Structural and functional properties of human and mouse apolipoprotein A-I

Area of Science:

• Lipid metabolism
• Protein biochemistry
• Cardiovascular research

Background:

• Apolipoprotein A-I (apo A-I) is crucial for high-density lipoprotein (HDL) structure and function.
• Understanding species-specific differences in apo A-I is vital for elucidating HDL metabolism and cardiovascular disease.
• Mouse apo A-I (apo A-Im) and human apo A-I (apo A-Ih) are key models for studying these processes.

Purpose of the Study:

• To compare molecular properties of apo A-Im and apo A-Ih in solution.
• To investigate their incorporation into discoidal complexes and stability within HDL.
• To assess their structural response to low-density lipoprotein (LDL) interaction.

Main Methods:

• Investigated apo A-Im and apo A-Ih in solution and in palmitoyloleoylphosphatidylcholine-apo A-I (POPC-apo A-I) discoidal complexes.
• Assessed structural stability in discoidal complexes and HDL using guanidine hydrochloride (GuHCl) denaturation.
• Analyzed interactions with human plasma LDL and compared hydrophobic properties of helical segments.

Main Results:

• Apo A-Im exhibited minimal concentration-dependent self-association compared to apo A-Ih.
• Both apo A-Im and apo A-Ih formed discoidal complexes, but apo A-Im showed deficiencies in larger complex formation.
• Apo A-Im-containing particles had reduced lipid stabilization and underwent more extensive conversion to smaller species upon LDL interaction.

Conclusions:

• Significant differences exist between apo A-Im and apo A-Ih in self-association, lipid incorporation, and stability.
• These molecular distinctions may explain altered HDL distribution and function observed in apo A-Ih transgenic mice.
• Findings highlight species-specific variations in apo A-I function relevant to HDL metabolism.