Human apolipoprotein A-I forms thermally stable complexes with anionic but not with zwitterionic phospholipids

Area of Science:

• Biochemistry
• Lipid-protein interactions
• Structural biology

Background:

• Apolipoprotein A-I (apo A-I) is crucial for high-density lipoprotein (HDL) structure and function.
• Understanding apo A-I's interaction with phospholipids is key to elucidating lipoprotein assembly and stability.
• Phospholipids vary in charge, influencing their interaction with proteins.

Purpose of the Study:

• To investigate the mechanism of apo A-I association with different types of phospholipids.
• To compare the stability and structural properties of apo A-I complexes with acidic versus zwitterionic phospholipids.
• To determine the thermodynamic and kinetic factors governing these interactions.

Main Methods:

• Turbidimetry
• Circular dichroism (CD) spectroscopy
• High-sensitivity differential scanning calorimetry (DSC)
• Electron microscopy (EM)

Main Results:

• Apo A-I rapidly associates with acidic phospholipids (e.g., DMPG) over a broad temperature range, especially above the lipid phase transition temperature (Tc).
• Association with zwitterionic phospholipids (e.g., DMPC) is restricted to a narrow temperature range around Tc.
• Apo A-I/DMPC complexes exhibit temperature-dependent denaturation, while apo A-I/acidic phospholipid complexes show high thermal stability.
• Both types of complexes form discoidal lipoprotein particles.

Conclusions:

• Complexes of apo A-I with acidic phospholipids are thermodynamically stable across a wide temperature range.
• Complexes of apo A-I with zwitterionic phospholipids exhibit stability primarily governed by kinetic factors near Tc.
• Despite differing stability profiles, apo A-I forms similar discoidal structures with both acidic and zwitterionic phospholipids, indicating conserved morphology.