Cooperativity of α-Synuclein Binding to Lipid Membranes

Katarzyna Makasewicz, Stefan Wennmalm, Björn Stenqvist, Marco Fornasier, Alexandra Andersson, Peter Jönsson, Sara Linse, Emma Sparr

Research output: Contribution to journalArticlepeer-review

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 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.

Original languageEnglish
Pages (from-to)2099-2109
JournalACS Chemical Neuroscience
Volume12
Issue number12
Early online date2021
DOIs
Publication statusPublished - 2021

Subject classification (UKÄ)

  • Biophysics

Free keywords

  • Adair equation
  • Cooperative binding
  • fluorescence correlation spectroscopy
  • homotropic allostery
  • lipid membrane
  • α-synuclein

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