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- EMDB-16019: Sarkosyl-extracted AppNL-G-F Abeta42 fibril structure (Methoxy-X0... -

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Basic information

Entry
Database: EMDB / ID: EMD-16019
TitleSarkosyl-extracted AppNL-G-F Abeta42 fibril structure (Methoxy-X04-labelled mice)
Map dataCryoEM map for extracted AppNLGF Abeta42 fibril after MOX04 labelling
Sample
  • Complex: Sarkosyl-extracted AppNL-G-F Abeta42 fibril
    • Protein or peptide: Amyloid-beta precursor protein
KeywordsAmyloid / fibril / helical / cross-beta / beta amyloid / PROTEIN FIBRIL / ex vivo / arctic mutant / alzheimers disease
Function / homology
Function and homology information


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 / smooth endoplasmic reticulum calcium ion homeostasis / axon midline choice point recognition / 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 / positive regulation of amyloid fibril formation / neuron remodeling / : / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / suckling behavior / nuclear envelope lumen / dendrite development / COPII-coated ER to Golgi transport vesicle / presynaptic active zone / modulation of excitatory postsynaptic potential / 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 / intracellular copper ion homeostasis / negative regulation of neuron differentiation / ECM proteoglycans / smooth endoplasmic reticulum / positive regulation of T cell migration / spindle midzone / Purinergic signaling in leishmaniasis infection / positive regulation of calcium-mediated signaling / protein serine/threonine kinase binding / positive regulation of chemokine production / clathrin-coated pit / regulation of peptidyl-tyrosine phosphorylation / forebrain development / Notch signaling pathway / Mitochondrial protein degradation / neuron projection maintenance / positive regulation of G2/M transition of mitotic cell cycle / positive regulation of protein metabolic process / ionotropic glutamate receptor signaling pathway / positive regulation of glycolytic process / cholesterol metabolic process / positive regulation of mitotic cell cycle / response to interleukin-1 / adult locomotory behavior / extracellular matrix organization / axonogenesis / platelet alpha granule lumen / trans-Golgi network membrane / positive regulation of peptidyl-threonine phosphorylation / dendritic shaft / learning / positive regulation of interleukin-1 beta production / positive regulation of long-term synaptic potentiation / locomotory behavior / central nervous system development / endosome lumen / astrocyte activation / positive regulation of JNK cascade / Post-translational protein phosphorylation / synapse organization / regulation of long-term neuronal synaptic plasticity / microglial cell activation / TAK1-dependent IKK and NF-kappa-B activation / visual learning / serine-type endopeptidase inhibitor activity / neuromuscular junction / recycling endosome / cognition / neuron cellular homeostasis / Golgi lumen / positive regulation of inflammatory response / positive regulation of non-canonical NF-kappaB signal transduction / endocytosis / cellular response to amyloid-beta / G2/M transition of mitotic cell cycle / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / positive regulation of interleukin-6 production / positive regulation of tumor necrosis factor production / neuron projection development / cell-cell junction / synaptic vesicle
Similarity search - Function
Amyloidogenic glycoprotein, copper-binding / Amyloidogenic glycoprotein, copper-binding domain conserved site / Amyloidogenic glycoprotein, copper-binding domain superfamily / Copper-binding of amyloid precursor, CuBD / Amyloid precursor protein (APP) copper-binding (CuBD) domain signature. / Amyloidogenic glycoprotein, amyloid-beta peptide superfamily / Beta-amyloid peptide (beta-APP) / Amyloidogenic glycoprotein, amyloid-beta peptide / Beta-amyloid precursor protein C-terminal / Amyloidogenic glycoprotein, intracellular domain, conserved site ...Amyloidogenic glycoprotein, copper-binding / Amyloidogenic glycoprotein, copper-binding domain conserved site / Amyloidogenic glycoprotein, copper-binding domain superfamily / Copper-binding of amyloid precursor, CuBD / Amyloid precursor protein (APP) copper-binding (CuBD) domain signature. / Amyloidogenic glycoprotein, amyloid-beta peptide superfamily / Beta-amyloid peptide (beta-APP) / Amyloidogenic glycoprotein, amyloid-beta peptide / Beta-amyloid precursor protein C-terminal / Amyloidogenic glycoprotein, intracellular domain, conserved site / Beta-amyloid precursor protein C-terminus / Amyloid precursor protein (APP) intracellular domain signature. / Amyloid precursor protein (APP) E1 domain profile. / Amyloid precursor protein (APP) E2 domain profile. / Amyloidogenic glycoprotein, extracellular / Amyloidogenic glycoprotein, heparin-binding / Amyloidogenic glycoprotein, E2 domain / E2 domain superfamily / Amyloidogenic glycoprotein, heparin-binding domain superfamily / Amyloid A4 N-terminal heparin-binding / E2 domain of amyloid precursor protein / amyloid A4 / Amyloidogenic glycoprotein / Proteinase inhibitor I2, Kunitz, conserved site / Pancreatic trypsin inhibitor (Kunitz) family signature. / BPTI/Kunitz family of serine protease inhibitors. / Pancreatic trypsin inhibitor Kunitz domain / Kunitz/Bovine pancreatic trypsin inhibitor domain / Pancreatic trypsin inhibitor (Kunitz) family profile. / Pancreatic trypsin inhibitor Kunitz domain superfamily / PH-like domain superfamily
Similarity search - Domain/homology
Amyloid-beta precursor protein
Similarity search - Component
Biological speciesMus musculus (house mouse) / house mouse (house mouse)
Methodhelical reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsWilkinson M / Leistner C / Burgess A / Goodfellow S / Deuchars S / Ranson NA / Radford SE / Frank RAW
Funding support United Kingdom, 2 items
OrganizationGrant numberCountry
Wellcome Trust United Kingdom
Medical Research Council (MRC, United Kingdom) United Kingdom
CitationJournal: Nat Commun / Year: 2023
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
DepositionOct 24, 2022-
Header (metadata) releaseMay 31, 2023-
Map releaseMay 31, 2023-
UpdateMay 31, 2023-
Current statusMay 31, 2023Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_16019.png

