DIBMA nanodiscs keep α-synuclein folded.

Area of Science:

• Biochemistry
• Structural Biology
• Biophysics

Background:

• Alpha-synuclein (αsyn) is an intrinsically disordered protein (IDP) that folds into an alpha-helical structure upon binding to membrane lipids, which can reduce protein aggregation.
• Model membranes like small unilamellar vesicles (SUVs) and nanodiscs are used to study protein folding and aggregation, but SUVs are mechanically strained and nanodiscs are expensive.

Purpose of the Study:

• To investigate the impact of lipid particle size on αsyn secondary-structure formation.
• To compare the efficacy of large unilamellar vesicles (LUVs) and diisobutylene/maleic acid copolymer (DIBMA) nanodiscs as membrane mimics for αsyn structuring.
• To assess the influence of lipid charge and composition on αsyn folding across different species.

Main Methods:

• Comparison of αsyn secondary-structure formation using LUVs and DIBMA/lipid particles (DIBMALPs) with varying lipid compositions.
• Testing human-, elephant-, and whale-αsyn to assess species-specific responses.
• Analysis of αsyn folding independent of lipid/protein ratio in DIBMALPs versus LUVs.

Main Results:

• Negatively charged lipids induced αsyn folding in human- and elephant-αsyn, but not whale-αsyn.
• No significant secondary structure increase was observed with a mixture of zwitterionic and negatively charged lipids at 45°C.
• DIBMALPs demonstrated effective αsyn structuring, with folding largely independent of the lipid/protein ratio, unlike LUVs.

Conclusions:

• DIBMA nanodiscs are highly suitable nanoscale membrane mimics for studying αsyn secondary-structure formation and aggregation.
• This study highlights a novel application for polymer-encapsulated nanodiscs in structuring disordered proteins like αsyn into non-toxic forms.
• Findings contribute to understanding protein-lipid interactions and α-helix formation, aiding in developing strategies to prevent protein aggregation and related diseases.