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Journal of Lipid Research, Vol. 48, 2428-2442, November 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Identification of an ABCA1-dependent phospholipid-rich plasma membrane apolipoprotein A-I binding site for nascent HDL formation: implications for current models of HDL biogenesis

Houssein Hajj Hassan¹, Maxime Denis¹, Dong-Young Donna Lee, Iulia Iatan, Dana Nyholt, Isabelle Ruel, Larbi Krimbou and Jacques Genest²

Cardiovascular Genetics Laboratory, Cardiology Division, McGill University Health Centre/Royal Victoria Hospital, Montréal, Québec H3A 1A1, Canada

Published, JLR Papers in Press, July 26, 2007.

¹ H. H. Hassan and M. Denis contributed equally to this work.

² To whom correspondence should be addressed. e-mail: jacques.genest{at}muhc.mcgill.ca

It is well accepted that both apolipoprotein A-I (apoA-I) and ABCA1 play crucial roles in HDL biogenesis and in the human atheroprotective system. However, the nature and specifics of apoA-I/ABCA1 interactions remain poorly understood. Here, we present evidence for a new cellular apoA-I binding site having a 9-fold higher capacity to bind apoA-I compared with the ABCA1 site in fibroblasts stimulated with 22-(R)-hydroxycholesterol/9-cis-retinoic acid. This new cellular apoA-I binding site was designated "high-capacity binding site" (HCBS). Glyburide drastically reduced ¹²⁵I-apoA-I binding to the HCBS, whereas ¹²⁵I-apoA-I showed no significant binding to the HCBS in ABCA1 mutant (Q597R) fibroblasts. Furthermore, reconstituted HDL exhibited reduced affinity for the HCBS. Deletion of the C-terminal region of apoA-I (187-243) drastically reduced the binding of apoA-I to the HCBS. Interestingly, overexpressing various levels of ABCA1 in BHK cells promoted the formation of the HCBS. The majority of the HCBS was localized to the plasma membrane (PM) and was not associated with membrane raft domains. Importantly, treatment of cells with phosphatidylcholine-specific phospholipase C, but not sphingomyelinase, concomitantly reduced the binding of ¹²⁵I-apoA-I to the HCBS, apoA-I-mediated cholesterol efflux, and the formation of nascent apoA-I-containing particles. Together, these data suggest that a functional ABCA1 leads to the formation of a major lipid-containing site for the binding and the lipidation of apoA-I at the PM. Our results provide a biochemical basis for the HDL biogenesis pathway that involves both ABCA1 and the HCBS, supporting a two binding site model for ABCA1-mediated nascent HDL genesis.

Supplementary key words ATP binding cassette transporter A1 • high density lipoprotein • atherosclerosis

Abbreviations: apoA-I, apolipoprotein A-I; 9CRA, 9-cis-retinoic acid; 2D-PAGGE, two-dimensional polyacrylamide nondenaturing gradient gel electrophoresis; DSP, dithiobis(succinimidylpropionate); HCBS, high-capacity binding site; ICC, intracellular compartment; LpA-I, nascent apolipoprotein A-I-containing particle; 22OH, rLpA-I, reconstituted high density lipoprotein particle; 22-(R)-hydroxycholesterol; PC-PLC, phosphatidylcholine-specific phospholipase C; PM, plasma membrane; SMase, sphingomyelinase; WT, wild-type

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