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A more recent version of this article appeared on January 1, 2006

Papers In Press, published online ahead of print October 6, 2005
J. Lipid Res., doi:10.1194/jlr.M500240-JLR200
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Submitted on June 10, 2005
Revised on October 5, 2005
Accepted on October 6, 2005

Janus kinase 2 modulates the lipid transport-mediating but not protein-stabilizing interactions of amphipathic helices with ABCA1

Chongren Tang, Ashley M. Vaughan, G. M. Anantharamaiah, and John F. Oram

Medicine, Box 356426, University of Washington, Seattle, WA 98195-6426

Corresponding Author: joram{at}u.washington.edu

ATP-binding cassette transporter A1 (ABCA1) mediates the transport of cellular cholesterol and phospholipids to HDL apolipoproteins. Apolipoprotein A-I (apoA-I) interactions with ABCA1-expressing cells elicit several responses, including removing cellular lipids, stabilizing ABCA1 protein, and activating Janis Kinase 2 (JAK2). Here we used synthetic apolipoprotein-mimetic peptides to characterize the relationship between these responses. Peptides containing one amphipathic helix of L- or D-amino acids (2F, D-2F, or 4F) and a peptide containing two helices (37pA) all promoted ABCA1-dependent cholesterol efflux, competed for apoA-I binding to ABCA1-expressing cells, blocked covalent cross-linking of apoA-I to ABCA1, and inhibited ABCA1 degradation. 37pA was cross-linked to ABCA1, confirming direct binding of amphipathic helices to ABCA1. 2F, 4F, 37pA, and D-37pA all stimulated JAK2 autophosphorylation. Inhibition of JAK2 greatly reduced peptide-mediated cholesterol efflux, peptide binding to ABCA1-expressing cells, and peptide cross-linking to ABCA1, indicating that these processes require an active JAK2. In contrast, apoA-I and peptides stabilized ABCA1 protein even in the absence of an active JAK2, implying that this process is independent of JAK2 and lipid efflux-promoting binding of amphipathic helices to ABCA1. These findings show that amphipathic helices coordinate the activity of ABCA1 by several distinct mechanisms that are likely to involve different cell-surface binding sites.


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