing
helical reconstruction
Aggregation state
filament
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Sample preparation
Buffer
pH: 7.4 / Details: PBS
Grid
Model: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec. / Pretreatment - Atmosphere: OTHER
Vitrification
Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 295 K / Instrument: FEI VITROBOT MARK IV
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Electron microscopy
Microscope
FEI TITAN KRIOS
Image recording
Film or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 1 / Number real images: 5901 / Average exposure time: 4.5 sec. / Average electron dose: 52.0 e/Å2
Electron beam
Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
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