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Journal of Lipid Research, Vol. 43, 1283-1292, August 2002
Copyright © 2002 by Lipid Research, Inc.

Structure-function studies of apoA-I variants

Dmitri Sviridov^1,*, Anh Hoang^*, Wei Huang^2, and Jun Sasaki^3,

^* Baker Medical Research Institute, P.O. Box 6492, St. Kilda Road Central, Melbourne, Victoria, 8008, Australia
Department of Internal Medicine, Fukuoka University, School of Medicine, 45-1, 7-chome Nanakuma, Jonan-ku, Fukuoka, 814-80, Japan

¹ To whom correspondence should be addressed. e-mail: dmitri.sviridov{at}baker.edu.au

Five mutants of apolipoprotein A-I (apoA-I), apoA-I(63–73), apoA-I(140–150), apoA-I(63–73@140–150), apoA-I(R149V), and apoA-I(P143A) were compared with human plasma apoA-I for their ability to promote cholesterol and phospholipid efflux from HepG2 cells. A significantly lower capacity to promote cholesterol and phospholipid efflux was observed with lipid-free apoA-I(63–73), while mutations apoA-I(140–150) and apoA-I(P143A) affected phospholipid efflux only. When added as apoA-I/palmitoyloleoyl phosphatidylcholine (POPC) complex, mutations apoA-I(63–73@140–150) and apoA-I(140–150) affected cholesterol efflux. None of the mutations affected -helicity of the lipid-free mutants or their self-association. Five natural mutations of apoA-I, apoA-I(A95D), apoA-I (Y100H), apoA-I(E110K), apoA-I(V156E), and apoA-I (H162Q) were studied for their ability to bind lipids and promote cholesterol efflux. None of the mutations affected lipid-binding properties, cholesterol efflux, or -helicity of lipid-free mutants. Two mutations affected self-association of apoA-I: apoA-I(A95D) was more prone to self-association, while apoA-I(E100H) did not self-associate.

The following conclusions could be made from the combined data: i) regions 210–243 and 63–100 are the lipid-binding sites of apoA-I and are also required for the efflux of lipids to lipid-free apoA-I, suggesting that initial lipidation of apoA-I is rate limiting in efflux; ii) in addition to the lipid-binding regions, the central region is important for cholesterol efflux to lipidated apoA-I, suggesting its possible involvement in interaction with cells.

Abbreviations: apoA-I, apolipoprotein A-I; DMPC, dimyristoyl phosphatidylcholine; POPC, palmitoyloleoyl phosphatidylcholine; rHDL, reconstituted HDL

Supplementary key words apolipoprotein A-I • high density lipoprotein • cholesterol efflux • reverse cholesterol transport • atherosclerosis • thin-layer chromatography

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