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Papers In Press, published online ahead of print November 16, 2003
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Lipid Metabolism Unit, Mass. General Hospital/ Harvard School of Medicine, Boston, MA 02114
Corresponding Author: freeman{at}molbio.mgh.harvard.edu
Apolipoproteins, such as apolipoprotein A-I (apoA-I), can stimulate cholesterol efflux from cells expressing the ABC transporter, ABCA1. The nature of the molecular interaction between these cholesterol acceptors and ABCA1 is controversial, and models suggesting a direct protein-protein interaction or indirect association have been proposed. To explore this issue, we performed competition binding and chemical cross-linking assays using six amphipathic plasma proteins and an 18 amino acid amphipathic helical peptide. All seven proteins stimulated lipid efflux and competed the cross-linking of apoA-I to ABCA1. Cross-linking of apoA-I to ABCA1 was saturable and occurred at high affinity (Kd of 7.0±1.9 nM), as was cross-linking of apoA-II. Following binding to ABCA1, apoA-I rapidly dissociated (t1/2 25min) from the complex and was released back into the media. A mutant form of ABCA1 (W590S) that avidly binds A-I, but fails to promote cholesterol efflux, released apoA-I with similar kinetics but without transfer of cholesterol to apoA-I. Thus, a high affinity, saturable, protein-protein interaction occurs between ABCA1 and all of its amphipathic protein ligands. Dissociation of the complex leads to the cellular release of cholesterol and the apolipoprotein. However, dissociation is not dependent on cholesterol transfer, which is a clearly separable event, distinguishable by ABCA1 mutants.
Revised on October 23, 2003
Accepted on November 3, 2003
ABCA1 and amphipathic apolipoproteins form high affinity molecular complexes required for cholesterol efflux
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