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

doi:10.1194/jlr.M700206-JLR200

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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 Hassan, Maxime Denis, Dong-Young Donna Lee, Iulia Iatan, Dana Nyholt, Isabelle Ruel, Larbi Krimbou, and Jacques Genest

Division of Cardiology, McGill University/Royal Victoria Hospital, Montreal, Quebec H3A 1A1

Corresponding Author: jacques.genest{at}muhc.mcgill.ca

It is well accepted that both apolipoprotein A-I (apoA-I) and the ATP-binding cassette transporter A1 (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 is presented evidence for a new cellular apoA-I binding site having a 9-fold higher capacity to bind apoA-I as compared to the ABCA1 site in fibroblasts stimulated with 22OH/9CRA. 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 (D187-243) 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 and was not associated with membrane raft domains. Importantly, treatment of cells with phosphatidylcholine-specific phospholipase C (PC-PLC), 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. Altogether 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 plasma membrane. 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.

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				M. Denis, Y. D. Landry, and X. Zha ATP-binding Cassette A1-mediated Lipidation of Apolipoprotein A-I Occurs at the Plasma Membrane and Not in the Endocytic Compartments J. Biol. Chem., June 6, 2008; 283(23): 16178 - 16186. [Abstract] [Full Text] [PDF]

				H. H. Hassan, D. Bailey, D.-Y. D. Lee, I. Iatan, A. Hafiane, I. Ruel, L. Krimbou, and J. Genest Quantitative Analysis of ABCA1-dependent Compartmentalization and Trafficking of Apolipoprotein A-I: IMPLICATIONS FOR DETERMINING CELLULAR KINETICS OF NASCENT HIGH DENSITY LIPOPROTEIN BIOGENESIS J. Biol. Chem., April 25, 2008; 283(17): 11164 - 11175. [Abstract] [Full Text] [PDF]

				J. F. Oram, G. Wolfbauer, C. Tang, W. S. Davidson, and J. J. Albers An Amphipathic Helical Region of the N-terminal Barrel of Phospholipid Transfer Protein Is Critical for ABCA1-dependent Cholesterol Efflux J. Biol. Chem., April 25, 2008; 283(17): 11541 - 11549. [Abstract] [Full Text] [PDF]

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