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J. Biol. Chem., Vol. 283, Issue 47, 32273-32282, November 21, 2008

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Asymmetry in the Lipid Affinity of Bihelical Amphipathic Peptides

A STRUCTURAL DETERMINANT FOR THE SPECIFICITY OF ABCA1-DEPENDENT CHOLESTEROL EFFLUX BY PEPTIDES^*

Amar A. Sethi¹, John A. Stonik, Fairwell Thomas, Steve J. Demosky, Marcelo Amar, Edward Neufeld, H. Bryan Brewer^¶, W. Sean Davidson^||2, Wilissa D'Souza^**, Dmitri Sviridov^**3, and Alan T. Remaley⁴

From the Lipoprotein Metabolism Section, Pulmonary and Vascular Medicine Branch, and the Lipid Trafficking Core, NHLBI, National Institutes of Health, Bethesda, Maryland 20892-1508, the ^¶Washington Hospital Center, Lipoprotein and Atherosclerosis Research, Cardiovascular Research Institute, MedStar Research Institute, Washington, D. C. 20010, the ^||Center for Lipid and Arteriosclerosis Studies, University of Cincinnati, Cincinnati, Ohio 45221, and the ^**Baker Heart Research Institute, Melbourne, Australia

ApoA-I contains a tandem array of amphipathic helices with varying lipid affinity, which are critical in its ability to bind and remove lipids from cells by the ABCA1 transporter. In this study, the effect of asymmetry in the lipid affinity of amphipathic helices in a bihelical apoA-I mimetic peptide, 37pA, on lipid efflux by the ABCA1 transporter was examined. Seven peptide variants of 37pA were produced by substituting a varying number of hydrophobic amino acids for alanine on either one or both helices. The 5A peptide with five alanine substitutions in the second helix had decreased helical content compared with 37pA (5A, 12 ± 1% helicity; 37pA, 28 ± 2% helicity) and showed less self-association but, similar to the parent peptide, was able to readily solubilize phospholipid vesicles. Furthermore, 5A, unlike the parent peptide 37pA, was not hemolytic (37pA, 27 ± 2% RBC lysis, 2 h, 18 µM). Finally, the 5A peptide stimulated cholesterol and phospholipid efflux by the ABCA1 transporter with higher specificity (ABCA1-transfected versus untransfected cells) than 37pA (5A, 9.7 ± 0.77%, 18 h, 18 µM versus 1.5 ± 0.27%, 18 h, 18 µM (p < 0.0001); 37pA, 7.4 ± 0.85%, 18 h, 18µM versus 5.8 ± 0.20%, 18 h, 18µM (p = 0.03)). In summary, we describe a novel bihelical peptide with asymmetry in the lipid affinity of its helices and properties similar to apoA-I in terms of specificity for cholesterol efflux by the ABCA1 transporter and low cytotoxicity.

Received for publication, June 10, 2008 , and in revised form, September 18, 2008.

^* This work was supported, in whole or in part, by intramural funds from the National Institutes of Health, NHLBI. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by the Danish Agency for Science Technology and Innovation.

² Supported by National Institutes of Health Grants HL67093 and HL62542.

³ Fellow of the National Health and Medical Research Council of Australia.

⁴ To whom correspondence should be addressed: NHLBI, National Institutes of Health, Bldg. 10, Rm. 7N-115, 10 Center Dr., Bethesda, MD 20892-1508. Tel.: 301-402-9796; Fax: 301-402-1885; E-mail: aremaley{at}cc.nih.gov.

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