Distinct lipid bilayer compositions have general and protein-specific effects on K+ channel function

Area of Science:

• Biophysics
• Molecular Biology
• Membrane Protein Function

Background:

• Cell membrane lipid composition critically impacts transmembrane protein function, including ion channels.
• Viral potassium (K+) channels offer a model system to study these lipid-protein interactions due to their diversity.

Purpose of the Study:

• To systematically investigate how bilayer lipid composition affects the function of single viral K+ channels.
• To determine the specific roles of cholesterol and anionic phospholipids (aPLs) on K+ channel conductance and gating.

Main Methods:

• In vitro synthesis and reconstitution of seven viral K+ channels into phosphatidylcholine bilayers.
• Incorporation of cholesterol or aPLs (e.g., phosphatidylserine) into bilayers.
• Single-channel electrophysiological recordings to measure unitary conductance and gating kinetics.

Main Results:

• Cholesterol (30%) showed minor, protein-specific effects on K+ channel conductance and gating, suggesting robust protein adaptation to hydrophobic mismatch.
• Anionic phospholipids (aPLs) consistently augmented unitary conductance across all seven K+ channels tested, indicating a general effect.
• aPLs also modulated gating in a protein-specific manner, demonstrating uncoupled effects on conductance and gating, potentially involving interactions with cationic residues.

Conclusions:

• Anionic phospholipids generally enhance K+ channel conductance, with effects dependent on protein sequence and lipid leaflet asymmetry.
• K+ channels possess mechanisms to mitigate the impact of cholesterol, but are sensitive to aPLs, particularly in the inner leaflet.
• The findings highlight the significant role of specific lipid-protein interactions in regulating ion channel function and membrane dynamics.