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- EMDB-8634: KVQIINKKLD, Structure of the amyloid spine from microtubule assoc... -

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Basic information

Entry
Database: EMDB / ID: EMD-8634
TitleKVQIINKKLD, 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: KVQIINKKLD Tau peptide
    • Protein or peptide: Microtubule-associated protein tau
  • Ligand: water
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 establishment of protein localization to mitochondrion / neurofibrillary tangle / microtubule lateral binding / axonal transport / positive regulation of protein localization to synapse / main axon / phosphatidylinositol bisphosphate binding / regulation of long-term synaptic depression ...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 / axonal transport / positive regulation of protein localization to synapse / main axon / phosphatidylinositol bisphosphate binding / regulation of long-term synaptic depression / tubulin complex / negative regulation of tubulin deacetylation / generation of neurons / regulation of chromosome organization / rRNA metabolic process / axonal transport of mitochondrion / regulation of mitochondrial fission / axon development / 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 / dynactin binding / negative regulation of mitochondrial membrane potential / apolipoprotein binding / glial cell projection / axolemma / protein polymerization / negative regulation of mitochondrial fission / Caspase-mediated cleavage of cytoskeletal proteins / regulation of microtubule polymerization or depolymerization / positive regulation of axon extension / neurofibrillary tangle assembly / Activation of AMPK downstream of NMDARs / synapse assembly / regulation of cellular response to heat / supramolecular fiber organization / positive regulation of protein localization / regulation of calcium-mediated signaling / somatodendritic compartment / cellular response to brain-derived neurotrophic factor stimulus / cytoplasmic microtubule organization / axon cytoplasm / positive regulation of microtubule polymerization / 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 / cellular response to nerve growth factor stimulus / response to lead ion / synapse organization / PKR-mediated signaling / protein homooligomerization / regulation of synaptic plasticity / SH3 domain binding / memory / microtubule cytoskeleton organization / cytoplasmic ribonucleoprotein granule / 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 / microtubule binding / protein-macromolecule adaptor activity / dendritic spine / sequence-specific DNA binding / microtubule / amyloid fibril formation / 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
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, 4 items
OrganizationGrant numberCountry
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
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)1F32 NS095661 United States
BrightFocus FoundationA2016588F 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 13, 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: 1
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 1
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-5v5b
  • Surface level: 1
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_8634.png

Downloads & links

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Map

FileDownload / File: emd_8634.map.gz / Format: CCP4 / Size: 2 MB / 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
AxesX (Sec.)Y (Row.)Z (Col.)
0.36 Å/pix.
x 78 pix.
= 28.236 Å		0.3 Å/pix.
x 52 pix.
= 15.704 Å		0.36 Å/pix.
x 128 pix.
= 46.08 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

generated in cubic-lattice coordinate

Voxel sizeX: 0.362 Å / Y: 0.302 Å / Z: 0.36 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 1.0 / Movie #1: 1
Minimum - Maximum-3.9691255 - 6.3345394
Average (Standard dev.)0.009696766 (±1.0072529)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin-25-47-19
Dimensions5212878
Spacing7852128
CellA: 28.236 Å / B: 15.7039995 Å / C: 46.08 Å
α: 90.0 ° / β: 100.53 ° / γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.3620.3020.36
M x/y/z7852128
origin x/y/z0.0000.0000.000
length x/y/z28.23615.70446.080
α/β/γ90.000100.53090.000
start NX/NY/NZ-19-25-47
NX/NY/NZ7852128
MAP C/R/S321
start NC/NR/NS-47-25-19
NC/NR/NS1285278
D min/max/mean-3.9696.3350.010

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Supplemental data

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Sample components

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Entire : KVQIINKKLD Tau peptide

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

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Supramolecule #1: KVQIINKKLD Tau peptide

SupramoleculeName: KVQIINKKLD Tau peptide / type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: #1
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: 1.201478 KDa
SequenceString:
KVQIINKKLD

UniProtKB: Microtubule-associated protein tau

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Macromolecule #2: water

MacromoleculeName: water / type: ligand / ID: 2 / Number of copies: 2 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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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: 4.2
VitrificationCryogen name: ETHANE

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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: 1850 mm

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Image processing

Final reconstructionResolution method: DIFFRACTION PATTERN/LAYERLINES
Crystallography statisticsNumber intensities measured: 20047 / Number structure factors: 2203 / Fourier space coverage: 84.8 / R sym: 25 / R merge: 25 / Overall phase error: 0 / Overall phase residual: 0.1 / Phase error rejection criteria: 0 / High resolution: 1.5 Å / Details: This is a crystallography experiment. / Shell - Shell ID: 1 / Shell - High resolution: 1.5 Å / Shell - Low resolution: 1.68 Å / Shell - Number structure factors: 370 / Shell - Phase residual: 0.1 / Shell - Fourier space coverage: 82.4 / Shell - Multiplicity: 6.2

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