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- PDB-8j47: CryoEM Structure of 40-Residue Arctic (E22G) Beta-Amyloid Fibril ... -

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Basic information

Entry
Database: PDB / ID: 8j47
TitleCryoEM Structure of 40-Residue Arctic (E22G) Beta-Amyloid Fibril Derived by Co-Analysis with Solid-State NMR | E22G Abeta40
ComponentsE22G Amyloid-beta
KeywordsPROTEIN FIBRIL / amyloid / Alzheimer's / Familial Alzheimer's
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 2.5 Å
AuthorsTehrani, M.J. / 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, 4items
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, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Sep 11, 2024Provider: repository / Type: Initial release
Revision 1.1Sep 18, 2024Group: Data collection / Database references / Category: citation / em_admin
Item: _citation.page_last / _citation.pdbx_database_id_PubMed ..._citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
D: E22G Amyloid-beta
C: E22G Amyloid-beta
F: E22G Amyloid-beta
E: E22G Amyloid-beta
B: E22G Amyloid-beta
A: E22G Amyloid-beta
H: E22G Amyloid-beta
G: E22G Amyloid-beta
J: E22G Amyloid-beta
I: E22G Amyloid-beta


Theoretical massNumber of molelcules
Total (without water)42,63810
Polymers42,63810
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, NMR Distance Restraints
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein/peptide
E22G Amyloid-beta


Mass: 4263.790 Da / Num. of mol.: 10 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)

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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: Amyloid Fibril of 40-Residue Beta-Amyloid with Arctic (E22G) mutation
Type: COMPLEX
Details: In-vitro Prepared Amyloid Fibril of 40-Residue Beta-Amyloid with Arctic (E22G) mutation
Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 42577.9 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 500 nm / Cs: 2.7 mm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19.1_4122: / Classification: refinement
EM software
IDNameCategory
7Cootmodel fitting
13PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: -2.17 ° / Axial rise/subunit: 4.77 Å / Axial symmetry: C1
3D reconstructionResolution: 2.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 151818 / Symmetry type: HELICAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0042110
ELECTRON MICROSCOPYf_angle_d0.6552830
ELECTRON MICROSCOPYf_dihedral_angle_d5.42290
ELECTRON MICROSCOPYf_chiral_restr0.057330
ELECTRON MICROSCOPYf_plane_restr0.003360

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