Amyloid β 42 fibril structure based on small-angle scattering
Lattanzi, Veronica LU ; Andre, Ingemar LU
; Gasser, Urs
; Dubackic, Marija
LU
; Olsson, Ulf
LU
and Linse, Sara
LU
(2021)
In Proceedings of the National Academy of Sciences of the United States of America
118(48).
- Abstract
Amyloid fibrils are associated with a number of neurodegenerative diseases, including fibrils of amyloid β42 peptide (Aβ42) in Alzheimer's disease. These fibrils are a source of toxicity to neuronal cells through surface-catalyzed generation of toxic oligomers. Detailed knowledge of the fibril structure may thus facilitate therapeutic development. We use small-angle scattering to provide information on the fibril cross-section dimension and shape for Aβ42 fibrils prepared in aqueous phosphate buffer at pH = 7.4 and pH 8.0 under quiescent conditions at 37°C from pure recombinant Aβ42 peptide. Fitting the data using a continuum model reveals an elliptical cross-section and a peptide mass-per-unit length compatible with two filaments of... (More)
Amyloid fibrils are associated with a number of neurodegenerative diseases, including fibrils of amyloid β42 peptide (Aβ42) in Alzheimer's disease. These fibrils are a source of toxicity to neuronal cells through surface-catalyzed generation of toxic oligomers. Detailed knowledge of the fibril structure may thus facilitate therapeutic development. We use small-angle scattering to provide information on the fibril cross-section dimension and shape for Aβ42 fibrils prepared in aqueous phosphate buffer at pH = 7.4 and pH 8.0 under quiescent conditions at 37°C from pure recombinant Aβ42 peptide. Fitting the data using a continuum model reveals an elliptical cross-section and a peptide mass-per-unit length compatible with two filaments of two monomers, four monomers per plane. To provide a more detailed atomistic model, the data were fitted using as a starting state a high-resolution structure of the two-monomer arrangement in filaments from solid-state NMR (Protein Data Bank ID 5kk3). First, a twofold symmetric model including residues 11 to 42 of two monomers in the filament was optimized in terms of twist angle and local packing using Rosetta. A two-filament model was then built and optimized through fitting to the scattering data allowing the two N-termini in each filament to take different conformations, with the same conformation in each of the two filaments. This provides an atomistic model of the fibril with twofold rotation symmetry around the fibril axis. Intriguingly, no polydispersity as regards the number of filaments was observed in our system over separate samples, suggesting that the two-filament arrangement represents a free energy minimum for the Aβ42 fibril.
(Less)
- author
- Lattanzi, Veronica
LU
; Andre, Ingemar
LU
; Gasser, Urs
; Dubackic, Marija
LU
; Olsson, Ulf
LU
and Linse, Sara
LU
- organization
- publishing date
- 2021-11
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Amyloid-beta, Atomistic model, Fibril structure in solution, Number of filaments, SAXS/SANS
- in
- Proceedings of the National Academy of Sciences of the United States of America
- volume
- 118
- issue
- 48
- article number
- e2112783118
- publisher
- National Academy of Sciences
- external identifiers
-
- scopus:85120344320
- pmid:34815346
- ISSN
- 0027-8424
- DOI
- 10.1073/pnas.2112783118
- language
- English
- LU publication?
- yes
- id
- a82566c1-b95c-4bab-ab2b-5d437d15e860
- date added to LUP
- 2021-12-15 11:56:42
- date last changed
- 2024-06-15 22:44:59
@article{a82566c1-b95c-4bab-ab2b-5d437d15e860,
abstract = {{<p>Amyloid fibrils are associated with a number of neurodegenerative diseases, including fibrils of amyloid β42 peptide (Aβ42) in Alzheimer's disease. These fibrils are a source of toxicity to neuronal cells through surface-catalyzed generation of toxic oligomers. Detailed knowledge of the fibril structure may thus facilitate therapeutic development. We use small-angle scattering to provide information on the fibril cross-section dimension and shape for Aβ42 fibrils prepared in aqueous phosphate buffer at pH = 7.4 and pH 8.0 under quiescent conditions at 37°C from pure recombinant Aβ42 peptide. Fitting the data using a continuum model reveals an elliptical cross-section and a peptide mass-per-unit length compatible with two filaments of two monomers, four monomers per plane. To provide a more detailed atomistic model, the data were fitted using as a starting state a high-resolution structure of the two-monomer arrangement in filaments from solid-state NMR (Protein Data Bank ID 5kk3). First, a twofold symmetric model including residues 11 to 42 of two monomers in the filament was optimized in terms of twist angle and local packing using Rosetta. A two-filament model was then built and optimized through fitting to the scattering data allowing the two N-termini in each filament to take different conformations, with the same conformation in each of the two filaments. This provides an atomistic model of the fibril with twofold rotation symmetry around the fibril axis. Intriguingly, no polydispersity as regards the number of filaments was observed in our system over separate samples, suggesting that the two-filament arrangement represents a free energy minimum for the Aβ42 fibril.</p>}},
author = {{Lattanzi, Veronica and Andre, Ingemar and Gasser, Urs and Dubackic, Marija and Olsson, Ulf and Linse, Sara}},
issn = {{0027-8424}},
keywords = {{Amyloid-beta; Atomistic model; Fibril structure in solution; Number of filaments; SAXS/SANS}},
language = {{eng}},
number = {{48}},
publisher = {{National Academy of Sciences}},
series = {{Proceedings of the National Academy of Sciences of the United States of America}},
title = {{Amyloid β 42 fibril structure based on small-angle scattering}},
url = {{http://dx.doi.org/10.1073/pnas.2112783118}},
doi = {{10.1073/pnas.2112783118}},
volume = {{118}},
year = {{2021}},
}