Electrostatic control of membrane disruption and amorphous coaggregation by dynorphin A variants

Area of Science:

• Biochemistry
• Neuroscience
• Molecular Biology

Background:

• Dynorphin A is a cationic neuropeptide with known opioid receptor functions.
• Its membrane activity extends beyond canonical signaling pathways.
• Sequence variants are associated with spinocerebellar ataxia type 23 (SCA23).

Purpose of the Study:

• To investigate how SCA23-associated Dynorphin A variants affect membrane disruption and aggregation.
• To elucidate the biophysical mechanisms underlying Dynorphin A-membrane interactions.
• To understand the impact of these variants on amyloid-β co-assembly.

Main Methods:

• Computational electrophysiology simulations.
• Liposome leakage assays.
• Fluorescence-based aggregation assays.
• Lipid bilayer interaction studies.

Main Results:

• Dynorphin A variants interact with lipid bilayers via electrostatic recruitment, followed by insertion and pore formation.
• Anionic lipids enhance bilayer disruption, while cholesterol modulates activity.
• Variants alter amyloid-β co-assembly by increasing hydrophobic surface exposure without significant fibrillization.

Conclusions:

• Subtle sequence variations in Dynorphin A fine-tune its membrane perturbation and co-aggregation properties.
• Electrostatic membrane recruitment is a critical factor in Dynorphin A bioactivity.
• These findings offer insights into the molecular basis of SCA23 and peptide-membrane interactions.