Membrane Phase, Charge, and Curvature Regulate α-Synuclein Binding Dynamics.

Area of Science:

• Biochemistry and Biophysics
• Neuroscience
• Molecular Biology

Background:

• Alpha-synuclein (αSyn) is intrinsically disordered and interacts with lipid membranes.
• These interactions are crucial for αSyn's function and its role in synucleopathies.
• Previous studies examined membrane charge, phase, and curvature independently.

Purpose of the Study:

• To investigate how membrane phase and charge jointly regulate αSyn binding.
• To understand the combined effects on αSyn's curvature sensitivity and dynamic membrane association.
• To resolve both equilibrium and kinetic contributions to protein-membrane binding.

Main Methods:

• Systematic investigation using fluorescence microscopy and circular dichroism spectroscopy.
• Utilized fluorescence recovery after photobleaching (FRAP) for dynamic measurements.
• Complemented experimental data with coarse-grained molecular dynamics simulations.

Main Results:

• αSyn preferentially binds curved gel-phase membranes under zwitterionic conditions.
• Anionic lipids enhance αSyn binding to liquid-phase membranes but reduce it in gel-phase.
• Membrane phase and charge influence the stability of membrane-associated αSyn, promoting kinetically stabilized states.
• Simulations indicate curvature-induced defect formation is amplified in gel-phase membranes.

Conclusions:

• αSyn-membrane interactions are governed by a cooperative interplay of membrane phase, curvature, and charge.
• Both thermodynamic and kinetic aspects of protein-membrane binding are critical.
• Findings provide insights into αSyn's role in synucleopathies.