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- EMDB-16027: Murine amyloid-beta filaments with the Arctic mutation (E22G) fro... -

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Basic information

Entry
Database: EMDB / ID: EMD-16027
TitleMurine amyloid-beta filaments with the Arctic mutation (E22G) from APP(NL-G-F) mouse brains | ABeta
Map data
Sample
  • Tissue: Amyloid-beta filaments extracted from the mouse brains with APP NL-G-F mutations
    • Protein or peptide: Amyloid-beta protein 40
KeywordsAmyloid / amyloid-beta / Arctic mutation / APP / NL-G-F / mouse brains / filaments / E22G / E693G / PROTEIN FIBRIL
Function / homology
Function and homology information


Formyl peptide receptors bind formyl peptides and many other ligands / Advanced glycosylation endproduct receptor signaling / ECM proteoglycans / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / TRAF6 mediated NF-kB activation / Lysosome Vesicle Biogenesis / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / Post-translational protein phosphorylation / TAK1-dependent IKK and NF-kappa-B activation / G alpha (q) signalling events ...Formyl peptide receptors bind formyl peptides and many other ligands / Advanced glycosylation endproduct receptor signaling / ECM proteoglycans / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / TRAF6 mediated NF-kB activation / Lysosome Vesicle Biogenesis / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / Post-translational protein phosphorylation / TAK1-dependent IKK and NF-kappa-B activation / G alpha (q) signalling events / G alpha (i) signalling events / Platelet degranulation / central nervous system neuron differentiation / Mitochondrial protein degradation / negative regulation of presynapse assembly / collateral sprouting in absence of injury / cytosolic mRNA polyadenylation / synaptic assembly at neuromuscular junction / regulation of synapse structure or activity / axo-dendritic transport / axon midline choice point recognition / smooth endoplasmic reticulum calcium ion homeostasis / mating behavior / ciliary rootlet / Golgi-associated vesicle / neuron remodeling / suckling behavior / COPII-coated ER to Golgi transport vesicle / intracellular vesicle / dendrite development / presynaptic active zone / signaling receptor activator activity / neuromuscular process controlling balance / transition metal ion binding / regulation of multicellular organism growth / intracellular copper ion homeostasis / negative regulation of neuron differentiation / spindle midzone / forebrain development / smooth endoplasmic reticulum / clathrin-coated pit / Notch signaling pathway / positive regulation of G2/M transition of mitotic cell cycle / extracellular matrix organization / ionotropic glutamate receptor signaling pathway / axonogenesis / cholesterol metabolic process / positive regulation of mitotic cell cycle / adult locomotory behavior / locomotory behavior / serine-type endopeptidase inhibitor activity / visual learning / recycling endosome / neuromuscular junction / cognition / long-term synaptic potentiation / memory / neuron cellular homeostasis / endocytosis / neuron projection development / neuron differentiation / G2/M transition of mitotic cell cycle / apical part of cell / synaptic vesicle / cell-cell junction / mitotic cell cycle / heparin binding / regulation of gene expression / regulation of translation / growth cone / cytoplasmic vesicle / perikaryon / neuron apoptotic process / response to oxidative stress / gene expression / early endosome / neuron projection / receptor complex / cell adhesion / RNA polymerase II cis-regulatory region sequence-specific DNA binding / protein domain specific binding / axon / protein kinase binding / perinuclear region of cytoplasm / cell surface / endoplasmic reticulum / Golgi apparatus / positive regulation of transcription by RNA polymerase II / extracellular region / identical protein binding / nucleus / membrane / plasma membrane / cytoplasm
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. / 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 ...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. / 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)
Methodhelical reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsYang Y / Zhang WJ / Murzin AG / Schweighauser M / Huang M / Lovestam SKA / Peak-Chew SY / Macdonald J / Lavenir I / Ghetti B ...Yang Y / Zhang WJ / Murzin AG / Schweighauser M / Huang M / Lovestam SKA / Peak-Chew SY / Macdonald J / Lavenir I / Ghetti B / Graff C / Kumar A / Nordber A / Goedert M / Scheres SHW
Funding support United Kingdom, 2 items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MC_UP_A025-1013 United Kingdom
Medical Research Council (MRC, United Kingdom)MC_U105184291 United Kingdom
CitationJournal: Acta Neuropathol / Year: 2023
Title: Cryo-EM structures of amyloid-β filaments with the Arctic mutation (E22G) from human and mouse brains.
Authors: Yang Yang / Wenjuan Zhang / Alexey G Murzin / Manuel Schweighauser / Melissa Huang / Sofia Lövestam / Sew Y Peak-Chew / Takashi Saito / Takaomi C Saido / Jennifer Macdonald / Isabelle ...Authors: Yang Yang / Wenjuan Zhang / Alexey G Murzin / Manuel Schweighauser / Melissa Huang / Sofia Lövestam / Sew Y Peak-Chew / Takashi Saito / Takaomi C Saido / Jennifer Macdonald / Isabelle Lavenir / Bernardino Ghetti / Caroline Graff / Amit Kumar / Agneta Nordberg / Michel Goedert / Sjors H W Scheres /
Abstract: The Arctic mutation, encoding E693G in the amyloid precursor protein (APP) gene [E22G in amyloid-β (Aβ)], causes dominantly inherited Alzheimer's disease. Here, we report the high-resolution cryo- ...The Arctic mutation, encoding E693G in the amyloid precursor protein (APP) gene [E22G in amyloid-β (Aβ)], causes dominantly inherited Alzheimer's disease. Here, we report the high-resolution cryo-EM structures of Aβ filaments from the frontal cortex of a previously described case (AβPParc1) with the Arctic mutation. Most filaments consist of two pairs of non-identical protofilaments that comprise residues V12-V40 (human Arctic fold A) and E11-G37 (human Arctic fold B). They have a substructure (residues F20-G37) in common with the folds of type I and type II Aβ42. When compared to the structures of wild-type Aβ42 filaments, there are subtle conformational changes in the human Arctic folds, because of the lack of a side chain at G22, which may strengthen hydrogen bonding between mutant Aβ molecules and promote filament formation. A minority of Aβ42 filaments of type II was also present, as were tau paired helical filaments. In addition, we report the cryo-EM structures of Aβ filaments with the Arctic mutation from mouse knock-in line App. Most filaments are made of two identical mutant protofilaments that extend from D1 to G37 (App murine Arctic fold). In a minority of filaments, two dimeric folds pack against each other in an anti-parallel fashion. The App murine Arctic fold differs from the human Arctic folds, but shares some substructure.
History
DepositionOct 27, 2022-
Header (metadata) releaseJan 18, 2023-
Map releaseJan 18, 2023-
UpdateMar 5, 2025-
Current statusMar 5, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_16027.png

