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- PDB-8bfb: Sarkosyl-extracted AppNL-G-F Abeta42 fibril structure (Methoxy-X0... -

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Basic information

Entry
Database: PDB / ID: 8bfb
TitleSarkosyl-extracted AppNL-G-F Abeta42 fibril structure (Methoxy-X04-labelled mice)
ComponentsAmyloid-beta precursor protein
KeywordsPROTEIN FIBRIL / Amyloid / fibril / helical / cross-beta / beta amyloid / ex vivo / arctic mutant / alzheimers disease
Function / homology
Function and homology information


amyloid-beta complex / growth cone lamellipodium / cellular response to norepinephrine stimulus / growth cone filopodium / microglia development / collateral sprouting in absence of injury / Formyl peptide receptors bind formyl peptides and many other ligands / axo-dendritic transport / regulation of Wnt signaling pathway / hippocampal neuron apoptotic process ...amyloid-beta complex / growth cone lamellipodium / cellular response to norepinephrine stimulus / growth cone filopodium / microglia development / collateral sprouting in absence of injury / Formyl peptide receptors bind formyl peptides and many other ligands / axo-dendritic transport / regulation of Wnt signaling pathway / hippocampal neuron apoptotic process / axon midline choice point recognition / astrocyte activation involved in immune response / regulation of synapse structure or activity / NMDA selective glutamate receptor signaling pathway / regulation of spontaneous synaptic transmission / mating behavior / growth factor receptor binding / peptidase activator activity / Golgi-associated vesicle / PTB domain binding / positive regulation of amyloid fibril formation / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / astrocyte projection / Lysosome Vesicle Biogenesis / neuron remodeling / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / nuclear envelope lumen / dendrite development / positive regulation of protein metabolic process / TRAF6 mediated NF-kB activation / signaling receptor activator activity / negative regulation of long-term synaptic potentiation / Advanced glycosylation endproduct receptor signaling / modulation of excitatory postsynaptic potential / transition metal ion binding / main axon / The NLRP3 inflammasome / regulation of multicellular organism growth / intracellular copper ion homeostasis / ECM proteoglycans / regulation of presynapse assembly / positive regulation of T cell migration / neuronal dense core vesicle / response to insulin-like growth factor stimulus / Purinergic signaling in leishmaniasis infection / positive regulation of chemokine production / Notch signaling pathway / cellular response to manganese ion / swimming behavior / clathrin-coated pit / extracellular matrix organization / neuron projection maintenance / astrocyte activation / Mitochondrial protein degradation / ionotropic glutamate receptor signaling pathway / positive regulation of calcium-mediated signaling / positive regulation of mitotic cell cycle / protein serine/threonine kinase binding / axonogenesis / response to interleukin-1 / regulation of neuron apoptotic process / platelet alpha granule lumen / cellular response to copper ion / cellular response to cAMP / positive regulation of glycolytic process / central nervous system development / dendritic shaft / trans-Golgi network membrane / endosome lumen / positive regulation of long-term synaptic potentiation / positive regulation of interleukin-1 beta production / adult locomotory behavior / learning / Post-translational protein phosphorylation / locomotory behavior / serine-type endopeptidase inhibitor activity / microglial cell activation / positive regulation of non-canonical NF-kappaB signal transduction / cellular response to nerve growth factor stimulus / TAK1-dependent IKK and NF-kappa-B activation / recycling endosome / regulation of long-term neuronal synaptic plasticity / synapse organization / visual learning / positive regulation of JNK cascade / response to lead ion / Golgi lumen / positive regulation of interleukin-6 production / cognition / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / cellular response to amyloid-beta / endocytosis / neuron projection development / positive regulation of tumor necrosis factor production / positive regulation of inflammatory response / calcium ion transport / Platelet degranulation / regulation of translation / heparin binding / regulation of gene expression
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. / 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 precursor protein (APP) E1 domain profile. / Amyloid precursor protein (APP) E2 domain profile. / 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)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsWilkinson, M. / Leistner, C. / Burgess, A. / Goodfellow, S. / Deuchars, S. / Ranson, N.A. / Radford, S.E. / Frank, R.A.W.
Funding support United Kingdom, 2items
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, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 31, 2023Provider: repository / Type: Initial release
Revision 1.1Jul 24, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond / em_admin / Item: _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Amyloid-beta precursor protein
B: Amyloid-beta precursor protein
C: Amyloid-beta precursor protein
D: Amyloid-beta precursor protein
E: Amyloid-beta precursor protein
F: Amyloid-beta precursor protein
G: Amyloid-beta precursor protein
H: Amyloid-beta precursor protein
I: Amyloid-beta precursor protein
J: Amyloid-beta precursor protein


Theoretical massNumber of molelcules
Total (without water)44,48010
Polymers44,48010
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area31920 Å2
ΔGint-117 kcal/mol
Surface area14550 Å2

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Components

#1: Protein/peptide
Amyloid-beta precursor protein / APP / ABPP / APPI / Alzheimer disease amyloid A4 protein homolog / Alzheimer disease amyloid ...APP / ABPP / APPI / Alzheimer disease amyloid A4 protein homolog / Alzheimer disease amyloid protein / Amyloid precursor protein / Amyloid-beta (A4) precursor protein / Amyloid-beta A4 protein / Cerebral vascular amyloid peptide / CVAP / PreA4 / Protease nexin-II / PN-II


Mass: 4448.025 Da / Num. of mol.: 10 / Source method: isolated from a natural source
Details: Humanised Abeta42 from App^NL-G-F mice with arctic mutation (E22G)
Source: (natural) Mus musculus (house mouse) / Tissue: Brain / References: UniProt: P05067

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: FILAMENT / 3D reconstruction method: helical reconstruction

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Sample preparation

ComponentName: Sarkosyl-extracted AppNL-G-F Abeta42 fibril / Type: COMPLEX
Details: Fibrils purified from mouse brain labelled with Methoxy-X04
Entity ID: all / Source: NATURAL
Molecular weightValue: 4.441 kDa/nm / Experimental value: NO
Source (natural)Organism: Mus musculus (house mouse) / Strain: AppNLGF / Tissue: Brain
Buffer solutionpH: 7.4
Buffer component
IDConc.NameFormulaBuffer-ID
150 mMsodium chlorideNaCl1
220 mMTris-HCl1
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: Sarkosyl-insoluble fibrils from App^NL-G-F mouse brain labelled with Methoxy-X04
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: C-flat-1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 90 % / Chamber temperature: 277 K / Details: 6s blot

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 130000 X / Nominal defocus max: 2900 nm / Nominal defocus min: 1400 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm / Alignment procedure: COMA FREE
Specimen holderSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 6 sec. / Electron dose: 41 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 4165
Details: 1442 raw EER frames were collected per image and combined into 40 fractions for processing
EM imaging opticsEnergyfilter name: TFS Selectris / Energyfilter slit width: 10 eV

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Processing

EM software
IDNameVersionCategory
1crYOLOparticle selection
2EPUimage acquisition
4CTFFINDCTF correction
7Cootmodel fitting
9RELION4initial Euler assignment
10RELION4final Euler assignment
11RELION4classification
12RELION43D reconstruction
13PHENIX1.17model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: 179.355 ° / Axial rise/subunit: 2.414 Å / Axial symmetry: C1
Particle selectionNum. of particles selected: 136214
Details: Manually picked a subset of images to train a model for automatic fibril segment picking in crYOLO
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 3640 / Symmetry type: HELICAL
Atomic model buildingB value: 52 / Protocol: AB INITIO MODEL / Space: REAL / Target criteria: Correlation coefficient

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