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- EMDB-18508: Amyloid-beta 40 quadruplet filament from the leptomeninges of ind... -

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Basic information

Entry
Database: EMDB / ID: EMD-18508
TitleAmyloid-beta 40 quadruplet filament from the leptomeninges of individuals with Alzheimer's disease and cerebral amyloid angiopathy
Map data
Sample
  • Tissue: Amyloid-beta 40
    • Protein or peptide: Amyloid-beta A4 protein
Keywordsamyloid-beta / amyloid / filaments / quadruplet / Abeta40 / human brain / cryo-EM / Alzheimer's disease / cerebral amyloid angiopathy / PROTEIN FIBRIL
Function / homology
Function and homology information


signaling receptor activator activity / Golgi-associated vesicle / clathrin-coated pit / axonogenesis / central nervous system development / heparin binding / growth cone / perikaryon / early endosome / membrane raft ...signaling receptor activator activity / Golgi-associated vesicle / clathrin-coated pit / axonogenesis / central nervous system development / heparin binding / growth cone / perikaryon / early endosome / membrane raft / signaling receptor binding / Golgi apparatus / cell surface / endoplasmic reticulum / extracellular region / nucleus / plasma membrane
Similarity search - Function
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 ...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 / PH-like domain superfamily
Similarity search - Domain/homology
Amyloid-beta A4 protein
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 2.4 Å
AuthorsYang Y / Murzin AS / Peak-Chew SY / Franco C / Newell KL / Ghetti B / Goedert M / Scheres SHW
Funding support United Kingdom, 3 items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom) United Kingdom
Wellcome Trust United Kingdom
Biotechnology and Biological Sciences Research Council (BBSRC) United Kingdom
CitationJournal: Acta Neuropathol Commun / Year: 2023
Title: Cryo-EM structures of Aβ40 filaments from the leptomeninges of individuals with Alzheimer's disease and cerebral amyloid angiopathy.
Authors: Yang Yang / Alexey G Murzin / Sew Peak-Chew / Catarina Franco / Holly J Garringer / Kathy L Newell / Bernardino Ghetti / Michel Goedert / Sjors H W Scheres /
Abstract: We used electron cryo-microscopy (cryo-EM) to determine the structures of Aβ40 filaments from the leptomeninges of individuals with Alzheimer's disease and cerebral amyloid angiopathy. In agreement ...We used electron cryo-microscopy (cryo-EM) to determine the structures of Aβ40 filaments from the leptomeninges of individuals with Alzheimer's disease and cerebral amyloid angiopathy. In agreement with previously reported structures, which were solved to a resolution of 4.4 Å, we found three types of filaments. However, our new structures, solved to a resolution of 2.4 Å, revealed differences in the sequence assignment that redefine the fold of Aβ40 peptides and their interactions. Filaments are made of pairs of protofilaments, the ordered core of which comprises D1-G38. The different filament types comprise one, two or three protofilament pairs. In each pair, residues H14-G37 of both protofilaments adopt an extended conformation and pack against each other in an anti-parallel fashion, held together by hydrophobic interactions and hydrogen bonds between main chains and side chains. Residues D1-H13 fold back on the adjacent parts of their own chains through both polar and non-polar interactions. There are also several additional densities of unknown identity. Sarkosyl extraction and aqueous extraction gave the same structures. By cryo-EM, parenchymal deposits of Aβ42 and blood vessel deposits of Aβ40 have distinct structures, supporting the view that Alzheimer's disease and cerebral amyloid angiopathy are different Aβ proteinopathies.
History
DepositionSep 25, 2023-
Header (metadata) releaseDec 13, 2023-
Map releaseDec 13, 2023-
UpdateJan 31, 2024-
Current statusJan 31, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_18508.png

Downloads & links

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Map

FileDownload / File: emd_18508.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.74 Å/pix.
x 320 pix.
= 238.08 Å		0.74 Å/pix.
x 320 pix.
= 238.08 Å		0.74 Å/pix.
x 320 pix.
= 238.08 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.744 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0065
Minimum - Maximum-0.019224355 - 0.038179643
Average (Standard dev.)0.0001253719 (±0.0021171707)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 238.08 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_18508_msk_1.map
Projections & Slices
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Half map: #2

Fileemd_18508_half_map_1.map
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Half map: #1

Fileemd_18508_half_map_2.map
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Sample components

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Entire : Amyloid-beta 40

EntireName: Amyloid-beta 40
Components
  • Tissue: Amyloid-beta 40
    • Protein or peptide: Amyloid-beta A4 protein

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Supramolecule #1: Amyloid-beta 40

SupramoleculeName: Amyloid-beta 40 / type: tissue / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Amyloid-beta A4 protein

MacromoleculeName: Amyloid-beta A4 protein / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 4.335852 KDa
SequenceString:
DAEFRHDSGY EVHHQKLVFF AEDVGSNKGA IIGLMVGGVV

UniProtKB: Amyloid-beta A4 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: FEI FALCON IV (4k 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: 2.4 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: 4.87 Å
Applied symmetry - Helical parameters - Δ&Phi: -0.78 °
Applied symmetry - Helical parameters - Axial symmetry: C2 (2 fold cyclic)
Resolution.type: BY AUTHOR / Resolution: 2.4 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 81140
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

7q4b

Final angle assignmentType: NOT APPLICABLE / Software - Name: RELION
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

7q4b


Chain - Source name: PDB / Chain - Initial model type: experimental model
Output model

PDB-8qn6:
Amyloid-beta 40 type 2 filament from the leptomeninges of individual with Alzheimer's disease and cerebral amyloid angiopathy

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