The Influence of Vesicle Size and Composition on α-Synuclein Structure and Stability

Abstract

Monomeric alpha-synuclein (alphaSN), which has no persistent structure in aqueous solution, is known to bind to anionic lipids with a resulting increase in alpha-helix structure. Here we show that at physiological pH and ionic strength, alphaSN incubated with different anionic lipid vesicles undergoes a marked increase in alpha-helical content at a temperature dictated either by the temperature of the lipid phase transition, or (in 1,2-DilauroylSN-Glycero-3-[Phospho-rac-(1-glycerol)] (DLPG), which is fluid down to 0 degrees C) by an intrinsic cold denaturation that occurs around 10-20 degrees C. This structure is subsequently lost in a thermal transition around 60 degrees C. Remarkably, this phenomenon is only observed for vesicles >100 nm in diameter and is sensitive to lipid chain length, longer chain lengths, and larger vesicles giving more cooperative unfolding transitions and a greater degree of structure. For both vesicle size and chain length, a higher degree of compressibility or permeability in the lipid thermal transition region is associated with a higher degree of alphaSN folding. Furthermore, the degree of structural change is strongly reduced by an increase in ionic strength or a decrease in the amount of anionic lipid. A simple binding-and-folding model that includes the lipid phase transition, exclusive binding of alphaSN to the liquid disordered phase, the thermodynamics of unfolding, and the electrostatics of binding of alphaSN to lipids is able to reproduce the two thermal transitions as well as the effect of ionic strength and anionic lipid. Thus the nature of alphaSN's binding to phospholipid membranes is intimately tied to the lipids' physico-chemical properties.

Implications of peptide assemblies in amyloid diseases

“…302 Binding of αS (isoelectric point of 4.74) 303 with membranes is elevated with increased acidic phospholipid content. 304–306 αS oligomers also show propensity for the liquid disordered phase of anionic vesicles. 307 The exact mechanism of αS association with lipid rafts is unclear, but is linked to the high lipid packing density of anionic head groups in the rafts.…”

Biophysics of α-synuclein membrane interactions

“…The lipid chain structure can influence α-syn membrane binding as well [91, 93, 103]. Specifically, polyunsaturated chains are favorable for α-syn-membrane binding [104, 105].…”

SDS-Induced Fibrillation of α-Synuclein: An Alternative Fibrillation Pathway

“…18,19 This is also supported by the presence of seven imperfect repeats of KTKEGV mainly located in the N-terminal region known to interact with lipid vesicles. Indeed, αSN is known to bind acidic lipid vesicles, and an acidic lipid-mediated interaction induces an α-helical structure in αSN, [20][21][22] which in turn prevents αSN from forming filaments and fibrils. 23 This putative function makes it interesting to explore αSN's interaction with lipids and amphiphiles in general.…”