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- PDB-5v5c: VQIINK, Structure of the amyloid-spine from microtubule associate... -
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Open data
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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 | ||||||||||||
![]() | Microtubule-associated protein tau | ||||||||||||
![]() | STRUCTURAL PROTEIN / Amyloid / tau / Alzheimer's Disease / tauopathy / MAPT | ||||||||||||
Function / homology | ![]() 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 / rRNA metabolic process / axonal transport of mitochondrion / regulation of chromosome organization / 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 / neurofibrillary tangle assembly / positive regulation of axon extension / 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 / microtubule cytoskeleton organization / cytoplasmic ribonucleoprotein granule / memory / 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 | ||||||||||||
Biological species | ![]() | ||||||||||||
Method | ELECTRON CRYSTALLOGRAPHY / electron crystallography / ![]() ![]() | ||||||||||||
![]() | Seidler, P.M. / Sawaya, M.R. / Rodriguez, J.A. / Eisenberg, D.S. / Cascio, D. / Boyer, D.R. | ||||||||||||
Funding support | ![]()
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![]() | ![]() 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
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Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 13.2 KB | Display | ![]() |
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PDB format | ![]() | 5.8 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Summary document | ![]() | 309 KB | Display | ![]() |
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Full document | ![]() | 308.6 KB | Display | |
Data in XML | ![]() | 1.2 KB | Display | |
Data in CIF | ![]() | 1.5 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8635MC ![]() 8634C ![]() 5v5bC M: map data used to model this data C: citing same article ( |
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Similar structure data |
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Links
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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.) ![]() |
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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 |
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Sample preparation
Component | Name: VQIINK Tau peptide / Type: ORGANELLE OR CELLULAR COMPONENT / Entity ID: all / Source: NATURAL |
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Source (natural) | Organism: ![]() |
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: ![]() | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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: ![]() |
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Processing
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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: ![]()
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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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