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Journal of Lipid Research, Vol. 49, 2419-2426, November 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Conformational change of apolipoprotein A-I and HDL formation from model membranes under intracellular acidic conditions

Masakazu Fukuda^*, Minoru Nakano^1,*, Masakazu Miyazaki^*, Masafumi Tanaka, Hiroyuki Saito, Satoe Kobayashi, Masaharu Ueno and Tetsurou Handa^*

^* Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
Department of Biophysical Chemistry, Kobe Pharmaceutical University, Kobe 658-8558, Japan
Faculty of Pharmaceutical Sciences, Toyama University, 2630 Sugitani, Toyama 930-0194, Japan

Published, JLR Papers in Press, July 21, 2008.

This study was supported in part by Grants-in-aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology (17390011 and 20790032), research fellowships from the Japan Society for the Promotion of Science for Young Scientists (202796), and the program for the Promotion of Fundamental Studies in Health Science (04-8) of the National Institute of Biomedical Innovation.

¹ To whom correspondence should be addressed: e-mail: mnakano{at}pharm.kyoto-u.ac.jp

The molecular mechanism by which nascent HDL forms via the interaction of apolipoprotein A-I (apoA-I) and transmembrane ABCA1 is poorly understood. Here, because ABCA1 has been reported to localize to acidic intracellular compartments, including the Golgi and endosome, we studied the interaction of apoA-I with model membranes under acidic conditions. Pure phosphatidylcholine liposomes were persistent against apoA-I at pH levels above 5.0, but were progressively transformed into reconstituted HDLs (rHDLs) by apoA-I at lower pH. Circular dichroism spectral measurements and 8-anilino-1-naphthalenesulfonic acid fluorescence measurements of lipid-free apoA-I ascribed this accelerated rHDL formation to the conformational change of the protein into a rather hydrophobic -helical structure under acidic conditions. The addition of phosphatidylserine (PS) increased acidity at the bilayer surface and enabled the formation of discoidal rHDLs even at the pH of the endosome and slightly lower pH of the Golgi. These results suggest the following new scenario of nascent HDL formation: ABCA1, which colocalizes with apoA-I in acidic intracellular compartments, including the Golgi and endosome, increases acidity at the membrane surface on the luminal side by PS translocase activity and causes apoA-I to form nascent HDL.

Supplementary key words endosome • Golgi • phosphatidylcholine • phosphatidylserine • reconstituted HDL • translocase activity

Abbreviations: ANS, 8-anilino-1-naphthalenesulfonic acid; apoA-I, apolipoprotein A-I; CD, circular dichroism; LUV, large unilamellar vesicle; PC, phosphatidylcholine; PL, phospholipid; PS, phosphatidylserine; rHDL, reconstituted HDL; Rho-DOPE, dioleoyl-sn-glycero-3-phosphoethanolamine-N-(lissamine rhodamine B sulfonyl)

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