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α-Synuclein cooperative binding to lipid membranes is a robust property over a wide range of conditions

Ferrante Carrante, Noemi LU ; Dubackic, Marija LU ; Makasewicz, Katarzyna LU ; Wennmalm, Stefan ; Hermodsson, Tova LU ; Bernfur, Katja LU ; Linse, Sara LU and Sparr, Emma LU (2025) In Cell Reports Physical Science 6(12).
Abstract

Cooperativity is an efficient way for nature to regulate complex processes, allowing for control over a narrower range of concentrations compared to noncooperative phenomena. Here, we investigate the cooperative binding of α-Synuclein to lipid membranes under different conditions, aiming to uncover the underlying molecular driving forces. We interrogate the role of electrostatic interactions by rationally tuning α-Synuclein charge and the range of electrostatic interactions through variation in pH and ionic strength. To explore potential physiological and pathological implications, we also examine the cooperative binding of the H50Q mutant, which is linked to early-onset Parkinson’s disease. Using a multi-technique approach, we show... (More)

Cooperativity is an efficient way for nature to regulate complex processes, allowing for control over a narrower range of concentrations compared to noncooperative phenomena. Here, we investigate the cooperative binding of α-Synuclein to lipid membranes under different conditions, aiming to uncover the underlying molecular driving forces. We interrogate the role of electrostatic interactions by rationally tuning α-Synuclein charge and the range of electrostatic interactions through variation in pH and ionic strength. To explore potential physiological and pathological implications, we also examine the cooperative binding of the H50Q mutant, which is linked to early-onset Parkinson’s disease. Using a multi-technique approach, we show that cooperativity is a robust property of α-Synuclein binding to anionic membranes, persisting in both the wild-type and mutant proteins. Our findings reveal that membrane-mediated effects, rather than electrostatics or direct protein-protein interactions, could be the main driving forces underlying this strong cooperativity.

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author
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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
charge modulation, charge screening, cooperativity, free-energy coupling, lipid-protein interactions, membrane-mediated interactions, protein clustering, protein patches, segregation, surface adsorption
in
Cell Reports Physical Science
volume
6
issue
12
article number
103024
publisher
Cell Press
external identifiers
  • scopus:105024887175
ISSN
2666-3864
DOI
10.1016/j.xcrp.2025.103024
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2025 The Author(s).
id
bad64019-d860-4afa-b2d8-97a6334b6f35
date added to LUP
2026-02-11 13:20:19
date last changed
2026-02-11 13:22:05
@article{bad64019-d860-4afa-b2d8-97a6334b6f35,
  abstract     = {{<p>Cooperativity is an efficient way for nature to regulate complex processes, allowing for control over a narrower range of concentrations compared to noncooperative phenomena. Here, we investigate the cooperative binding of α-Synuclein to lipid membranes under different conditions, aiming to uncover the underlying molecular driving forces. We interrogate the role of electrostatic interactions by rationally tuning α-Synuclein charge and the range of electrostatic interactions through variation in pH and ionic strength. To explore potential physiological and pathological implications, we also examine the cooperative binding of the H50Q mutant, which is linked to early-onset Parkinson’s disease. Using a multi-technique approach, we show that cooperativity is a robust property of α-Synuclein binding to anionic membranes, persisting in both the wild-type and mutant proteins. Our findings reveal that membrane-mediated effects, rather than electrostatics or direct protein-protein interactions, could be the main driving forces underlying this strong cooperativity.</p>}},
  author       = {{Ferrante Carrante, Noemi and Dubackic, Marija and Makasewicz, Katarzyna and Wennmalm, Stefan and Hermodsson, Tova and Bernfur, Katja and Linse, Sara and Sparr, Emma}},
  issn         = {{2666-3864}},
  keywords     = {{charge modulation; charge screening; cooperativity; free-energy coupling; lipid-protein interactions; membrane-mediated interactions; protein clustering; protein patches; segregation; surface adsorption}},
  language     = {{eng}},
  month        = {{12}},
  number       = {{12}},
  publisher    = {{Cell Press}},
  series       = {{Cell Reports Physical Science}},
  title        = {{α-Synuclein cooperative binding to lipid membranes is a robust property over a wide range of conditions}},
  url          = {{http://dx.doi.org/10.1016/j.xcrp.2025.103024}},
  doi          = {{10.1016/j.xcrp.2025.103024}},
  volume       = {{6}},
  year         = {{2025}},
}