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On the transient interactions of α-synuclein in different dimensions

Ortigosa-Pascual, L. LU orcid ; Ferrante-Carrante, N. LU ; Bernfur, K. LU ; Makasewicz, K. LU ; Sparr, E. LU and Linse, S. LU (2025)
Abstract
α-Synuclein (αSyn) is a neuronal protein predominantly found in the brain, whose native function seems to be associated with vesicle trafficking. While intrinsically disordered in solution, the first ca. 100 residues adopt an amphipathic α-helical structure when the protein adsorbs onto membranes. Additionally, the aggregation of αSyn into highly ordered β-sheet rich amyloid fibrils is associated with Parkinson′s disease. The different regions of αSyn and the interactions between them have been reported to play a key role in the behaviour of the protein in solution, its membrane binding, and its aggregation into fibrils. This study employs photo-induced cross-linking of unmodified proteins (PICUP) to capture and identify the transient... (More)
α-Synuclein (αSyn) is a neuronal protein predominantly found in the brain, whose native function seems to be associated with vesicle trafficking. While intrinsically disordered in solution, the first ca. 100 residues adopt an amphipathic α-helical structure when the protein adsorbs onto membranes. Additionally, the aggregation of αSyn into highly ordered β-sheet rich amyloid fibrils is associated with Parkinson′s disease. The different regions of αSyn and the interactions between them have been reported to play a key role in the behaviour of the protein in solution, its membrane binding, and its aggregation into fibrils. This study employs photo-induced cross-linking of unmodified proteins (PICUP) to capture and identify the transient contacts of αSyn in different conformational states: free in solution, adsorbed to membranes, and aggregated into fibrils. By using tyrosine-to-phenylalanine mutations to block the reactivity of specific amino acid residues, we establish key cross-links in each state. In solution, we identify internal contacts between the N and C termini of monomers, as well as inter-monomer contacts between C termini in oligomers. When αSyn is adsorbed to membranes, the internal cross-linking is blocked, while cross-linking between C-terminal regions persists. In fibrils, cross-linking is significantly reduced, primarily occurring between C-terminal residues of adjacent monomers. This work highlights the utility of PICUP for reporting on the transient contacts that occur on the pathways of self- and co-assembly of αSyn. (Less)
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author
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organization
publishing date
type
Working paper/Preprint
publication status
published
subject
pages
30 pages
publisher
bioRxiv
DOI
10.1101/2025.01.29.635265
language
English
LU publication?
yes
id
f108e6f4-93ad-46ce-b171-61986bd5702d
date added to LUP
2025-02-26 10:16:35
date last changed
2025-04-04 15:10:24
@misc{f108e6f4-93ad-46ce-b171-61986bd5702d,
  abstract     = {{α-Synuclein (αSyn) is a neuronal protein predominantly found in the brain, whose native function seems to be associated with vesicle trafficking. While intrinsically disordered in solution, the first ca. 100 residues adopt an amphipathic α-helical structure when the protein adsorbs onto membranes. Additionally, the aggregation of αSyn into highly ordered β-sheet rich amyloid fibrils is associated with Parkinson′s disease. The different regions of αSyn and the interactions between them have been reported to play a key role in the behaviour of the protein in solution, its membrane binding, and its aggregation into fibrils. This study employs photo-induced cross-linking of unmodified proteins (PICUP) to capture and identify the transient contacts of αSyn in different conformational states: free in solution, adsorbed to membranes, and aggregated into fibrils. By using tyrosine-to-phenylalanine mutations to block the reactivity of specific amino acid residues, we establish key cross-links in each state. In solution, we identify internal contacts between the N and C termini of monomers, as well as inter-monomer contacts between C termini in oligomers. When αSyn is adsorbed to membranes, the internal cross-linking is blocked, while cross-linking between C-terminal regions persists. In fibrils, cross-linking is significantly reduced, primarily occurring between C-terminal residues of adjacent monomers. This work highlights the utility of PICUP for reporting on the transient contacts that occur on the pathways of self- and co-assembly of αSyn.}},
  author       = {{Ortigosa-Pascual, L. and Ferrante-Carrante, N. and Bernfur, K. and Makasewicz, K. and Sparr, E. and Linse, S.}},
  language     = {{eng}},
  note         = {{Preprint}},
  publisher    = {{bioRxiv}},
  title        = {{On the transient interactions of α-synuclein in different dimensions}},
  url          = {{http://dx.doi.org/10.1101/2025.01.29.635265}},
  doi          = {{10.1101/2025.01.29.635265}},
  year         = {{2025}},
}