Downloads & links

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Map

FileDownload / File: emd_16027.map.gz / Format: CCP4 / Size: 30.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1.2 Å/pix.
x 200 pix.
= 240.8 Å		1.2 Å/pix.
x 200 pix.
= 240.8 Å		1.2 Å/pix.
x 200 pix.
= 240.8 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.204 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.03
Minimum - Maximum-0.05223707 - 0.084781475
Average (Standard dev.)0.00048409565 (±0.005094125)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions200200200
Spacing200200200
CellA=B=C: 240.8 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_16027_msk_1.map
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Half map: #1

Fileemd_16027_half_map_1.map
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Half map: #2

Fileemd_16027_half_map_2.map
Projections & Slices
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Sample components

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Entire : Amyloid-beta filaments extracted from the mouse brains with APP N...

EntireName: Amyloid-beta filaments extracted from the mouse brains with APP NL-G-F mutations
Components
  • Tissue: Amyloid-beta filaments extracted from the mouse brains with APP NL-G-F mutations
    • Protein or peptide: Amyloid-beta protein 40

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Supramolecule #1: Amyloid-beta filaments extracted from the mouse brains with APP N...

SupramoleculeName: Amyloid-beta filaments extracted from the mouse brains with APP NL-G-F mutations
type: tissue / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Mus musculus (house mouse)

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Macromolecule #1: Amyloid-beta protein 40

MacromoleculeName: Amyloid-beta protein 40 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 4.008476 KDa
SequenceString:
DAEFRHDSGY EVHHQKLVFF AGDVGSNKGA IIGLMVG

UniProtKB: Amyloid-beta precursor protein

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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: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.6 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 2.46009 Å
Applied symmetry - Helical parameters - Δ&Phi: 179.347 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 39823
Startup modelType of model: NONE
Final angle assignmentType: NOT APPLICABLE / Software - Name: RELION
FSC plot (resolution estimation)

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