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J. Biol. Chem., Vol. 278, Issue 9, 6719-6730, February 28, 2003

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The Central Helices of ApoA-I Can Promote ATP-binding Cassette Transporter A1 (ABCA1)-mediated Lipid Efflux
AMINO ACID RESIDUES 220-231 OF THE WILD-TYPE ApoA-I ARE REQUIRED FOR LIPID EFFLUX IN VITRO AND HIGH DENSITY LIPOPROTEIN FORMATION IN VIVO^*

Angeliki Chroni, Tong Liu, Irina Gorshkova^§, Horng-Yuan Kan, Yoshinari Uehara^¶, Arnold von Eckardstein^¶, and Vassilis I. Zannis^**

From the  Section of Molecular Genetics, Whitaker Cardiovascular Institute, Departments of Medicine and Biochemistry, and the ^§ Department of Physiology and Biophysics, Boston University School of Medicine, Boston, Massachusetts 02118 and the ^¶ Institute of Clinical Chemistry and Laboratory Medicine, University of Munster, Albert-Schweitzer-Strasse 33, 48149 Munster, Germany

We have mapped the domains of lipid-free apoA-I that promote cAMP-dependent and cAMP-independent cholesterol and phospholipid efflux. The cAMP-dependent lipid efflux in J774 mouse macrophages was decreased by ~80-92% by apoA-I[(185-243)], only by 15% by apoA-I[(1-41)] or apoA-I[(1-59)], and was restored to 75-80% of the wild-type apoA-I control value by double deletion mutants apoA-I[(1-41)(185-243)] and apoA-I[(1-59)(185-243)]. Similar results were obtained in HEK293 cells transfected with an ATP-binding cassette transporter A1 (ABCA1) expression plasmid. The double deletion mutant of apoA-I had reduced thermal and chemical stability compared with wild-type apoA-I. Sequential carboxyl-terminal deletions showed that cAMP-dependent cholesterol efflux was diminished in all the mutants tested, except the apoA-I[(232-243)] which had normal cholesterol efflux. In cAMP-untreated or in mock-transfected cells, cholesterol efflux was not affected by the amino-terminal deletions, but decreased by 30-40% and 50-65% by the carboxyl-terminal and double deletions, respectively. After adenovirus-mediated gene transfer in apoA-I-deficient mice, wild-type apoA-I and apoA-I[(1-41)] formed spherical high density lipoprotein (HDL) particles, whereas apoA-I[(1-41)(185-243)] formed discoidal HDL. The findings suggest that although the central helices of apoA-I alone can promote ABCA1-mediated lipid efflux, residues 220-231 are necessary to allow functional interactions between the full-length apoA-I and ABCA1 that are required for lipid efflux and HDL biogenesis.

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