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- PDB-8bfa: Sarkosyl-extracted AppNL-G-F Abeta42 fibril structure -

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Basic information

Entry
Database: PDB / ID: 8bfa
TitleSarkosyl-extracted AppNL-G-F Abeta42 fibril structure
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


negative regulation of presynapse assembly / cytosolic mRNA polyadenylation / collateral sprouting in absence of injury / microglia development / regulation of synapse structure or activity / regulation of Wnt signaling pathway / synaptic assembly at neuromuscular junction / Formyl peptide receptors bind formyl peptides and many other ligands / axo-dendritic transport / axon midline choice point recognition ...negative regulation of presynapse assembly / cytosolic mRNA polyadenylation / collateral sprouting in absence of injury / microglia development / regulation of synapse structure or activity / regulation of Wnt signaling pathway / synaptic assembly at neuromuscular junction / Formyl peptide receptors bind formyl peptides and many other ligands / axo-dendritic transport / axon midline choice point recognition / smooth endoplasmic reticulum calcium ion homeostasis / astrocyte activation involved in immune response / NMDA selective glutamate receptor signaling pathway / mating behavior / regulation of spontaneous synaptic transmission / Golgi-associated vesicle / ciliary rootlet / PTB domain binding / Lysosome Vesicle Biogenesis / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / positive regulation of amyloid fibril formation / neuron remodeling / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / nuclear envelope lumen / COPII-coated ER to Golgi transport vesicle / suckling behavior / signaling receptor activator activity / dendrite development / modulation of excitatory postsynaptic potential / TRAF6 mediated NF-kB activation / presynaptic active zone / neuromuscular process controlling balance / The NLRP3 inflammasome / Advanced glycosylation endproduct receptor signaling / negative regulation of long-term synaptic potentiation / regulation of presynapse assembly / transition metal ion binding / regulation of multicellular organism growth / intracellular copper ion homeostasis / negative regulation of neuron differentiation / ECM proteoglycans / spindle midzone / positive regulation of T cell migration / regulation of peptidyl-tyrosine phosphorylation / smooth endoplasmic reticulum / Purinergic signaling in leishmaniasis infection / protein serine/threonine kinase binding / forebrain development / positive regulation of chemokine production / clathrin-coated pit / Notch signaling pathway / positive regulation of G2/M transition of mitotic cell cycle / positive regulation of protein metabolic process / neuron projection maintenance / positive regulation of peptidyl-threonine phosphorylation / Mitochondrial protein degradation / extracellular matrix organization / ionotropic glutamate receptor signaling pathway / positive regulation of mitotic cell cycle / response to interleukin-1 / axonogenesis / cholesterol metabolic process / positive regulation of calcium-mediated signaling / dendritic shaft / platelet alpha granule lumen / adult locomotory behavior / positive regulation of glycolytic process / positive regulation of interleukin-1 beta production / trans-Golgi network membrane / central nervous system development / learning / positive regulation of long-term synaptic potentiation / endosome lumen / astrocyte activation / locomotory behavior / Post-translational protein phosphorylation / positive regulation of JNK cascade / microglial cell activation / serine-type endopeptidase inhibitor activity / regulation of long-term neuronal synaptic plasticity / synapse organization / TAK1-dependent IKK and NF-kappa-B activation / positive regulation of non-canonical NF-kappaB signal transduction / positive regulation of peptidyl-serine phosphorylation / visual learning / neuromuscular junction / recycling endosome / positive regulation of interleukin-6 production / Golgi lumen / cognition / neuron cellular homeostasis / endocytosis / positive regulation of inflammatory response / cellular response to amyloid-beta / neuron projection development / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / G2/M transition of mitotic cell cycle / positive regulation of tumor necrosis factor production / apical part of cell / cell-cell junction
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 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, mass spectrometry, 50% Abeta1-42, 30% Abeta1-38
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area31870 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: App^NL-G-F, humanised abeta42 with arctic mutation (E22G), processed form of APP cleaved in the brain
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 / Entity ID: all / Source: NATURAL
Molecular weightValue: 4.441 kDa/nm / Experimental value: YES
Source (natural)Organism: Mus musculus (house mouse) / 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
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: 96000 X / Nominal defocus max: 3100 nm / Nominal defocus min: 1600 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: 8 sec. / Electron dose: 52 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 2428
Details: 1925 raw EER frames were collected per image and combined into 40 fractions for processing

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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: 179.352 ° / Axial rise/subunit: 2.418 Å / Axial symmetry: C1
Particle selectionNum. of particles selected: 63680
Details: Manually picked a subset of images to train a model for automatic fibril segment picking in crYOLO
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 2568 / Symmetry type: HELICAL
Atomic model buildingB value: 89 / Protocol: AB INITIO MODEL / Space: REAL / Target criteria: Correlation coefficient

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