The interaction of apolipoprotein A I (apoA I) with transmembrane ATP binding cassette transporter A1 (ABCA1) is a crucial step for high-density lipoprotein (HDL) formation, however, its molecular mechanism is less well understood. Here, we used apoA I and its model peptide, Ac 18A NH 2 , to investigate their interaction with mixed membranes of phosphatidylcholine (PC) with phosphatidylethanolamine (PE) or sphingomyelin (SM). It was shown that PE, possessing the negative spontaneous

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... ure, increased both the degree of hydration at the membrane interface and the acyl chain order, and that Ac 18A NH 2 had opposite eŠects to PE, since the a-helix formation at the membrane surface induced positive curvature strain. In addition, increased PE in PC/PE large unilamellar vesicles (LUVs) enhanced the peptide's binding. Although SM signiˆcantly lowered the peptide binding capacity, the peptide's binding to PC/SM LUV led to membrane disruption. The interaction with PC/SM LUVs was then investigated using ApoA I. The spontaneous rHDL formation from pure PC LUV proceeded very slowly at 37°C, but SM-rich PC/SM LUVs, which are in a gel/liquid-disordered (L d ) phase at this temperature, were rapidly solubilized to form rHDL by apoA I. The addition of cholesterol decreased the rate of the rHDL formation and induced the selective extraction of lipids by apoA I, which preferably extracted lipids of L d phase rather than lipids of liquid-ordered (L o ) phase. These results suggest that heterogeneous interface of the mixed membranes facilitates the insertion of apoA I and induces L d phase-selective lipid extraction to form rHDL, and are compatible with recent cell works on the apoA I dependent HDL generation.