Downloads & links

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Map

FileDownload / File: emd_16019.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryoEM map for extracted AppNLGF Abeta42 fibril after MOX04 labelling
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.94 Å/pix.
x 256 pix.
= 240.64 Å		0.94 Å/pix.
x 256 pix.
= 240.64 Å		0.94 Å/pix.
x 256 pix.
= 240.64 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.94 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.012
Minimum - Maximum-0.042240314 - 0.06871328
Average (Standard dev.)0.00016212047 (±0.003495169)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 240.64 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: halfmap2

Fileemd_16019_half_map_1.map
Annotationhalfmap2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: halfmap1

Fileemd_16019_half_map_2.map
Annotationhalfmap1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Sarkosyl-extracted AppNL-G-F Abeta42 fibril

EntireName: Sarkosyl-extracted AppNL-G-F Abeta42 fibril
Components
  • Complex: Sarkosyl-extracted AppNL-G-F Abeta42 fibril
    • Protein or peptide: Amyloid-beta precursor protein

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Supramolecule #1: Sarkosyl-extracted AppNL-G-F Abeta42 fibril

SupramoleculeName: 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
Source (natural)Organism: Mus musculus (house mouse) / Strain: AppNLGF / Tissue: Brain
Molecular weightTheoretical: 4.441 kDa/nm

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Macromolecule #1: Amyloid-beta precursor protein

MacromoleculeName: 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
Source (natural)Organism: house mouse (house mouse) / Tissue: Brain
Molecular weightTheoretical: 4.448025 KDa
SequenceString:
DAEFRHDSGY EVHHQKLVFF AGDVGSNKGA IIGLMVGGVV IA

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statefilament

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Sample preparation

BufferpH: 7.4
Component:
ConcentrationFormulaName
50.0 mMNaClsodium chloride
20.0 mMTris-HCl
GridModel: 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.
VitrificationCryogen name: ETHANE / Chamber humidity: 90 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV / Details: 6s blot.
DetailsSarkosyl-insoluble fibrils from App^NL-G-F mouse brain labelled with Methoxy-X04

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Specialist opticsEnergy filter - Name: TFS Selectris / Energy filter - Slit width: 10 eV
Image recordingFilm 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 beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 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 stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied 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
Segment selectionNumber selected: 136214 / Software - Name: crYOLO
Details: Manually picked a subset of images to train a model for automatic fibril segment picking in crYOLO
Startup modelType of model: INSILICO MODEL
Details: Model generated from 2D class averages using relion_helix_inimodel2d
Final angle assignmentType: NOT APPLICABLE / Software - Name: RELION (ver. 4.0)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: AB INITIO MODEL / Overall B value: 52 / Target criteria: Correlation coefficient
Output model

PDB-8bfb:
Sarkosyl-extracted AppNL-G-F Abeta42 fibril structure (Methoxy-X04-labelled mice)

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