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J. Biol. Chem., Vol. 279, Issue 40, 41529-41536, October 1, 2004

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Characterization of Oligomeric Human ATP Binding Cassette Transporter A1

POTENTIAL IMPLICATIONS FOR DETERMINING THE STRUCTURE OF NASCENT HIGH DENSITY LIPOPROTEIN PARTICLES^*

Maxime Denis, Bassam Haidar, Michel Marcil, Michel Bouvier, Larbi Krimbou, and Jacques Genest¶

From the Cardiovascular Genetics Laboratory, Cardiology Division, McGill University Health Centre/Royal Victoria Hospital, Montréal, Québec H3A 1A1, Canada and the Department of Biochemistry, Université de Montréal, Montréal, Québec H3C 3J7, Canada

The oligomeric structure of ABCA1 transporter and its function related to the biogenesis of nascent apoA-I-containing particles (LpA-I) were investigated. Using n-dodecylmaltoside and perfluoro-octanoic acid combined with non-denaturing gel, the majority of ABCA1 was found as a tetramer in ABCA1-induced human fibroblasts. Furthermore, using chemical cross-linking and SDS-PAGE, ABCA1 dimers but not the tetramers were found covalently linked. Oligomeric ABCA1 was present in isolated plasma membranes as well as in intracellular compartments. Interestingly, apoA-I was found to be associated with both dimeric and tetrameric, but not monomeric, forms of ABCA1. Neither apoA-I nor lipid molecules did affect ABCA1 oligomerization. Immunoprecipitation analysis showed that oligomeric ABCA1 did not contain other associated proteins. We next investigated the relationship between the oligomeric ABCA1 complex and the structure of LpA-I. Lipid-free apoA-I incubated with normal cells generated LpA-I with diameters between 9.5 and 20 nm. Subsequent isolation of LpA-I followed by cross-linking revealed the presence of four and eight apoA-I molecules per particle, whereas apoA-I incubated with ABCA1 mutant (Q597R) cells was unable to form such particles and remained in the monomeric form. These results demonstrate that: 1) ABCA1 exists as an oligomeric complex; and 2) ABCA1 oligomerization was independent of apoA-I binding and lipid molecules. The findings that the majority of ABCA1 exists as a tetramer that binds apoA-I, together with the observation that LpA-I contains at least four molecules of apoA-I per particle, support the concept that the homotetrameric ABCA1 complex constitutes the minimum functional unit required for the biogenesis of high density lipoprotein particles.

Received for publication, June 21, 2004 , and in revised form, July 23, 2004.

^* This work was supported by grants MOP 15042 from the Canadian Institutes of Health Research (to J. G.) and the Heart and Stroke Foundation of Québec (to J. G., L. K., and M. M.). 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.

^¶ The McGill University-Novartis Chair in Cardiology. To whom correspondence should be addressed: Division of Cardiology, McGill University Health Center/Royal Victoria Hospital, 687 Pine Ave. W., Montreal, QC, Canada H3A 1A1. Tel.: 514-934-1934 (ext. 34642); Fax: 514-843-2813; E-mail: jacques.genest{at}muhc.mcgill.ca.

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