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Cooperativity of α-Synuclein Binding to Lipid Membranes

Makasewicz, Katarzyna LU ; Wennmalm, Stefan ; Stenqvist, Björn LU ; Fornasier, Marco LU orcid ; Andersson, Alexandra LU ; Jönsson, Peter LU ; Linse, Sara LU and Sparr, Emma LU (2021) In ACS Chemical Neuroscience 12(12). p.2099-2109
Abstract

Cooperative binding is a key feature of metabolic pathways, signaling, and transport processes. It provides tight regulation over a narrow concentration interval of a ligand, thus enabling switching to be triggered by small concentration variations. The data presented in this work reveal strong positive cooperativity of α-synuclein binding to phospholipid membranes. Fluorescence cross-correlation spectroscopy, confocal microscopy, and cryo-TEM results show that in excess of vesicles α-synuclein does not distribute randomly but binds only to a fraction of all available vesicles. Furthermore, α-synuclein binding to a supported lipid bilayer observed with total internal reflection fluorescence microscopy displays a much steeper dependence... (More)

Cooperative binding is a key feature of metabolic pathways, signaling, and transport processes. It provides tight regulation over a narrow concentration interval of a ligand, thus enabling switching to be triggered by small concentration variations. The data presented in this work reveal strong positive cooperativity of α-synuclein binding to phospholipid membranes. Fluorescence cross-correlation spectroscopy, confocal microscopy, and cryo-TEM results show that in excess of vesicles α-synuclein does not distribute randomly but binds only to a fraction of all available vesicles. Furthermore, α-synuclein binding to a supported lipid bilayer observed with total internal reflection fluorescence microscopy displays a much steeper dependence of bound protein on total protein concentration than expected for independent binding. The same phenomenon was observed in the case of α-synuclein binding to unilamellar vesicles of sizes in the nm and μm range as well as to flat supported lipid bilayers, ruling out that nonuniform binding of the protein is governed by differences in membrane curvature. Positive cooperativity of α-synuclein binding to lipid membranes means that the affinity of the protein to a membrane is higher where there is already protein bound compared to a bare membrane. The phenomenon described in this work may have implications for α-synuclein function in synaptic transmission and other membrane remodeling events.

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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Adair equation, Cooperative binding, fluorescence correlation spectroscopy, homotropic allostery, lipid membrane, α-synuclein
in
ACS Chemical Neuroscience
volume
12
issue
12
pages
2099 - 2109
publisher
The American Chemical Society (ACS)
external identifiers
  • scopus:85108386476
  • pmid:34076426
ISSN
1948-7193
DOI
10.1021/acschemneuro.1c00006
language
English
LU publication?
yes
id
b6fc1cc8-0aa6-4ee5-bf62-3e6a39a69bb4
date added to LUP
2021-07-15 13:25:39
date last changed
2022-08-04 17:51:59
@article{b6fc1cc8-0aa6-4ee5-bf62-3e6a39a69bb4,
  abstract     = {{<p>Cooperative binding is a key feature of metabolic pathways, signaling, and transport processes. It provides tight regulation over a narrow concentration interval of a ligand, thus enabling switching to be triggered by small concentration variations. The data presented in this work reveal strong positive cooperativity of α-synuclein binding to phospholipid membranes. Fluorescence cross-correlation spectroscopy, confocal microscopy, and cryo-TEM results show that in excess of vesicles α-synuclein does not distribute randomly but binds only to a fraction of all available vesicles. Furthermore, α-synuclein binding to a supported lipid bilayer observed with total internal reflection fluorescence microscopy displays a much steeper dependence of bound protein on total protein concentration than expected for independent binding. The same phenomenon was observed in the case of α-synuclein binding to unilamellar vesicles of sizes in the nm and μm range as well as to flat supported lipid bilayers, ruling out that nonuniform binding of the protein is governed by differences in membrane curvature. Positive cooperativity of α-synuclein binding to lipid membranes means that the affinity of the protein to a membrane is higher where there is already protein bound compared to a bare membrane. The phenomenon described in this work may have implications for α-synuclein function in synaptic transmission and other membrane remodeling events.</p>}},
  author       = {{Makasewicz, Katarzyna and Wennmalm, Stefan and Stenqvist, Björn and Fornasier, Marco and Andersson, Alexandra and Jönsson, Peter and Linse, Sara and Sparr, Emma}},
  issn         = {{1948-7193}},
  keywords     = {{Adair equation; Cooperative binding; fluorescence correlation spectroscopy; homotropic allostery; lipid membrane; α-synuclein}},
  language     = {{eng}},
  number       = {{12}},
  pages        = {{2099--2109}},
  publisher    = {{The American Chemical Society (ACS)}},
  series       = {{ACS Chemical Neuroscience}},
  title        = {{Cooperativity of α-Synuclein Binding to Lipid Membranes}},
  url          = {{http://dx.doi.org/10.1021/acschemneuro.1c00006}},
  doi          = {{10.1021/acschemneuro.1c00006}},
  volume       = {{12}},
  year         = {{2021}},
}