Interplay of alpha-synuclein binding and conformational switching probed by single-molecule fluorescence

Area of Science:

• Biophysics
• Structural Biology
• Neuroscience

Background:

• Alpha-synuclein is an intrinsically disordered protein associated with Parkinson's disease.
• Understanding its conformational changes upon binding is crucial for disease mechanism insights.

Purpose of the Study:

• To investigate the coupled binding and folding of alpha-synuclein.
• To explore how membrane interactions modulate its structure and dynamics.

Main Methods:

• Single-molecule fluorescence resonance energy transfer (smFRET).
• Single-molecule fluorescence correlation spectroscopy (smFCS).
• Utilized micelles and lipid vesicles as model membrane systems.

Main Results:

• Alpha-synuclein exhibits two primary conformational states (broken and extended helical structures) rather than continuous structural tuning.
• Binding to amphiphilic molecules or membrane-like surfaces triggers these conformational transitions.
• A low fraction of negatively charged lipids on vesicles is sufficient to induce alpha-synuclein folding into an extended helical structure.

Conclusions:

• The two folded structures of alpha-synuclein are encoded in its amino acid sequence.
• Binding partners and membrane properties act as tunable control elements for alpha-synuclein conformation.
• These findings offer insights into the regulation of alpha-synuclein in biological systems and amyloid formation.