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- EMDB-35972: CryoEM Structure of 40-Residue Arctic (E22G) Beta-Amyloid Fibril ... -

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Basic information

Entry
Database: EMDB / ID: EMD-35972
TitleCryoEM Structure of 40-Residue Arctic (E22G) Beta-Amyloid Fibril Derived by Co-Analysis with Solid-State NMR | E22G Abeta40
Map data
Sample
  • Complex: Amyloid Fibril of 40-Residue Beta-Amyloid with Arctic (E22G) mutation
    • Protein or peptide: E22G Amyloid-beta
Keywordsamyloid / Alzheimer's / Familial Alzheimer's / PROTEIN FIBRIL
Biological speciesHomo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 2.5 Å
AuthorsTehrani MJ / Matsuda I / Yamagata A / Matsunaga T / Sato M / Toyooka K / Shirouzu M / Ishii Y / Kodama Y / McElheny D / Kobayashi N
Funding support United States, Japan, 4 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)5U01GM098033 United States
Japan Science and TechnologyJPMJMI17A2, Japan Japan
Japan Society for the Promotion of Science (JSPS)JP22K18328, Japan Japan
Japan Society for the Promotion of Science (JSPS)JP21H05733 Japan
CitationJournal: Nat Commun / Year: 2024
Title: E22G Aβ40 fibril structure and kinetics illuminate how Aβ40 rather than Aβ42 triggers familial Alzheimer's.
Authors: Mohammad Jafar Tehrani / Isamu Matsuda / Atsushi Yamagata / Yu Kodama / Tatsuya Matsunaga / Mayuko Sato / Kiminori Toyooka / Dan McElheny / Naohiro Kobayashi / Mikako Shirouzu / Yoshitaka Ishii /
Abstract: Arctic (E22G) mutation in amyloid-β (Aβ enhances Aβ40 fibril accumulation in Alzheimer's disease (AD). Unlike sporadic AD, familial AD (FAD) patients with the mutation exhibit more Aβ40 in the ...Arctic (E22G) mutation in amyloid-β (Aβ enhances Aβ40 fibril accumulation in Alzheimer's disease (AD). Unlike sporadic AD, familial AD (FAD) patients with the mutation exhibit more Aβ40 in the plaque core. However, structural details of E22G Aβ40 fibrils remain elusive, hindering therapeutic progress. Here, we determine a distinctive W-shaped parallel β-sheet structure through co-analysis by cryo-electron microscopy (cryoEM) and solid-state nuclear magnetic resonance (SSNMR) of in-vitro-prepared E22G Aβ40 fibrils. The E22G Aβ40 fibrils displays typical amyloid features in cotton-wool plaques in the FAD, such as low thioflavin-T fluorescence and a less compact unbundled morphology. Furthermore, kinetic and MD studies reveal previously unidentified in-vitro evidence that E22G Aβ40, rather than Aβ42, may trigger Aβ misfolding in the FAD, and prompt subsequent misfolding of wild-type (WT) Aβ40/Aβ42 via cross-seeding. The results provide insight into how the Arctic mutation promotes AD via Aβ40 accumulation and cross-propagation.
History
DepositionApr 19, 2023-
Header (metadata) releaseSep 11, 2024-
Map releaseSep 11, 2024-
UpdateSep 18, 2024-
Current statusSep 18, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_35972.png

Downloads & links

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Map

FileDownload / File: emd_35972.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 300 pix.
= 248.55 Å		0.83 Å/pix.
x 300 pix.
= 248.55 Å		0.83 Å/pix.
x 300 pix.
= 248.55 Å

Surface

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Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.8285 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0154
Minimum - Maximum-0.07681454 - 0.15893324
Average (Standard dev.)0.00011057351 (±0.005201634)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 248.54999 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_35972_msk_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Amyloid Fibril of 40-Residue Beta-Amyloid with Arctic (E22G) mutation

EntireName: Amyloid Fibril of 40-Residue Beta-Amyloid with Arctic (E22G) mutation
Components
  • Complex: Amyloid Fibril of 40-Residue Beta-Amyloid with Arctic (E22G) mutation
    • Protein or peptide: E22G Amyloid-beta

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Supramolecule #1: Amyloid Fibril of 40-Residue Beta-Amyloid with Arctic (E22G) mutation

SupramoleculeName: Amyloid Fibril of 40-Residue Beta-Amyloid with Arctic (E22G) mutation
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Details: In-vitro Prepared Amyloid Fibril of 40-Residue Beta-Amyloid with Arctic (E22G) mutation
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 42577.9 MDa

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Macromolecule #1: E22G Amyloid-beta

MacromoleculeName: E22G Amyloid-beta / type: protein_or_peptide / ID: 1 / Number of copies: 10 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 4.26379 KDa
SequenceString:
DAEFRHDSGY EVHHQKLVFF AGDVGSNKGA IIGLMVGGVV

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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
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 4.77 Å
Applied symmetry - Helical parameters - Δ&Phi: -2.17 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 2.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 151818
Startup modelType of model: NONE
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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