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Yorodumi- PDB-5v5c: VQIINK, Structure of the amyloid-spine from microtubule associate... -
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-Basic information
Entry | Database: PDB / ID: 5v5c | ||||||||||||
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Title | VQIINK, Structure of the amyloid-spine from microtubule associated protein tau Repeat 2 | ||||||||||||
Components | Microtubule-associated protein tau | ||||||||||||
Keywords | STRUCTURAL PROTEIN / Amyloid / tau / Alzheimer's Disease / tauopathy / MAPT | ||||||||||||
Function / homology | Function and homology information plus-end-directed organelle transport along microtubule / histone-dependent DNA binding / neurofibrillary tangle assembly / positive regulation of diacylglycerol kinase activity / axonal transport / negative regulation of establishment of protein localization to mitochondrion / neurofibrillary tangle / positive regulation of protein localization to synapse / microtubule lateral binding / negative regulation of mitochondrial fission ...plus-end-directed organelle transport along microtubule / histone-dependent DNA binding / neurofibrillary tangle assembly / positive regulation of diacylglycerol kinase activity / axonal transport / negative regulation of establishment of protein localization to mitochondrion / neurofibrillary tangle / positive regulation of protein localization to synapse / microtubule lateral binding / negative regulation of mitochondrial fission / 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 / positive regulation of protein localization / rRNA metabolic process / internal protein amino acid acetylation / regulation of chromosome organization / regulation of mitochondrial fission / axonal transport of mitochondrion / intracellular distribution of mitochondria / 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 / 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 / cytoplasmic microtubule organization / supramolecular fiber organization / regulation of cellular response to heat / stress granule assembly / positive regulation of superoxide anion generation / regulation of calcium-mediated signaling / axon cytoplasm / positive regulation of microtubule polymerization / somatodendritic compartment / synapse assembly / cellular response to brain-derived neurotrophic factor stimulus / astrocyte activation / phosphatidylinositol binding / nuclear periphery / cellular response to nerve growth factor stimulus / protein phosphatase 2A binding / regulation of autophagy / response to lead ion / synapse organization / microglial cell activation / cellular response to reactive oxygen species / Hsp90 protein binding / PKR-mediated signaling / protein homooligomerization / regulation of synaptic plasticity / memory / activation of cysteine-type endopeptidase activity involved in apoptotic process / microtubule cytoskeleton organization / SH3 domain binding / cytoplasmic ribonucleoprotein granule / microtubule cytoskeleton / neuron projection development / cell-cell signaling / double-stranded DNA binding / protein-macromolecule adaptor activity / single-stranded DNA binding / actin binding / protein-folding chaperone binding / cellular response to heat / cell body / growth cone / microtubule binding / sequence-specific DNA binding / amyloid fibril formation / microtubule / learning or memory / dendritic spine / 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 | ||||||||||||
Biological species | Homo sapiens (human) | ||||||||||||
Method | ELECTRON CRYSTALLOGRAPHY / electron crystallography / MOLECULAR REPLACEMENT / molecular replacement / cryo EM / Resolution: 1.25 Å | ||||||||||||
Authors | Seidler, P.M. / Sawaya, M.R. / Rodriguez, J.A. / Eisenberg, D.S. / Cascio, D. / Boyer, D.R. | ||||||||||||
Funding support | United States, 3items
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Citation | Journal: Nat Chem / Year: 2018 Title: Structure-based inhibitors of tau aggregation. Authors: P M Seidler / D R Boyer / J A Rodriguez / M R Sawaya / D Cascio / K Murray / T Gonen / D S Eisenberg / Abstract: Aggregated tau protein is associated with over 20 neurological disorders, which include Alzheimer's disease. Previous work has shown that tau's sequence segments VQIINK and VQIVYK drive its ...Aggregated tau protein is associated with over 20 neurological disorders, which include Alzheimer's disease. Previous work has shown that tau's sequence segments VQIINK and VQIVYK drive its aggregation, but inhibitors based on the structure of the VQIVYK segment only partially inhibit full-length tau aggregation and are ineffective at inhibiting seeding by full-length fibrils. Here we show that the VQIINK segment is the more powerful driver of tau aggregation. Two structures of this segment determined by the cryo-electron microscopy method micro-electron diffraction explain its dominant influence on tau aggregation. Of practical significance, the structures lead to the design of inhibitors that not only inhibit tau aggregation but also inhibit the ability of exogenous full-length tau fibrils to seed intracellular tau in HEK293 biosensor cells into amyloid. We also raise the possibility that the two VQIINK structures represent amyloid polymorphs of tau that may account for a subset of prion-like strains of tau. | ||||||||||||
