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- EMDB-16019: Sarkosyl-extracted AppNL-G-F Abeta42 fibril structure (Methoxy-X0... -
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Open data
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Basic information
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Title | Sarkosyl-extracted AppNL-G-F Abeta42 fibril structure (Methoxy-X04-labelled mice) | |||||||||
![]() | CryoEM map for extracted AppNLGF Abeta42 fibril after MOX04 labelling | |||||||||
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![]() | Amyloid / fibril / helical / cross-beta / beta amyloid / PROTEIN FIBRIL / ex vivo / arctic mutant / alzheimers disease | |||||||||
Function / homology | ![]() regulation of epidermal growth factor-activated receptor activity / cytosolic mRNA polyadenylation / collateral sprouting in absence of injury / microglia development / regulation of synapse structure or activity / regulation of Wnt signaling pathway / Formyl peptide receptors bind formyl peptides and many other ligands / axo-dendritic transport / synaptic assembly at neuromuscular junction / signaling receptor activator activity ...regulation of epidermal growth factor-activated receptor activity / cytosolic mRNA polyadenylation / collateral sprouting in absence of injury / microglia development / regulation of synapse structure or activity / regulation of Wnt signaling pathway / Formyl peptide receptors bind formyl peptides and many other ligands / axo-dendritic transport / synaptic assembly at neuromuscular junction / signaling receptor activator activity / axon midline choice point recognition / smooth endoplasmic reticulum calcium ion homeostasis / astrocyte activation involved in immune response / regulation of spontaneous synaptic transmission / mating behavior / NMDA selective glutamate receptor signaling pathway / ciliary rootlet / Lysosome Vesicle Biogenesis / PTB domain binding / Golgi-associated vesicle / neuron remodeling / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / positive regulation of amyloid fibril formation / positive regulation of G2/M transition of mitotic cell cycle / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / nuclear envelope lumen / COPII-coated ER to Golgi transport vesicle / suckling behavior / dendrite development / presynaptic active zone / modulation of excitatory postsynaptic potential / regulation of peptidyl-tyrosine phosphorylation / TRAF6 mediated NF-kB activation / Advanced glycosylation endproduct receptor signaling / neuromuscular process controlling balance / The NLRP3 inflammasome / regulation of presynapse assembly / transition metal ion binding / negative regulation of long-term synaptic potentiation / regulation of multicellular organism growth / negative regulation of neuron differentiation / ECM proteoglycans / intracellular copper ion homeostasis / smooth endoplasmic reticulum / positive regulation of T cell migration / spindle midzone / Purinergic signaling in leishmaniasis infection / protein serine/threonine kinase binding / positive regulation of chemokine production / clathrin-coated pit / forebrain development / Notch signaling pathway / neuron projection maintenance / positive regulation of protein metabolic process / positive regulation of calcium-mediated signaling / astrocyte activation / ionotropic glutamate receptor signaling pathway / positive regulation of glycolytic process / response to interleukin-1 / cholesterol metabolic process / positive regulation of mitotic cell cycle / extracellular matrix organization / adult locomotory behavior / axonogenesis / platelet alpha granule lumen / trans-Golgi network membrane / positive regulation of peptidyl-threonine phosphorylation / positive regulation of interleukin-1 beta production / learning / dendritic shaft / positive regulation of long-term synaptic potentiation / Mitochondrial protein degradation / central nervous system development / locomotory behavior / endosome lumen / positive regulation of JNK cascade / Post-translational protein phosphorylation / synapse organization / microglial cell activation / regulation of long-term neuronal synaptic plasticity / TAK1-dependent IKK and NF-kappa-B activation / visual learning / neuromuscular junction / positive regulation of non-canonical NF-kappaB signal transduction / recycling endosome / cognition / G2/M transition of mitotic cell cycle / Golgi lumen / positive regulation of inflammatory response / neuron cellular homeostasis / positive regulation of interleukin-6 production / cellular response to amyloid-beta / endocytosis / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / serine-type endopeptidase inhibitor activity / positive regulation of peptidyl-serine phosphorylation / positive regulation of tumor necrosis factor production / neuron projection development / cell-cell junction / synaptic vesicle Similarity search - Function | |||||||||
Biological species | ![]() ![]() | |||||||||
Method | helical reconstruction / cryo EM / Resolution: 3.2 Å | |||||||||
![]() | Wilkinson M / Leistner C / Burgess A / Goodfellow S / Deuchars S / Ranson NA / Radford SE / Frank RAW | |||||||||
Funding support | ![]()
