Structure–function relationships in human apolipoprotein A-I: role of a central helix pair

Abstract

Apolipoprotein (Apo)A-I plays a key role in reverse cholesterol transport, a process of antiatherogenic relevance that removes excess cholesterol from peripheral tissues. This protein is constituted almost exclusively of amphipathic ±-helices and undergoes large conformational changes during its functional cycle. Conformational changes in relationship with the functional role of this protein are discussed, with focus on a central á-helix pair with a particular charge distribution. This domain inserts preferentially into cholesterol-containing membranes where it facilitates cholesterol desorption, and it is also responsible for triggering mobilization of intracellular cholesterol depots towards the cell membrane. It is proposed that the active domain would be an intermolecular á-helix bundle formed by two central helix pairs belonging to both ApoA-I molecules, which constitute a discoidal high-density lipoprotein particle. For the activity of this domain, a specific sequence would not be required, but the charge distribution of class 'Y' amphipathic ±-helices and an adequate orientation of the hydrophobic and hydrophilic helix faces would be necessary.

Key words:

• Amphipathic α-Helices
• Apolipoprotein A-I
• Cell-Cholesterol Efflux
• Exchangeable Apolipoproteins
• Lipid Transport
• Mutant Proteins
• Synthetic Peptides