History |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | Molecule: MolmilJmol/JSmol |
-Downloads & links
-Download
PDBx/mmCIF format | 5v5c.cif.gz | 13.2 KB | Display | PDBx/mmCIF format |
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PDB format | pdb5v5c.ent.gz | 5.8 KB | Display | PDB format |
PDBx/mmJSON format | 5v5c.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 5v5c_validation.pdf.gz | 311 KB | Display | wwPDB validaton report |
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Full document | 5v5c_full_validation.pdf.gz | 310.6 KB | Display | |
Data in XML | 5v5c_validation.xml.gz | 1.2 KB | Display | |
Data in CIF | 5v5c_validation.cif.gz | 1.4 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/v5/5v5c ftp://data.pdbj.org/pub/pdb/validation_reports/v5/5v5c | HTTPS FTP |
-Related structure data
Related structure data | 8635MC 8634C 5v5bC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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Unit cell |
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-Components
#1: Protein/peptide | Mass: 714.873 Da / Num. of mol.: 1 / Fragment: Repeat 2 peptide (UNP residues 592-597) / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P10636*PLUS |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON CRYSTALLOGRAPHY |
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EM experiment | Aggregation state: 3D ARRAY / 3D reconstruction method: electron crystallography |
-Sample preparation
Component | Name: VQIINK Tau peptide / Type: ORGANELLE OR CELLULAR COMPONENT / Entity ID: all / Source: NATURAL |
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Source (natural) | Organism: Homo sapiens (human) |
EM crystal formation | Temperature: 291 K |
Buffer solution | pH: 7 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: 3D micro-crystal |
Vitrification | Cryogen name: ETHANE |
Crystal | Density Matthews: 1.48 Å3/Da / Density % sol: 17.08 % |
Crystal grow | Temperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7 / Details: 0.29 M lithium nitrate, 24% PEG3350 |
-Data collection
Microscopy | Model: FEI TECNAI 20 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Electron lens | Mode: DIFFRACTION | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Image recording | Electron dose: 0.1 e/Å2 / Film or detector model: TVIPS TEMCAM-F416 (4k x 4k) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
EM diffraction | Camera length: 730 mm | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
EM diffraction shell | Resolution: 1.25→1.31 Å / Fourier space coverage: 71.6 % / Multiplicity: 2.5 / Num. of structure factors: 106 / Phase residual: 0.1 ° | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
EM diffraction stats | Details: This is a crystallography experiment. Phases were not measured. Fourier space coverage: 86.8 % / High resolution: 1.25 Å / Num. of intensities measured: 5454 / Num. of structure factors: 1226 / Phase error: 0.1 ° / Phase residual: 0.1 ° / Phase error rejection criteria: 0.1 / Rmerge: 23.9 / Rsym: 23.9 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Diffraction | Mean temperature: 100 K | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Diffraction source | Source: ELECTRON MICROSCOPE / Type: TECNAI F20 TEM / Wavelength: 0.0251 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Detector | Type: TVIPS TEMCAM-F416 / Detector: CMOS / Date: Aug 25, 2016 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Radiation wavelength | Wavelength: 0.0251 Å / Relative weight: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reflection | Resolution: 1.25→10.18 Å / Num. obs: 1226 / % possible obs: 86.8 % / Observed criterion σ(I): -3 / Redundancy: 4.449 % / Biso Wilson estimate: 5.87 Å2 / CC1/2: 0.986 / Rmerge(I) obs: 0.239 / Rrim(I) all: 0.265 / Χ2: 0.821 / Net I/σ(I): 3.58 / Num. measured all: 5454 / Scaling rejects: 5 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reflection shell | Diffraction-ID: 1
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-Phasing
Phasing | Method: molecular replacement |
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-Processing
Software |
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EM software |
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EM 3D crystal entity | ∠α: 90 ° / ∠β: 90 ° / ∠γ: 90 ° / A: 20.36 Å / B: 43.22 Å / C: 4.82 Å / Space group name: P21212 / Space group num: 18 | ||||||||||||||||||||||||
CTF correction | Type: NONE | ||||||||||||||||||||||||
3D reconstruction | Resolution method: DIFFRACTION PATTERN/LAYERLINES / Symmetry type: 3D CRYSTAL | ||||||||||||||||||||||||
Refinement | Method to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.25→10.18 Å / Cor.coef. Fo:Fc: 0.9086 / Cor.coef. Fo:Fc free: 0.9428 / SU R Cruickshank DPI: 0.072 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.067 / SU Rfree Blow DPI: 0.074 / SU Rfree Cruickshank DPI: 0.07
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Displacement parameters | Biso max: 49.96 Å2 / Biso mean: 15.3 Å2 / Biso min: 3 Å2
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LS refinement shell | Resolution: 1.25→1.4 Å / Rfactor Rfree error: 0 / Total num. of bins used: 5
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