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![]() | ![]() Title: The in-tissue molecular architecture of β-amyloid pathology in the mammalian brain. Authors: Conny Leistner / Martin Wilkinson / Ailidh Burgess / Megan Lovatt / Stanley Goodbody / Yong Xu / Susan Deuchars / Sheena E Radford / Neil A Ranson / René A W Frank / ![]() Abstract: Amyloid plaques composed of Aβ fibrils are a hallmark of Alzheimer's disease (AD). However, the molecular architecture of amyloid plaques in the context of fresh mammalian brain tissue is unknown. ...Amyloid plaques composed of Aβ fibrils are a hallmark of Alzheimer's disease (AD). However, the molecular architecture of amyloid plaques in the context of fresh mammalian brain tissue is unknown. Here, using cryogenic correlated light and electron tomography we report the in situ molecular architecture of Aβ fibrils in the App familial AD mouse model containing the Arctic mutation and an atomic model of ex vivo purified Arctic Aβ fibrils. We show that in-tissue Aβ fibrils are arranged in a lattice or parallel bundles, and are interdigitated by subcellular compartments, extracellular vesicles, extracellular droplets and extracellular multilamellar bodies. The Arctic Aβ fibril differs significantly from an earlier App fibril structure, indicating a striking effect of the Arctic mutation. These structural data also revealed an ensemble of additional fibrillar species, including thin protofilament-like rods and branched fibrils. Together, these results provide a structural model for the dense network architecture that characterises β-amyloid plaque pathology. | |||||||||
History |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 5.7 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 18.2 KB 18.2 KB | Display Display | ![]() |
Images | ![]() | 91.5 KB | ||
Filedesc metadata | ![]() | 5.8 KB | ||
Others | ![]() ![]() | 56.6 MB 56.7 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Validation report
Summary document | ![]() | 954.5 KB | Display | ![]() |
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Full document | ![]() | 954 KB | Display | |
Data in XML | ![]() | 12.4 KB | Display | |
Data in CIF | ![]() | 14.6 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8bfbMC ![]() 8bfaC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Annotation | CryoEM map for extracted AppNLGF Abeta42 fibril after MOX04 labelling | ||||||||||||||||||||
Voxel size | X=Y=Z: 0.94 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: halfmap2
File | emd_16019_half_map_1.map | ||||||||||||
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Annotation | halfmap2 | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: halfmap1
File | emd_16019_half_map_2.map | ||||||||||||
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Annotation | halfmap1 | ||||||||||||
Projections & Slices |
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Density Histograms |
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Sample components
-Entire : Sarkosyl-extracted AppNL-G-F Abeta42 fibril
Entire | Name: Sarkosyl-extracted AppNL-G-F Abeta42 fibril |
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Components |
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-Supramolecule #1: Sarkosyl-extracted AppNL-G-F Abeta42 fibril
Supramolecule | Name: Sarkosyl-extracted AppNL-G-F Abeta42 fibril / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all Details: Fibrils purified from mouse brain labelled with Methoxy-X04 |
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Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 4.441 kDa/nm |
-Macromolecule #1: Amyloid-beta precursor protein
Macromolecule | Name: Amyloid-beta precursor protein / type: protein_or_peptide / ID: 1 Details: Humanised Abeta42 from App^NL-G-F mice with arctic mutation (E22G) Number of copies: 10 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 4.448025 KDa |
Sequence | String: DAEFRHDSGY EVHHQKLVFF AGDVGSNKGA IIGLMVGGVV IA UniProtKB: Amyloid-beta precursor protein |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | helical reconstruction |
Aggregation state | filament |
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Sample preparation
Buffer | pH: 7.4 Component:
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Grid | Model: C-flat-1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: PLASMA CLEANING / Pretreatment - Time: 60 sec. | |||||||||
Vitrification | Cryogen name: ETHANE / Chamber humidity: 90 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV / Details: 6s blot. | |||||||||
Details | Sarkosyl-insoluble fibrils from App^NL-G-F mouse brain labelled with Methoxy-X04 |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Specialist optics | Energy filter - Name: TFS Selectris / Energy filter - Slit width: 10 eV |
Image recording | Film or detector model: FEI FALCON IV (4k x 4k) / Number grids imaged: 1 / Number real images: 4165 / Average exposure time: 6.0 sec. / Average electron dose: 41.0 e/Å2 Details: 1442 raw EER frames were collected per image and combined into 40 fractions for processing |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | C2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.9 µm / Nominal defocus min: 1.4000000000000001 µm / Nominal magnification: 130000 |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
Final reconstruction | Applied symmetry - Helical parameters - Δz: 2.414 Å Applied symmetry - Helical parameters - Δ&Phi: 179.355 ° Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric) Resolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 4.0) / Number images used: 3640 |
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Segment selection | Number selected: 136214 / Software - Name: crYOLO Details: Manually picked a subset of images to train a model for automatic fibril segment picking in crYOLO |
Startup model | Type of model: INSILICO MODEL Details: Model generated from 2D class averages using relion_helix_inimodel2d |
Final angle assignment | Type: NOT APPLICABLE / Software - Name: RELION (ver. 4.0) |
-Atomic model buiding 1
Refinement | Space: REAL / Protocol: AB INITIO MODEL / Overall B value: 52 / Target criteria: Correlation coefficient |
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Output model | ![]() PDB-8bfb: |