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- EMDB-8635: VQIINK, Structure of the amyloid-spine from microtubule associate... -

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Basic information

Entry
Database: EMDB / ID: EMD-8635
TitleVQIINK, Structure of the amyloid-spine from microtubule associated protein tau Repeat 2
Map dataamyloid-spine from microtubule associated protein tau Repeat 2
Sample
  • Organelle or cellular component: VQIINK Tau peptide
    • Protein or peptide: Microtubule-associated protein tau
KeywordsAmyloid / 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 / negative regulation of protein localization to mitochondrion / neurofibrillary tangle / microtubule lateral binding / axonal transport / tubulin complex / positive regulation of protein localization to synapse / phosphatidylinositol bisphosphate binding / generation of neurons ...plus-end-directed organelle transport along microtubule / histone-dependent DNA binding / negative regulation of protein localization to mitochondrion / neurofibrillary tangle / microtubule lateral binding / axonal transport / tubulin complex / positive regulation of protein localization to synapse / phosphatidylinositol bisphosphate binding / generation of neurons / rRNA metabolic process / axonal transport of mitochondrion / regulation of mitochondrial fission / axon development / regulation of microtubule-based movement / regulation of chromosome organization / intracellular distribution of mitochondria / central nervous system neuron development / minor groove of adenine-thymine-rich DNA binding / lipoprotein particle binding / microtubule polymerization / negative regulation of mitochondrial membrane potential / regulation of microtubule polymerization / dynactin binding / apolipoprotein binding / main axon / protein polymerization / axolemma / Caspase-mediated cleavage of cytoskeletal proteins / regulation of microtubule polymerization or depolymerization / negative regulation of mitochondrial fission / glial cell projection / neurofibrillary tangle assembly / positive regulation of axon extension / regulation of cellular response to heat / Activation of AMPK downstream of NMDARs / positive regulation of superoxide anion generation / positive regulation of protein localization / regulation of long-term synaptic depression / cellular response to brain-derived neurotrophic factor stimulus / supramolecular fiber organization / positive regulation of microtubule polymerization / cytoplasmic microtubule organization / somatodendritic compartment / synapse assembly / regulation of calcium-mediated signaling / axon cytoplasm / astrocyte activation / phosphatidylinositol binding / nuclear periphery / enzyme inhibitor activity / stress granule assembly / protein phosphatase 2A binding / regulation of microtubule cytoskeleton organization / regulation of autophagy / cellular response to reactive oxygen species / Hsp90 protein binding / microglial cell activation / cellular response to nerve growth factor stimulus / protein homooligomerization / synapse organization / PKR-mediated signaling / regulation of synaptic plasticity / response to lead ion / SH3 domain binding / microtubule cytoskeleton organization / memory / neuron projection development / cytoplasmic ribonucleoprotein granule / cell-cell signaling / single-stranded DNA binding / protein-folding chaperone binding / cellular response to heat / microtubule cytoskeleton / growth cone / actin binding / cell body / double-stranded DNA binding / microtubule binding / sequence-specific DNA binding / protein-macromolecule adaptor activity / amyloid fibril formation / dendritic spine / microtubule / learning or memory / neuron projection / membrane raft / negative regulation of gene expression / axon / neuronal cell body / DNA damage response / dendrite / protein kinase binding / enzyme binding / mitochondrion / DNA binding / RNA binding / extracellular region / identical protein binding / nucleus
Similarity search - Function
Microtubule-associated protein Tau / Microtubule associated protein, tubulin-binding repeat / 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)
Methodelectron crystallography / cryo EM
AuthorsSeidler PM / Sawaya MR
Funding support United States, 3 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)1F32 NS095661 United States
National Institutes of Health/National Institute on Aging (NIH/NIA)1R01 AG029430 United States
National Institutes of Health/National Institute on Aging (NIH/NIA)RF1 AG054022 United States
CitationJournal: 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
DepositionMar 14, 2017-
Header (metadata) releaseFeb 7, 2018-
Map releaseFeb 7, 2018-
UpdateMar 13, 2024-
Current statusMar 13, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.2
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.2
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-5v5c
  • Surface level: 0.2
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_8635.png

Downloads & links

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Map

FileDownload / File: emd_8635.map.gz / Format: CCP4 / Size: 244.1 KB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationamyloid-spine from microtubule associated protein tau Repeat 2
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesY (Sec.)X (Row.)Z (Col.)
0.4 Å/pix.
x 108 pix.
= 43.2 Å		0.42 Å/pix.
x 48 pix.
= 20.352 Å		0.4 Å/pix.
x 12 pix.
= 4.824 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

generated in cubic-lattice coordinate

Voxel sizeX: 0.424 Å / Y: 0.4 Å / Z: 0.402 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 1.0 / Movie #1: 0.2
Minimum - Maximum-0.6224728 - 1.373249
Average (Standard dev.)0.000000000025266 (±0.2043117)
SymmetrySpace group: 18
Details

EMDB XML:

Map geometry
Axis orderZXY
Origin000
Dimensions4812108
Spacing4810812
CellA: 20.352 Å / B: 43.2 Å / C: 4.8240004 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.4240.40.402
M x/y/z4810812
origin x/y/z0.0000.0000.000
length x/y/z20.35243.2004.824
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ4810812
MAP C/R/S312
start NC/NR/NS000
NC/NR/NS1248108
D min/max/mean-0.6221.3730.000

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Supplemental data

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Sample components

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Entire : VQIINK Tau peptide

EntireName: VQIINK Tau peptide
Components
  • Organelle or cellular component: VQIINK Tau peptide
    • Protein or peptide: Microtubule-associated protein tau

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Supramolecule #1: VQIINK Tau peptide

SupramoleculeName: VQIINK Tau peptide / type: organelle_or_cellular_component / 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 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 714.873 Da
SequenceString:
VQIINK

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Experimental details

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Structure determination

Methodcryo EM
Processingelectron crystallography
Aggregation state3D array

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Sample preparation

BufferpH: 7
VitrificationCryogen name: ETHANE
Details3D micro-crystal
Crystal formationTemperature: 291.0 K

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Electron microscopy

MicroscopeFEI TECNAI 20
Image recordingFilm or detector model: TVIPS TEMCAM-F416 (4k x 4k) / Average electron dose: 0.1 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: DIFFRACTION / Camera length: 730 mm

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Image processing

Final reconstructionResolution method: DIFFRACTION PATTERN/LAYERLINES
Molecular replacementSoftware - Name: Phaser
Symmetry determination software listSoftware - Name: XDS
Merging software listSoftware - Name: XSCALE
Crystallography statisticsNumber intensities measured: 5454 / Number structure factors: 1226 / Fourier space coverage: 86.8 / R sym: 23.9 / R merge: 23.9 / Overall phase error: 0.1 / Overall phase residual: 0.1 / Phase error rejection criteria: 0.1 / High resolution: 1.25 Å
Details: This is a crystallography experiment. Phases were not measured.
Shell - Shell ID: 1 / Shell - High resolution: 1.25 Å / Shell - Low resolution: 1.31 Å / Shell - Number structure factors: 106 / Shell - Phase residual: 0.1 / Shell - Fourier space coverage: 71.6 / Shell - Multiplicity: 2.5

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