J. Lipid Res.
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A more recent version of this article appeared on June 1, 2005

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J. Lipid Res., doi:10.1194/jlr.M400401-JLR200
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Submitted on October 12, 2004
Revised on March 4, 2005
Accepted on March 23, 2005

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

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

Department of Biochemistry and Molecular Biology, Chinese Academy of Medical Sciences, Beijing 100005

Corresponding Author: bschen{at}ibms.pumc.edu.cn

ApolipoproteinA-IMilano (apoA-IM) (R173C), a natural mutant of human apoA-I, could protect its carriers against vascular disease. To penetrate the structure and biological activities of cysteine mutants, we generated apoA-IM (R173C) and 5 other cysteine variants of apoA-I at residues 52(S52C), 74(N74C), 107(K107C), 129(G129C) and 195(K195C) by site-directed mutagenesis. Cysteine residues were incorporated in each of the various helical domains at the same helical wheel position as for the substitution in apoA-IM. The secondary structural properties of the monomeric mutants, their capabilities to bind lipid, to promote cholesterol efflux from THP-1 macrophages, and the possibility of anti-peroxidation against lipoxygenase were investigated, respectively. Results showed that the a helical contents of all the cysteine mutants were similar to that of wild-type apoA-I(wtapoA-I). A-IM (R173C) exhibited a weakening structural stability, whereas A-I(G129C) a more stable structure than wtapoA-I as determined by free energy of unfolding. A-I(G129C) and A-I(K195C) exhibited significantly impaired capabilities to bind lipid compared to wtapoA-I. A-I(K107C) possessed a higher capacity to promote the cholesterol efflux from THP-1 macrophages than wtapoA-I, whereas 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 our study. In summary, in spite of the similar mutant position on the helix, these variants exhibited different features in structure or biological activities, suggesting the potential influence of the local environment of mutations on the whole polypeptide chain.


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