Mechanism of ATP-binding Cassette Transporter A1-mediated Cellular Lipid Efflux to Apolipoprotein A-I and Formation of High Density Lipoprotein Particles

Abstract

The ATP-binding cassette transporter A1 (ABCA1) plays a critical role in the biogenesis of high density lipoprotein (HDL) particles and in mediating cellular cholesterol efflux. The mechanism by which ABCA1 achieves these effects is not established, despite extensive investigation. Here, we present a model that explains the essential features, especially the effects of ABCA1 activity in inducing apolipoprotein (apo) A-I binding to cells and the compositions of the discoidal HDL particles that are produced. The apo A-I/ABCA1 reaction scheme involves three steps. First, there is binding of a small regulatory pool of apo A-I to ABCA1, thereby enhancing net phospholipid translocation to the plasma membrane exofacial leaflet; this leads to unequal lateral packing densities in the two leaflets of the phospholipid bilayer. Second, the resultant membrane strain is relieved by bending and by creation of exovesiculated lipid domains. The formation of highly curved membrane surface promotes high affinity binding of apo A-I to these domains. Third, this pool of bound apo A-I spontaneously solubilizes the exovesiculated domain to create discoidal nascent HDL particles. These particles contain two, three, or four molecules of apo A-I and a complement of membrane phospholipid classes together with some cholesterol. A key feature of this mechanism is that membrane bending induced by ABCA1 lipid translocase activity creates the conditions required for nascent HDL assembly by apo A-I. Overall, this mechanism is consistent with the known properties of ABCA1 and apo A-I and reconciles many of the apparently discrepant findings in the literature.

Structure and mechanism of ATP-dependent phospholipid transporters

“…This evidence is confirmed by reconstitution experiments, in which MsbA has been shown to translocate a wide variety of fluorescent-labeled phospholipids, albeit with low activity [72]. In the case of P-glycoprotein, studies in cell lines and reconstituted systems have suggested the involvement of this protein in transport of a variety of phospho-and glycolipids [65,70,[89][90][91]. However, this protein was first identified as the multidrug resistance transporter responsible for the inefficiency of long-term pharmacological treatments [92].…”

ApoA1 and ApoA1-specific self-antibodies in cardiovascular disease

“…64 The ability of ApoA1 to solubilize and bind lipids has a key role in formation of nascent HDL. 65 ApoA1/ABCA1-dependent generation of nascent HDL particles involves three stages. On the first stage, ApoA1 (lipid free or lipid bound) binds to ABCA1 that results in enhancing activity of the transporter in translocating phospholipids from the inner plasma membrane layer to the outer layer.…”

Effects of Protein Oxidation on the Structure and Stability of Model Discoidal High-Density Lipoproteins

“…ApoA-I also plays key roles at various stages of RCT. It promotes efflux of cell cholesterol and phospholipids to HDL via the interactions with ATP-binding cassette transporter A1 (11); it provides a co-factor for lecithin:cholesterol acyltransferase (LCAT), which esterifies cholesterol and converts nascent discoidal to mature spherical HDL (2); it binds to the hepatic scavenger receptor and mediates selective uptake of HDL cholesterol esters by the liver (12).…”