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Yorodumi- EMDB-8635: VQIINK, Structure of the amyloid-spine from microtubule associate... -
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-Basic information
Entry | Database: EMDB / ID: EMD-8635 | ||||||||||||
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Title | VQIINK, Structure of the amyloid-spine from microtubule associated protein tau Repeat 2 | ||||||||||||
Map data | amyloid-spine from microtubule associated protein tau Repeat 2 | ||||||||||||
Sample |
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Keywords | Amyloid / tau / Alzheimer's Disease / tauopathy / MAPT / STRUCTURAL PROTEIN | ||||||||||||
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 / cryo EM | ||||||||||||
Authors | Seidler PM / Sawaya MR | ||||||||||||
Funding support | United States, 3 items
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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 | EM map: SurfViewMolmilJmol/JSmol |
Supplemental images |
-Downloads & links
-EMDB archive
Map data | emd_8635.map.gz | 225.6 KB | EMDB map data format | |
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Header (meta data) | emd-8635-v30.xml emd-8635.xml | 11.3 KB 11.3 KB | Display Display | EMDB header |
Images | emd_8635.png | 101 KB | ||
Filedesc metadata | emd-8635.cif.gz | 4.4 KB | ||
Filedesc structureFactors | emd_8635_sf.cif.gz | 36 KB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-8635 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-8635 | HTTPS FTP |
-Validation report
Summary document | emd_8635_validation.pdf.gz | 337.6 KB | Display | EMDB validaton report |
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Full document | emd_8635_full_validation.pdf.gz | 337.2 KB | Display | |
Data in XML | emd_8635_validation.xml.gz | 4 KB | Display | |
Data in CIF | emd_8635_validation.cif.gz | 4.4 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-8635 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-8635 | HTTPS FTP |
-Related structure data
Related structure data | 5v5cMC 8634C 5v5bC C: citing same article (ref.) M: atomic model generated by this map |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_8635.map.gz / Format: CCP4 / Size: 244.1 KB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Annotation | amyloid-spine from microtubule associated protein tau Repeat 2 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X: 0.424 Å / Y: 0.4 Å / Z: 0.402 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 18 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Sample components
-Entire : VQIINK Tau peptide
Entire | Name: VQIINK Tau peptide |
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Components |
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-Supramolecule #1: VQIINK Tau peptide
Supramolecule | Name: VQIINK Tau peptide / type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: all |
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Source (natural) | Organism: Homo sapiens (human) |
-Macromolecule #1: Microtubule-associated protein tau
Macromolecule | Name: Microtubule-associated protein tau / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 714.873 Da |
Sequence | String: VQIINK |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | electron crystallography |
Aggregation state | 3D array |
-Sample preparation
Buffer | pH: 7 |
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Vitrification | Cryogen name: ETHANE |
Details | 3D micro-crystal |
Crystal formation | Temperature: 291.0 K |
-Electron microscopy
Microscope | FEI TECNAI 20 |
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Image recording | Film or detector model: TVIPS TEMCAM-F416 (4k x 4k) / Average electron dose: 0.1 e/Å2 |
Electron beam | Acceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: DIFFRACTION / Camera length: 730 mm |