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Morphology-Dependent Interactions between α-Synuclein Monomers and Fibrils

Pálmadóttir, Tinna LU ; Waudby, Christopher A. ; Bernfur, Katja LU ; Christodoulou, John ; Linse, Sara LU and Malmendal, Anders LU (2023) In International Journal of Molecular Sciences 24(6).
Abstract

Amyloid fibrils may adopt different morphologies depending on the solution conditions and the protein sequence. Here, we show that two chemically identical but morphologically distinct α-synuclein fibrils can form under identical conditions. This was observed by nuclear magnetic resonance (NMR), circular dichroism (CD), and fluorescence spectroscopy, as well as by cryo-transmission electron microscopy (cryo-TEM). The results show different surface properties of the two morphologies, A and B. NMR measurements show that monomers interact differently with the different fibril surfaces. Only a small part of the N-terminus of the monomer interacts with the fibril surface of morphology A, compared to a larger part of the monomer for... (More)

Amyloid fibrils may adopt different morphologies depending on the solution conditions and the protein sequence. Here, we show that two chemically identical but morphologically distinct α-synuclein fibrils can form under identical conditions. This was observed by nuclear magnetic resonance (NMR), circular dichroism (CD), and fluorescence spectroscopy, as well as by cryo-transmission electron microscopy (cryo-TEM). The results show different surface properties of the two morphologies, A and B. NMR measurements show that monomers interact differently with the different fibril surfaces. Only a small part of the N-terminus of the monomer interacts with the fibril surface of morphology A, compared to a larger part of the monomer for morphology B. Differences in ThT binding seen by fluorescence titrations, and mesoscopic structures seen by cryo-TEM, support the conclusion of the two morphologies having different surface properties. Fibrils of morphology B were found to have lower solubility than A. This indicates that fibrils of morphology B are thermodynamically more stable, implying a chemical potential of fibrils of morphology B that is lower than that of morphology A. Consequently, at prolonged incubation time, fibrils of morphology B remained B, while an initially monomorphic sample of morphology A gradually transformed to B.

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author
; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
aggregation, monomorphic, morphology, NMR spectroscopy, polymorphic, self-assembly, stability
in
International Journal of Molecular Sciences
volume
24
issue
6
article number
5191
publisher
MDPI AG
external identifiers
  • pmid:36982264
  • scopus:85151947730
ISSN
1661-6596
DOI
10.3390/ijms24065191
language
English
LU publication?
yes
id
43e9a10e-1ea8-466b-96ed-b1d211c4c8b9
date added to LUP
2023-09-20 16:10:17
date last changed
2024-04-19 01:13:05
@article{43e9a10e-1ea8-466b-96ed-b1d211c4c8b9,
  abstract     = {{<p>Amyloid fibrils may adopt different morphologies depending on the solution conditions and the protein sequence. Here, we show that two chemically identical but morphologically distinct α-synuclein fibrils can form under identical conditions. This was observed by nuclear magnetic resonance (NMR), circular dichroism (CD), and fluorescence spectroscopy, as well as by cryo-transmission electron microscopy (cryo-TEM). The results show different surface properties of the two morphologies, A and B. NMR measurements show that monomers interact differently with the different fibril surfaces. Only a small part of the N-terminus of the monomer interacts with the fibril surface of morphology A, compared to a larger part of the monomer for morphology B. Differences in ThT binding seen by fluorescence titrations, and mesoscopic structures seen by cryo-TEM, support the conclusion of the two morphologies having different surface properties. Fibrils of morphology B were found to have lower solubility than A. This indicates that fibrils of morphology B are thermodynamically more stable, implying a chemical potential of fibrils of morphology B that is lower than that of morphology A. Consequently, at prolonged incubation time, fibrils of morphology B remained B, while an initially monomorphic sample of morphology A gradually transformed to B.</p>}},
  author       = {{Pálmadóttir, Tinna and Waudby, Christopher A. and Bernfur, Katja and Christodoulou, John and Linse, Sara and Malmendal, Anders}},
  issn         = {{1661-6596}},
  keywords     = {{aggregation; monomorphic; morphology; NMR spectroscopy; polymorphic; self-assembly; stability}},
  language     = {{eng}},
  number       = {{6}},
  publisher    = {{MDPI AG}},
  series       = {{International Journal of Molecular Sciences}},
  title        = {{Morphology-Dependent Interactions between α-Synuclein Monomers and Fibrils}},
  url          = {{http://dx.doi.org/10.3390/ijms24065191}},
  doi          = {{10.3390/ijms24065191}},
  volume       = {{24}},
  year         = {{2023}},
}