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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 tauTau protein
KeywordsAmyloid / tau / Alzheimer's Disease / tauopathy / MAPT / STRUCTURAL PROTEIN
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 / lipoprotein particle binding / 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 / negative regulation of mitochondrial membrane potential / dynactin binding / glial cell projection / apolipoprotein binding / 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 / supramolecular fiber organization / Activation of AMPK downstream of NMDARs / cytoplasmic microtubule organization / regulation of microtubule cytoskeleton organization / stress granule assembly / regulation of cellular response to heat / regulation of calcium-mediated signaling / axon cytoplasm / positive regulation of microtubule polymerization / cellular response to brain-derived neurotrophic factor stimulus / somatodendritic compartment / 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 / synapse organization / microglial cell activation / response to lead ion / Hsp90 protein binding / regulation of synaptic plasticity / PKR-mediated signaling / protein homooligomerization / cytoplasmic ribonucleoprotein granule / memory / microtubule cytoskeleton organization / SH3 domain binding / cellular response to reactive oxygen species / neuron projection development / activation of cysteine-type endopeptidase activity involved in apoptotic process / microtubule cytoskeleton / protein-macromolecule adaptor activity / single-stranded DNA binding / cell-cell signaling / cellular response to heat / cell body / actin binding / growth cone / protein-folding chaperone binding / double-stranded DNA binding / microtubule binding / microtubule / amyloid fibril formation / sequence-specific DNA binding / dendritic spine / learning or memory / neuron projection / nuclear speck / membrane raft / axon / negative regulation of gene expression / dendrite / neuronal cell body / DNA damage response / 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
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 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 tauTau protein

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

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Image processing

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
Molecular replacementSoftware - Name: Phaser
Symmetry determination software listSoftware - Name: XDS
Final reconstructionResolution method: DIFFRACTION PATTERN/LAYERLINES
Merging software listSoftware - Name: XSCALE

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