J. Lipid Res. Neurobiology of Lipids (ISSN1683-5506)
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Originally published In Press as doi:10.1194/jlr.M400401-JLR200 on April 1, 2005

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Journal of Lipid Research, Vol. 46, 1303-1311, June 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Cysteine mutants of human apolipoprotein A-I: a study of secondary structural and functional properties

Xuewei Zhu, Gang Wu, Wuwei Zeng, Hong Xue and Baosheng Chen1

Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China 100005

Published, JLR Papers in Press, April 1, 2005. DOI 10.1194/jlr.M400401-JLR200

1 To whom correspondence should be addressed. e-mail: bschen{at}ibms.pumc.edu.cn

Apolipoprotein A-IMilano (A-IM) (R173C), a natural mutant of human apolipoprotein A-I (apoA-I), and five other cysteine variants of apoA-I at residues 52 (S52C), 74 (N74C), 107 (K107C), 129 (G129C), and 195 (K195C) were generated. Cysteine residues were incorporated in each of the various helices at the same helical wheel position as for the substitution in A-IM. The secondary structural properties of the monomeric mutants, their abilities to bind lipid and to promote cholesterol efflux from THP-1 macrophages, and the possibility of antiperoxidation were investigated. Results showed that the {alpha} helical contents of all of the cysteine mutants were similar to that of wild-type apoA-I (wtapoA-I). The cysteine variant of A-IM at residue 173 [A-IM(R173C)] exhibited weakened structural stability, whereas A-I(G129C) a more stable structure than wtapoA-I. A-I(G129C) and A-I(K195C) exhibited significantly impaired capabilities to bind lipid compared with wtapoA-I. A-I(K107C) possessed a higher capacity to promote cholesterol efflux from macrophages than wtapoA-I, and A-IM(R173C) and A-I(K195C) exhibited an impaired efflux capability. Neither A-IM(R173C) nor any other cysteine mutant could resist oxidation against lipoxygenase.

In summary, in spite of the similar mutant position on the helix, these variants exhibited different structural features or biological activities, suggesting the potential influence of the local environment of mutations on the whole polypeptide chain.

Abbreviations: A-IM, apolipoprotein A-IMilano; A-I(S52C), A-I(N74C), A-I(K107C), A-I(G129C), A-IM(R173C), and A-I(K195C), the cysteine variants of apolipoprotein A-I at residues Ser-52, Asn-74, Lys-107, Gly-129, Arg-173, and Lys-195, respectively; apoA-I, apolipoprotein A-I; BCA, bicinchoninic acid; CD, circular dichroism; DMPC, 1,2-dimyristoyl-sn-glycerol-3-phosphatidylcholine; {Delta}GD0, free energy of unfolding; PLPC, 1-palmitoyl-2-linoleoylphosphatidycholine; wtapoA-I, recombinant wild-type human apolipoprotein A-I

Supplementary key words apolipoprotein A-IMilano • cysteine variants • lipid binding • cholesterol efflux • antiperoxidation


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