Specific docking of apolipoprotein A-I at the cell surface requires a functional ABCA1 transporter

The identification of defects in ABCA1 as the molecular basis of Tangier di sease has highlighted its crucial role in the loading with phospholipids an d cholesterol of nascent apolipoprotein particles. Indeed the expression of ABCA1 affects apolipoprotein A-I (apoA-I)-mediated removal of lipids from cell membranes, and the possible role of ABCA1 as an apoA-I surface recepto r has been recently suggested, In the present study, we have investigated t he role of the ABCA1 transporter as an apoA-I receptor with the analysis of a panel of transfectants expressing functional or mutant forms of ABCA1, W e provide experimental evidence that the forced expression of a functional ABCA1 transporter confers surface competence for apoA-I binding. This, howe ver, appears to be dependent on ABCA1 function. Structurally intact but ATP ase-deficient forms of the transporter fail to elicit a specific cell assoc iation of the ligand, In addition the diffusion parameters of membrane-asso ciated apoA-I indicate an interaction with membrane lipids rather than prot eins. These results do not support a direct molecular interaction between A BCA1 and apoA-I, but rather suggest that the ABCA1-induced modification of the lipid distribution in the membrane, evidenced by the phosphatidylserine exofacial flopping, generates a biophysical microenvironment required for the docking of apoA-I at the cell surface.