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Transient Interactions of α‑Synuclein N- and C‑Termini

Ortigosa-Pascual, Lei LU orcid ; Ferrante Carrante, Noemi LU ; Bernfur, Katja LU ; Makasewicz, Katarzyna LU ; Sparr, Emma LU and Linse, Sara LU (2026) In ACS Chemical Neuroscience
Abstract
α-Synuclein (αSyn) is a neuronal protein predominantly found at the
synapse, involved in vesicle trafficking. αSyn aggregates are also the
main component of Lewy bodies, the hallmarks of Parkinson’s disease.
Interactions between the N- and C-termini of αSyn play crucial roles in
its behavior in solution, membrane binding, and aggregation. Studying
these interactions provides valuable insights into the physiological and
pathological functions of αSyn. Here, we employed photoinduced
cross-linking of unmodified proteins (PICUP) to identify the transient
contacts of αSyn in different conformational states. By using
tyrosine-to-phenylalanine mutations to block the reactivity of specific
amino... (More)
α-Synuclein (αSyn) is a neuronal protein predominantly found at the
synapse, involved in vesicle trafficking. αSyn aggregates are also the
main component of Lewy bodies, the hallmarks of Parkinson’s disease.
Interactions between the N- and C-termini of αSyn play crucial roles in
its behavior in solution, membrane binding, and aggregation. Studying
these interactions provides valuable insights into the physiological and
pathological functions of αSyn. Here, we employed photoinduced
cross-linking of unmodified proteins (PICUP) to identify the transient
contacts of αSyn in different conformational states. By using
tyrosine-to-phenylalanine mutations to block the reactivity of specific
amino acids, 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 intermonomer contacts between C-termini in oligomers. When αSyn
is bound to membranes, the internal cross-linking is blocked, while the
cross-linking between C-terminal regions persists. In fibrils,
cross-linking is significantly reduced, primarily occurring between the
C-termini of adjacent monomers. This work highlights the effectiveness
of PICUP for reporting on the transient contacts involved in αSyn
self-assembly and its coassembly with lipid membranes, while providing a
streamlined protocol that opens avenues for studying protein–protein
interactions for a wide range of systems. (Less)
Abstract (Swedish)
α-Synuclein (αSyn) is a neuronal protein predominantly found at the synapse, involved in vesicle trafficking. αSyn
aggregates are also the main component of Lewy bodies, the hallmarks of Parkinson’s disease. Interactions between the N- and Ctermini
of αSyn play crucial roles in its behavior in solution, membrane binding, and aggregation. Studying these interactions
provides valuable insights into the physiological and pathological functions of αSyn. Here, we employed photoinduced cross-linking
of unmodified proteins (PICUP) to identify the transient contacts of αSyn in different conformational states. By using tyrosine-tophenylalanine
mutations to block the reactivity of specific amino acids, we establish key... (More)
α-Synuclein (αSyn) is a neuronal protein predominantly found at the synapse, involved in vesicle trafficking. αSyn
aggregates are also the main component of Lewy bodies, the hallmarks of Parkinson’s disease. Interactions between the N- and Ctermini
of αSyn play crucial roles in its behavior in solution, membrane binding, and aggregation. Studying these interactions
provides valuable insights into the physiological and pathological functions of αSyn. Here, we employed photoinduced cross-linking
of unmodified proteins (PICUP) to identify the transient contacts of αSyn in different conformational states. By using tyrosine-tophenylalanine
mutations to block the reactivity of specific amino acids, 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 intermonomer contacts between C-termini in
oligomers. When αSyn is bound to membranes, the internal cross-linking is blocked, while the cross-linking between C-terminal
regions persists. In fibrils, cross-linking is significantly reduced, primarily occurring between the C-termini of adjacent monomers.
This work highlights the effectiveness of PICUP for reporting on the transient contacts involved in αSyn self-assembly and its
coassembly with lipid membranes, while providing a streamlined protocol that opens avenues for studying protein−protein
interactions for a wide range of systems. (Less)
Please use this url to cite or link to this publication:
author
; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
epub
subject
in
ACS Chemical Neuroscience
publisher
The American Chemical Society (ACS)
external identifiers
  • pmid:41911551
ISSN
1948-7193
DOI
10.1021/acschemneuro.6c00108
language
English
LU publication?
yes
id
8c2ea2e9-fb9e-4acf-82f1-d781d93a1de6
date added to LUP
2026-04-01 16:29:58
date last changed
2026-04-07 12:45:57
@article{8c2ea2e9-fb9e-4acf-82f1-d781d93a1de6,
  abstract     = {{α-Synuclein (αSyn) is a neuronal protein predominantly found at the <br>
synapse, involved in vesicle trafficking. αSyn aggregates are also the <br>
main component of Lewy bodies, the hallmarks of Parkinson’s disease. <br>
Interactions between the N- and C-termini of αSyn play crucial roles in <br>
its behavior in solution, membrane binding, and aggregation. Studying <br>
these interactions provides valuable insights into the physiological and<br>
 pathological functions of αSyn. Here, we employed photoinduced <br>
cross-linking of unmodified proteins (PICUP) to identify the transient <br>
contacts of αSyn in different conformational states. By using <br>
tyrosine-to-phenylalanine mutations to block the reactivity of specific <br>
amino acids, we establish key cross-links in each state. In solution, we<br>
 identify internal contacts between the N- and C-termini of monomers, as<br>
 well as intermonomer contacts between C-termini in oligomers. When αSyn<br>
 is bound to membranes, the internal cross-linking is blocked, while the<br>
 cross-linking between C-terminal regions persists. In fibrils, <br>
cross-linking is significantly reduced, primarily occurring between the <br>
C-termini of adjacent monomers. This work highlights the effectiveness <br>
of PICUP for reporting on the transient contacts involved in αSyn <br>
self-assembly and its coassembly with lipid membranes, while providing a<br>
 streamlined protocol that opens avenues for studying protein–protein <br>
interactions for a wide range of systems.}},
  author       = {{Ortigosa-Pascual, Lei and Ferrante Carrante, Noemi and Bernfur, Katja and Makasewicz, Katarzyna and Sparr, Emma and Linse, Sara}},
  issn         = {{1948-7193}},
  language     = {{eng}},
  month        = {{03}},
  publisher    = {{The American Chemical Society (ACS)}},
  series       = {{ACS Chemical Neuroscience}},
  title        = {{Transient Interactions of α‑Synuclein N- and C‑Termini}},
  url          = {{http://dx.doi.org/10.1021/acschemneuro.6c00108}},
  doi          = {{10.1021/acschemneuro.6c00108}},
  year         = {{2026}},
}